Genome-wide association study of acute kidney injury after coronary bypass graft surgery identifies susceptibility loci.

Acute kidney injury (AKI) is a common, serious complication of cardiac surgery. Since prior studies have supported a genetic basis for postoperative AKI, we conducted a genome-wide association study (GWAS) for AKI following coronary bypass graft (CABG) surgery. The discovery data set consisted of 873 nonemergent CABG surgery patients with cardiopulmonary bypass (PEGASUS), while a replication data set had 380 cardiac surgical patients (CATHGEN). Single-nucleotide polymorphism (SNP) data were based on Illumina Human610-Quad (PEGASUS) and OMNI1-Quad (CATHGEN) BeadChips. We used linear regression with adjustment for a clinical AKI risk score to test SNP associations with the postoperative peak rise relative to preoperative serum creatinine concentration as a quantitative AKI trait. Nine SNPs meeting significance in the discovery set were detected. The rs13317787 in GRM7|LMCD1-AS1 intergenic region (3p21.6) and rs10262995 in BBS9 (7p14.3) were replicated with significance in the CATHGEN data set and exhibited significantly strong overall association following meta-analysis. Additional fine mapping using imputed SNPs across these two regions and meta-analysis found genome-wide significance at the GRM7|LMCD1-AS1 locus and a significantly strong association at BBS9. Thus, through an unbiased GWAS approach, we found two new loci associated with post-CABG AKI providing new insights into the pathogenesis of perioperative AKI.

Diastolic dysfunction in patients undergoing cardiac surgery: the role of gender and age-gender interaction.

OBJECTIVES: To test the hypothesis that females presenting for coronary artery bypass graft (CABG) surgery are at a higher risk of left ventricular diastolic dysfunction (LVDD) and that age and gender interact to influence this risk. DESIGN: Retrospective observational study. SETTING: Tertiary university hospital. PARTICIPANTS: Eight hundred-ninety-five adult patients undergoing CABG surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Baseline diastolic function was graded according to a predefined Doppler-based algorithm, which defined LVDD as a binary variable (grades 2 and 3 only) and as a continuous variable (E/e' ratio). The authors found that women were more likely to present with LVDD in 2 multivariate regression models using both LVDD definitions (odds ratio = 2.7; p<0.0001 for logistic model, and parameter estimate (PE) = 2.8; p<0.0001 for the linear model). In addition, there was a significant age and gender interaction on the risk of LVDD in the linear model (PE = 0.08; p = 0.01). A restricted cubic splines analysis revealed a progressively higher risk of LVDD (predicted E/e' ratio) among older women. CONCLUSIONS: The authors confirmed that women undergoing CABG surgery are at higher risk of LVDD compared to men with a significant age-gender interaction suggesting a possible age-related differential effect on LVDD between the genders, a phenomenon previously demonstrated in preclinical studies. Therapies aimed at amelioration of diastolic dysfunction additionally should consider the higher risk in females, especially within the older subset of the patient population.

S100B and brain natriuretic peptide predict functional neurological outcome after intracerebral haemorrhage.

OBJECTIVE: To determine the predictive value of S100b and brain natriuretic peptide (BNP) in order to determine accurately and quickly a discharge prognosis after primary supratentorial intracerebral haemorrhage (ICH). METHODS: After IRB approval and informed consent, blood samples were obtained and analysed from 28 adult patients consecutively admitted to the neuroscience intensive care unit with computed tomography-proven supratentorial ICH from June 2003 and December 2004 within the first 24 h after symptom onset for S100b and BNP. Functional outcomes on discharge were dichotomized to favourable (mRS < 3) or unfavourable. RESULTS: BNP (a neurohormone) and S100b (a marker of glial activation) were found to be independently highly predictive of functional neurological outcome at the time of discharge as measured by the modified Rankin Score (BNP: p < 0.01, r = 0.46; S100b: p < 0.01, r = 0.42) and the Barthel Index (BNP: p < 0.01, r = 0.54; s100b: p < 0.01, r = 0.50). Although inclusion of either biomarker produced additive value when included with traditional clinical prognostic variables, such as the ICH score (Barthel index: p < 0.01, r = 0.66; mRS: p < 0.01, r = 0.96), little predictive power is added with inclusion of both biomarkers in a regression model for neurological outcome. CONCLUSIONS: Serum S100b and BNP levels in the first 24 h after injury accurately predict neurological function at discharge after supratentorial ICH.

Mortality trends associated with acute renal failure requiring dialysis after CABG surgery in the United States.

BACKGROUND/AIMS: Acute renal failure is associated with a high risk of mortality when it complicates coronary artery bypass graft (CABG) surgery. We examined a large nationwide database from 1988 to 2003 and hypothesized that mortality in CABG-associated acute renal failure needing dialysis (ARF-D) had declined during this period. METHODS: The Nationwide Inpatient Sample containing data on inpatient stays across 20% of US hospitals was used for our study. Multivariate logistic regression was used to determine an association between year and ARF-D mortality with standardized risk adjustment. RESULTS: Incidence of ARF-D increased from 0.2 to 0.6% while mortality simultaneously decreased from 47.4% in 1988 to 29.7% in 2003. In the multivariable model, year was significantly associated with declining ARF-D mortality. CONCLUSIONS: The incidence of post-CABG ARF-D more than doubled from 1988 to 2003, while mortality simultaneously decreased by over one-third. Improved survival after ARF-D following CABG may be counterbalanced by increased morbidity and resource utilization.

Assessing teamwork in medical education and practice: relating behavioural teamwork ratings and clinical performance.

BACKGROUND: Problems with communication and team coordination are frequently linked to adverse events in medicine. However, there is little experimental evidence to support a relationship between observer ratings of teamwork skills and objective measures of clinical performance. AIM: Our main objective was to test the hypothesis that observer ratings of team skill will correlate with objective measures of clinical performance. METHODS: Nine teams of medical students were videotaped performing two types of teamwork tasks: (1) low fidelity classroom-based patient assessment and (2) high fidelity simulated emergent care. Observers used a behaviourally anchored rating scale to rate each individual on skills representative of assertiveness, decision-making, situation assessment, leadership, and communication. A checklist-based measure was used to assess clinical team performance. RESULTS: Moderate to high inter-observer correlations and moderate correlations between cases established the validity of a behaviourally anchored team skill rating tool for simulated emergent care. There was moderate to high correlation between observer ratings of team skill and checklist-based measures of team performance for the simulated emergent care cases (r = 0.65, p = 0.06 and r = 0.97, p < 0.0001). CONCLUSIONS: These results provide prospective evidence of a positive relationship between observer ratings of team skills and clinical team performance in a simulated dynamic health care task.

Trends in cardiac surgery-associated acute renal failure in the United States: a disproportionate increase after heart transplantation.

Acute renal failure (ARF) is common after cardiac surgery and more frequent after complex cardiac surgery. While the incidence of ARF is increasing after coronary artery bypass graft (CABG) surgery, trends in other forms of cardiac surgery remain unclear. We investigated the trend of ARF in various cardiac procedures and compared patterns using CABG surgery as a reference group. The study population consisted of discharges from the Nationwide Inpatient Sample from 1988 to 2003, grouped according to surgery as: CABG, CABG with mitral valve, CABG with other valve, valve alone, and heart transplant. Standard diagnostic codes were used to identify ARF among discharges. Multivariable regression was used to determine trends in ARF among various procedures with CABG as a reference group. The incidence of ARF increased in all five groups (p < 0.001) over the 16-year period. The ARF incidence was highest in the heart transplant group (17%). Compared to the CABG population, patients following heart transplantation developed ARF at higher rates during the study period. In contrast, while ARF increased over time in other groups, the rates of rise were slower than in CABG patients. Among heart surgery procedures, ARF incidence is highest in heart transplantation. The incidence of ARF is also increasing at a faster rate in this group of patients in contrast to other procedure groups when compared to CABG surgery. The disproportionate increase in ARF burden after heart transplantation is a concern due to its strong association with chronic kidney disease and mortality.

A bibliometric analysis of global clinical research by anesthesia departments.

BACKGROUND: Few studies have investigated the diversity in research conducted by anesthesia-based researchers. We examined global clinical research attributed to anesthesia departments using Medline and Ovid databases. We also investigated the impact of economic development on national academic productivity. METHODS: We conducted a Medline search for English-language publications from 2000 to 2005. The search included only clinical research in which institutional affiliation included words relating to anesthesia (e.g., anesthesiology, anesthesia, etc.). Population and gross national income data were obtained from publicly available databases. Impact factors for journals were obtained from Journal Citation Reports (Thomson Scientific). RESULTS: There were 6736 publications from 64 countries in 551 journals. About 85% of all publications were represented by 46 journals. Randomized controlled trials constituted 4685 (70%) of publications. Turkey had the highest percentage of randomized controlled trials (88%). The United States led the field in quantity (20% of total) and mean impact factor (3.0) of publications. Finland had the highest productivity when adjusted for population (36 publications per million population). Publications from the United States declined from 23% in 2000 to 17% in 2005. CONCLUSIONS: Clinical research attributable to investigators in our specialty is diverse, and extends beyond the traditional field of anesthesia and intensive care. The United States produces the most clinical research, but per capita output is higher in European nations.

Transcutaneous acupoint electrical stimulation with the ReliefBand for the prevention of nausea and vomiting during and after cesarean delivery under spinal anesthesia.

We randomized 94 patients undergoing cesarean delivery with spinal anesthesia to receive transcutaneous acupoint electrical stimulation using the ReliefBand at the P6 point (active group) or an active ReliefBand applied to the dorsum of the wrist (sham control group). The ReliefBand was applied 30-60 min preoperatively and left in place for 24 h. There was no statistically significant difference between the active and sham control groups in the incidence of intraoperative/postoperative nausea (30% versus 43%/23% versus 41%), vomiting (13% versus 9%/26 versus 37%), need for rescue antiemetics (23% versus 18%/34% versus 39%), or complete response (55% versus 57%/51% versus 34%). There was also no difference between the two groups in nausea scores, number of vomiting episodes, or patient satisfaction with postoperative nausea and vomiting management.

The association of lowest hematocrit during cardiopulmonary bypass with acute renal injury after coronary artery bypass surgery.

BACKGROUND: Acute renal injury is a common serious complication of cardiac surgery. Moderate hemodilution is thought to reduce the risk of kidney injury but the current practice of extreme hemodilution (target hematocrit 22% to 24%) during cardiopulmonary bypass (CPB) has been linked to adverse outcomes after cardiac surgery. Therefore we tested the hypothesis that lowest hematocrit during CPB is independently associated with acute renal injury after cardiac surgery. METHODS: Demographic, perioperative, and laboratory data were gathered for 1,404 primary elective coronary bypass surgery patients. Preoperative and daily postoperative creatinine values were measured until hospital discharge per institutional protocol. Stepwise multivariable linear regression analysis was performed to determine whether lowest hematocrit during CPB was independently associated with peak fractional change in creatinine (defined as the difference between the preoperative and peak postoperative creatinine represented as a percentage of the preoperative value). A p value of less than 0.05 was considered significant. RESULTS: Multivariable analyses including preoperative hematocrit and other perioperative variables revealed that lowest hematocrit during CPB demonstrated a significant interaction with body weight and was highly associated with peak fractional change in serum creatinine (parameter estimate [PE] = 4.5; p = 0.008) and also with highest postoperative creatinine value (PE = 0.06; p = 0.004). Although other renal risk factors were significant covariates in both models, TM50 (an index of hypotension during CPB) was notably absent. CONCLUSIONS: These results add to concerns that current CPB management guidelines accepting extreme hemodilution may contribute to postoperative acute renal and other organ injury after cardiac surgery.

Predictors of extraventricular drain-associated bacterial ventriculitis.

PURPOSE: Bacterial ventriculitis (BV) may develop in patients requiring external ventricular drains (EVDs). The purpose of this study was to determine predictors of EVD-associated BV onset. MATERIALS AND METHODS: A retrospective review of Duke University Hospital patients with EVD device placement between January 2005 and May 2010 was conducted. Subject data were captured for predefined variables. Outcomes included in-hospital mortality, length of stay, and neurologic status at discharge. RESULTS: In 410 subjects with 420 EVDs, the BV rate was 10.2%. Univariate analysis indicated that age, sex, positive blood culture, duration of EVD placement, and the number of cerebrospinal fluid (CSF) samples taken were associated with BV. Of these, the number of CSF samples and sex retained significance in multivariable modeling (female: odds ratio, 0.47 [confidence interval, 0.23-0.97]; CSF samples: odds ratio, 1.08 [confidence interval 1.01-1.17]; P = .04; c index = 0.69). In this model, each CSF sample taken expanded the likelihood of BV by 8.3%. The most common pathogens were Staphylococcus or proprioniobacter (n = 26). Bacterial ventriculitis was associated with an increase in hospital length of stay (33 ± 22.9 days vs 24.6 ± 20.4 days; P = .04) but not mortality. CONCLUSION: An association exists between CSF sampling frequency and the development of EVD-associated BV. Larger prospective studies should be aimed at identifying causal relationships between these variables.

Utility of a simple algorithm to grade diastolic dysfunction and predict outcome after coronary artery bypass graft surgery.

BACKGROUND: Inclusion of a measure of left ventricular diastolic dysfunction (LVDD) may improve risk prediction after cardiac surgery. Current LVDD grading guidelines rely on echocardiographic variables that are not always available or aligned to allow grading. We hypothesized that a simplified algorithm involving fewer variables would enable more patients to be assigned a LVDD grade compared with a comprehensive algorithm, and also be valid in identifying patients at risk of long-term major adverse cardiac events (MACE). METHODS: Intraoperative transesophageal echocardiography data were gathered on 905 patients undergoing coronary artery bypass graft surgery, including flow and tissue Doppler-based measurements. Two algorithms were constructed to categorize LVDD: a comprehensive four-variable algorithm, A, was compared with a simplified version, B, with only two variables-transmitral early flow velocity and early mitral annular tissue velocity-for ease of grading and association with MACE. RESULTS: Using algorithm A, only 563 patients (62%) could be graded, whereas 895 patients (99%) received a grade with algorithm B. Over the median follow-up period of 1,468 days, Cox modeling showed that LVDD was significantly associated with MACE when graded with algorithm B (p=0.013), but not algorithm A (p=0.79). Patients with the highest incidence of MACE could not be graded with algorithm A. CONCLUSIONS: We found that an LVDD algorithm with fewer variables enabled grading of a significantly greater number of coronary artery bypass graft patients, and was valid, as evidenced by worsening grades being associated with MACE. This simplified algorithm could be extended to similar populations as a valid method of characterizing LVDD.

Impact of early renal recovery on survival after cardiac surgery-associated acute kidney injury.

BACKGROUND: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a major postoperative complication. Although some early recovery is common, its effect on long-term outcomes is unclear. We tested the hypothesis that early renal recovery after CSA-AKI is independently associated with improved long-term survival. METHODS: Data were examined for 10,275 consecutive patients undergoing isolated coronary artery bypass grafting from 1996 to 2005. Patients with CSA-AKI were identified, defined as a peak postoperative creatinine level exceeding 50% above baseline. Renal recovery was characterized using postoperative creatinine values. The recovery variable with the strongest association with 1-year survival was selected and validated internally. The independent association of early renal recovery with long-term survival during a 10-year follow-up was assessed with Cox proportional hazards modeling. RESULTS: CSA-AKI occurred in 1113 patients (10.8%). The renal recovery variable with the strongest association with 1-year survival was the percentage decrease in creatinine 24 hours after its peak value (PD24; C index, 0.72; p=0.002). Cox proportional hazards analysis showed a significant negative association between PD24 and long-term mortality (0.82 hazard ratio for each 10% change). CONCLUSIONS: Early recovery of renal function is associated with improved long-term survival after CSA-AKI. This variable is clinically useful because it occurs immediately after the peak creatinine level and simultaneously helps define the severity of AKI and the magnitude of recovery. Given the high risk of death associated with postoperative AKI, early renal recovery seems to offer a distinct survival benefit and may represent an important therapeutic focus.

Aprotinin's effect on blood product transfusion in off-pump bilateral lung transplantation.

In lung transplants necessitating cardiopulmonary bypass (CPB), aprotinin has been shown to decrease transfusion requirements. More recently, off-pump transplantation has become the standard of care. The efficacy of aprotinin use in this population has yet to be definitively examined. We completed a retrospective review of all adult OP-BOLTs performed between January 2000 and January 2006 at a single university center (n=215). Aprotinin use was determined by the attending anesthesiologist or surgeon. It was administered at the time of induction. The primary outcome was total blood products utilized in terms of units transfused during postoperative days 0, 1 and 2. One-hundred and one patients received aprotinin and 114 did not. An overall analysis of all of the patients in this study demonstrated a trend towards statistical significance for reduced total blood product transfusion for the aprotinin group compared to the non-aprotinin group (P=0.13). A subgroup analysis was performed in relation to each diagnosis. The use of aprotinin was associated with a significant reduction in peri-operative total blood products transfused in COPD patients (P=0.03) undergoing OP-BOLT. Subgroup analysis demonstrated that the use of aprotinin in the COPD population did result in a statistically significant decrease in total blood products transfused, specifically the total number of units of packed red blood cells given. These findings suggest that aprotinin administration should be considered for all patients undergoing OP-BOLT to reduce exposure to blood products and potential immune sensitization and infectious complications.

Increasing healthcare resource utilization after coronary artery bypass graft surgery in the United States.

BACKGROUND: Despite declining lengths of stay, postdischarge healthcare resource utilization may be increasing because of shifts to nonacute care settings. Although changes in hospital stay after coronary artery bypass graft (CABG) surgery have been described, patterns of discharge remain unclear. Our objective was to determine patterns of discharge disposition after CABG surgery in the United States. METHODS AND RESULTS: We examined discharge disposition after CABG procedures from 1988 to 2005 using the Nationwide Inpatient Sample. Discharges with a "nonroutine" disposition defined patients discharged with continued healthcare needs. Multivariable regression models were constructed to assess trends and factors associated with nonroutine discharge. Median length of stay among 8,398,554 discharges decreased from 11 to 8 days between 1988 and 2005 (P<0.0001). There was a simultaneous increase in nonroutine discharges from 12% in 1988 to 45% in 2005 (P<0.0001), primarily comprising home healthcare and long-term facility use. Multivariable regression models showed age, female gender, comorbidities, concurrent valve surgery, and lower-volume hospitals more likely to be associated with nonroutine discharge. CONCLUSIONS: We found a significant increase in nonroutine discharges after CABG surgery across the United States from 1988 to 2005. The significant shortening of length of stay during CABG may be counterbalanced by the increased requirement for additional postoperative healthcare services. Nonacute care institutions are playing an increasingly significant role in providing CABG patients with postdischarge healthcare and should be considered in investigations of postoperative healthcare resource utilization. The impact of these changes on long-term outcomes and net resource utilization remain unknown.

Acute kidney injury and chronic kidney disease after cardiac surgery.

Kidney dysfunction is common after cardiac surgery and predicts mortality risk and poorer long-term outcome, particularly when acute injury superimposes upon chronic kidney disease. Numerous insults contribute to perioperative renal impairment including major surgical trespass, procedure-specific interventions (eg, deep hypothermic circulatory arrest), and postoperative complications. Regardless of cause, evidence supports a role for renal impairment and accumulation of "uremic toxins" as direct contributors to adverse outcome. No one has yet characterized a loss of renal function small enough to be insignificant. Despite considerable research focus, progress in development of interventions aimed at perioperative renoprotection has been disappointing. However, practice modifications can influence the likelihood of acute kidney injury, and several recent advances provide hope for the future. We review pathophysiologic understanding of this disorder; evaluate the confusing relationship (causal v epiphenomena) among acute kidney injury, chronic kidney disease, and adverse outcome after cardiac surgery; and provide an evidence-based assessment of the conduct of cardiac surgery and renoprotection strategies.

Trends in acute renal failure associated with coronary artery bypass graft surgery in the United States.

OBJECTIVE: Acute renal failure remains a major complication of coronary artery bypass graft surgery that is strongly associated with in-hospital mortality. Based on similar observations in other clinical settings, we tested the hypothesis that the diagnosis of acute renal failure associated with coronary artery bypass graft surgery is increasing in the United States. DESIGN: Observational cohort study. SETTING: The Nationwide Inpatient Sample database was used to test the hypothesis. This database contains discharge information from 20% of U.S. hospitals. PATIENTS: Hospital discharges coded for coronary artery bypass graft surgery from 1988 to 2003 comprised the study population; those also coded for acute renal failure formed the subset of interest. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Multivariable regression models were constructed, including adjustment for risk factors and comorbidities, to identify the relationship between year of surgery and diagnosis of acute renal failure and mortality. The incidence of acute renal failure diagnosis increased significantly during the study period from 1.1% to 4.1% (p < .0001). The proportion of acute renal failure cases that required dialysis decreased from 15.8% to 8.7% (p < .0001). Despite an increase in comorbid disease burden, mortality in the acute renal failure subgroup declined from 39.5% to 17.9% (p < .0001). The percentage of acute renal failure survivors with postdischarge special-care requirements increased from 35.5% to 64.5% (p < .0001). CONCLUSIONS: Our findings suggest that the observed increase in acute renal failure diagnosis rates may be partly attributable to less restrictive criteria for acute renal failure diagnosis, consistent with acute renal failure patterns observed in other clinical settings. Although the need for dialysis is a relatively clear benchmark for diagnosing acute renal failure, use of alternate criteria to define this disorder has become more common, perhaps contributing to higher diagnosis rates. We conclude that the nationwide trend of acute renal failure associated with coronary artery bypass graft surgery has significantly increased from 1988 to 2003. Despite declining mortality, acute renal failure remains a burden on healthcare resources.

An assessment of two different methods of left ventricular ejection time measurement by transesophageal echocardiography.

Left ventricular ejection time (LVET) is an important component in evaluating left ventricular performance. This measurement is usually made by measuring the timing of the transaortic valve flow velocity by continuous-wave Doppler. Although M-mode has also been used for measuring LVET, it has not been compared with the Doppler method. We tested the hypothesis that the M-mode-measured duration of aortic valve opening is comparable to Doppler-derived measurement of LVET by transesophageal echocardiography (TEE). Measurements were made in 31 patients undergoing nonaortic valve cardiac surgery. The timing of transaortic flow by continuous-wave Doppler was compared with the M-mode-derived timing of aortic valve opening. There was close correlation (Pearson correlation coefficient, r = 0.86; P < 0.0001) between M-mode and Doppler measurements. There was no significant difference between the two techniques by linearity tests (P > 0.1). Bland-Altman analysis showed no significant bias. We confirmed the hypothesis that M-mode-derived measurement of LVET is comparable to Doppler-derived measurement of LVET. M-mode may be an acceptable alternative to the Doppler method, especially when transvalvular velocity gradients cannot be readily obtained. M-mode is a simple, yet often underused, method of evaluating LVET during TEE.

Prediction of tracheal tube size in children using multiple variables.

BACKGROUND: Tracheal tube (TT) size selection in children is important to avoid complications. Formulae utilizing age and physical characteristics to predict appropriate tube size are not entirely predictive. METHODS: Using an automated anaesthesia record keeper database, the anaesthetic records of 8504 children, aged up to 7 years, who required tracheal intubation, were reviewed. Age, height and weight data were related to TT size. The total number of patients whose age, height and weight were independently available was 8396, 3929 and 7823, respectively. The number having all three variables was 3814. A linear regression analysis was performed for patients with all three variables and for each variable individually. RESULTS: Tracheal tube size is best predicted using multivariate analysis and, for any child aged up to 7 years, is represented by the formula: 2.44 + (age x 0.1) + (height x 0.02) + (weight x 0.016). Formulae utilizing these variables individually are also reviewed. CONCLUSIONS: Prediction of TT size is best accomplished using multiple variables. Further prospective study is suggested.

Caffeine affects cardiovascular and neuroendocrine activation at work and home.

OBJECTIVE: This study investigated the effects of moderate doses of caffeine on ambulatory blood pressure and heart rate, urinary excretion of epinephrine, norepinephrine, and cortisol, and subjective measures of stress during normal activities at work and at home in the evening. METHODS: Healthy, nonsmoking, habitual coffee drinkers (N = 47) participated in 3 days of ambulatory study. After a day of ad lib caffeine consumption, caffeine (500 mg) and placebo were administered double-blind in counter-balanced order on separate workdays. Ambulatory blood pressure and heart rate were monitored from the start of the workday until bedtime. Urinary excretion of catecholamines and cortisol was assessed during the workday and evening. RESULTS: Caffeine administration significantly raised average ambulatory blood pressure during the workday and evening by 4/3 mm Hg and reduced average heart rate by 2 bpm. Caffeine also increased by 32% the levels of free epinephrine excreted during the workday and the evening. In addition, caffeine amplified the increases in blood pressure and heart rate associated with higher levels of self-reported stress during the activities of the day. Effects were undiminished through the evening until bedtime. CONCLUSIONS: Caffeine has significant hemodynamic and humoral effects in habitual coffee drinkers that persist for many hours during the activities of everyday life. Furthermore, caffeine may exaggerate sympathetic adrenal-medullary responses to the stressful events of normal daily life. Repeated daily blood pressure elevations and increases in stress reactivity caused by caffeine consumption could contribute to an increased risk of coronary heart disease in the adult population.