Thomas L. Whitsett

Sensitivity and Specificity of Helical Computed Tomography in the Diagnosis of Pulmonary Embolism: A Systematic Review

Pulmonary embolism is a major health problem in the United States. The estimated annual incidence is 69 cases per 100 000 persons (1), which means that more than 175 000 persons develop established pulmonary embolism each year. Prospective studies have documented a 30% to 40% prevalence of pulmonary embolism in patients who have clinical features of suspected pulmonary embolism (2-4). Therefore, clinically suspected pulmonary embolism is present in more than 575 000 persons in the United States each year. It is difficult to diagnose pulmonary embolism because the clinical diagnosis is nonspecific (2-8) and all of the objective tests have clinical or practical limitations (2-6). The ventilation-perfusion lung scan has been the first-line test for more than 20 years. However, 60% to 70% of lung scans are nondiagnostic (2-4), and combining clinical assessment with lung scan results or using a clinical algorithm fails to identify 20% of patients with pulmonary embolism (3, 4, 8). Pulmonary angiography is the gold standard (9-12), but it is invasive and expensive, may be impractical or unavailable in some clinical settings, and causes cardiac or pulmonary complications in 3% to 4% of patients (12, 13). Objective testing for deep venous thrombosis is useful if the results are positive (4-6, 14), but negative results do not exclude pulmonary embolism (4-6, 11, 14, 15). Serial testing for proximal deep venous thrombosis can be used as an alternative to pulmonary angiography in selected patients, such as those with adequate cardiorespiratory reserve or a low or moderate suspicion of pulmonary embolism (14, 16, 17). The d-dimer assay is promising as an exclusion test, but a positive result is nonspecific and occurs in 40% to 69% of patients (18, 19). Therefore, definitive testing for the presence or absence of pulmonary embolism is required for many patients, such as those with severe underlying cardiopulmonary disease and inadequate cardiorespiratory reserve (5, 6, 17, 20). Recently, interest has developed in using helical computed tomography (CT), also known as spiral CT, for the diagnosis of pulmonary embolism (21-23). Helical CT scanning produces a volumetric two-dimensional image of the lung by rotating the detector around the patient. Total acquisition time is less than 30 seconds. Pulmonary embolism appears as a filling defect that may be central, eccentric, or mural and may partially or totally occlude the vessel. Helical CT is minimally invasive and can help identify other disorders that may be responsible for the patients symptoms. However, it is expensive to perform and interpret; it requires that a contrast agent be intravenously injected; and it is often difficult or impossible to perform in patients who require ventilation, are hemodynamically unstable, or cannot cooperate. Some researchers have recommended helical CT as a first-line replacement for lung scans and pulmonary angiography (23-25), and others have suggested that diagnostic algorithms based on helical CT be used in selected patients (24, 26, 27). Several experts have called for more research (24-26, 28). Because of the debate about the role of helical CT in the diagnosis of pulmonary embolism (29), we performed a systematic review of the literature (30). Our review had two objectives: to determine the sensitivity and specificity of helical CT for the diagnosis of pulmonary embolism in symptomatic patients, and to determine the safety of withholding anticoagulant therapy without further objective testing for venous thromboembolism in patients who have clinically suspected pulmonary embolism and negative results on helical CT. Methods Literature Search and Data Sources We searched the MEDLINE database for literature published from 1986 through November 1999. The MeSH terms pulmonary embolism and tomography, x-ray computed were used in separate searches, and studies found during each search were combined. Limits were set for human only and English language only. We supplemented this reference list by cross-checking bibliographies of retrieved articles to identify additional studies. Study Selection and Data Extraction Before performing the literature review, we defined criteria for inclusion of studies and for assessing the validity of these studies (31). We decided a priori to include all prospective studies identified by the literature search, including abstracts. Retrospective studies, review articles, and case reports were excluded. Two of the authors reviewed each article or abstract independently using the criteria outlined in Table 1. These criteria were established a priori before the articles were reviewed, according to established methodologic standards for evaluation of diagnostic tests (32, 33). Different criteria were used to assess studies that evaluated the sensitivity and specificity of helical CT for diagnosis of pulmonary embolism and studies that evaluated the safety of withholding anticoagulant therapy in patients with negative results on helical CT. A third independent reviewer resolved disagreements by adjudication. Table 1. Criteria Used To Appraise Prospective Studies Identified by Literature Search Data Synthesis Literature Search and Data Sources The literature search identified 20 articles (34-53) and 6 abstracts (54-59). Five articles were excluded; 4 were retrospective studies (49-52), and 1 was a series of case reports (53). The abstracts were excluded from further analysis because they reported the results of subsequent articles or contained insufficient information for evaluation of study validity. Fifteen original prospective studies (34-48) were assessed by using the criteria in Table 1. Of these 15 studies, 13 were unique. Two studies by van Rossum and colleagues (38, 40) included some of the same patients (van Rossum AB. Personal communication). These studies evaluated 249 and 149 patients, respectively (38, 40) (Table 2). Study Appraisal Table 2 summarizes the results of our assessment of the 15 prospective studies. Only 2 studies (36, 38) explicitly stated that a consecutive series of all patients with suspected pulmonary embolism was evaluated. In 8 studies, helical CT and pulmonary angiography were interpreted independently (34-37, 39, 41, 43, 46). Only 1 study (34) included enough data to allow us to conclude that a broad spectrum of patients had been evaluated. Thirteen articles included a description of the size of the vessels imaged by helical CT (34-39, 41, 43-48). Six studies described the size of the pulmonary embolism on angiography (34, 37, 40, 41, 44, 47). Table 2. Prospective Studies Evaluating the Use of Helical Computed Tomography in the Diagnosis of Suspected Pulmonary Embolism Sensitivity and Specificity The reported sensitivity of helical CT ranged from 53% to 100%, and the reported specificity ranged from 81% to 100% (Table 2). Only four articles reported 95% CIs (40, 41, 44, 46). Safety of Withholding Anticoagulant Therapy No prospective study was identified in which anticoagulant therapy was withheld without additional testing for venous thromboembolism in consecutive patients who had suspected pulmonary embolism and negative results on helical CT. One study prospectively followed up selected patients who had suspected pulmonary embolism and negative results on helical CT (44). Patients were eligible if they had an intermediate-probability ventilation-perfusion lung scan and negative results on duplex ultrasonography of the legs. Computed tomography yielded positive results in 39 of 164 patients and negative results in 125 of 164 patients. Pulmonary angiography was performed in 15 of these 125 patients and showed pulmonary embolism in 1 patient. All 15 patients were treated with anticoagulant therapy. A total of 109 patients with negative results on helical CT did not receive anticoagulant therapy and were followed for 3 months. Fatal pulmonary embolism was strongly suspected in 1 patient who died 10 days after study entry. In addition, high-probability ventilation-perfusion lung scans documented symptomatic pulmonary embolism in 2 patients at 2 months and 3 months of follow-up (44). Discussion We sought to determine the sensitivity and specificity of helical CT for the diagnosis of pulmonary embolism and the safety of withholding anticoagulant therapy in patients with negative results on helical CT. Our results support four major inferences. First, none of the studies met all of the methodologic criteria for adequately evaluating the sensitivity and specificity of a diagnostic test (32, 33). Several studies were missing key data on the methods used to select patients, whether helical CT and the reference test were interpreted independently, and whether the study sample included a broad spectrum of patients with suspected pulmonary embolism. Details were often missing on the clinical features of patients at presentation, the size of pulmonary embolism on angiography, and the presence or absence of comorbid conditions that may have confused the diagnosis. All studies to date have included relatively few patients who underwent both helical CT and an appropriate reference test. Second, a wide range of sensitivity (53% to 100%) was reported for helical CT (Table 2). Two recent studies reported sensitivities of 60% and 67% (46, 47), and in one of these studies (47) all cases of pulmonary embolism documented by pulmonary angiography involved segmental or lobar arteries. The wide range of sensitivity among these studies may be due to differences in patient selection, extent of pulmonary embolism, technology and testing methods (including pitch, collimator thickness, and the concentration of the contrast agent), methods of interpretation (workstations or hard copy, windowing of images), reader experience, and interobserver variation. Third, our results suggest that interobserver variation is a potentially important limitation of helical CT. Three studies reported interobserver variation in the s

The Clinical Validity of Normal Compression Ultrasonography in Outpatients Suspected of Having Deep Venous Thrombosis

Clinical trials have shown that, because the symptoms and signs of deep venous thrombosis are highly nonspecific, objective testing is required for patients suspected of having the condition [1-9]. Ultrasonography is the most commonly used test in the United States [10-13]; it is highly sensitive and specific for proximal venous thrombosis (thrombosis of the popliteal or more proximal veins) [10-14]. A recent report described a simplified ultrasonography technique in which imaging is limited to the deep veins at the groin and popliteal fossa [14]. These anatomic areas are evaluated by using the single criterion of vein compressibility [14]. This simplified compression ultrasonography technique is highly sensitive and specific for proximal venous thrombosis in outpatients suspected of having deep venous thrombosis [14]. Although imaging with the simplified technique is limited to the groin and popliteal fossa, it is very sensitive because thrombosis isolated to the iliac vein or superficial femoral vein is rare in symptomatic patients [15]. However, thrombosis confined to the deep veins of the calf is not rare, occurring in up to 13% of symptomatic patients [4-6]. Ultrasonography done by using compression, either alone or with color Doppler capacity, does not uniformly visualize the deep veins of the calf and has limited sensitivity (40% to 70%) for thrombosis of the calf veins [10-13, 16]. Therefore, serial testing is required to identify patients who develop extension of thrombosis into the popliteal vein or more proximal veins [6-917, 18], for whom treatment is required [19-21]. A clinical outcome study has shown that it is safe to withhold anticoagulation in symptomatic outpatients in whom the results of simplified compression ultrasonography are normal on initial testing and two repeated tests [17]. More than 500 000 patients are referred for testing each year in the United States [22]; 80% of these patients (400 000) will have a normal result on the first test and will need repeated testing [17]. Cost analysis shows that a single repeated test compared with two repeated tests results in substantial savings-

Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement

260 per patient (in 1990 U.S. dollars) [23]. Therefore, more than

Cardiovascular effects of coffee and caffeine

100 million could be saved yearly in the United States if the use of two repeated tests were replaced by the use of one repeated test. However, the safety of this approach is uncertain because it has not been evaluated by clinical trials. Of the patients with normal initial ultrasonography results who then have abnormal results on repeated testing, half have abnormal results the day after presentation and half have abnormal results on day 7 [17]. Patients whose results are abnormal the day after presentation may have detectable thrombosis on the initial test if the popliteal vein is imaged beyond the popliteal fossa to its most distal point (that is, to the trifurcation of the calf veins) because compression ultrasonography is sensitive for thrombi that barely extend out of the calf veins into the popliteal vein [24]. Repeated testing could then be limited to a single test done 5 to 7 days after the first test [16, 23]. We performed a prospective cohort study of outpatients suspected of having first-episode deep venous thrombosis. This was done to test the safety of withholding anticoagulation in patients who 1) have normal results on simplified compression ultrasonography that was done at presentation and that completely imaged the popliteal vein to its most distal point and 2) have a normal result on a single repeated test done 5 to 7 days after the first test. We used long-term follow-up to test the validity of this approach because inadequate management of proximal venous thrombosis results in clinically evident venous thromboembolic events that can be measured objectively [19-21]. Methods Patients and Study Protocol The study sample consisted of consecutive outpatients who were suspected of having first-episode deep venous thrombosis and were referred by their physicians to the noninvasive vascular laboratory of University Hospital or Veterans Administration Medical Center in Oklahoma City, Oklahoma, between December 1993 and 31 December 1995. Each patient was seen by a consultant physician who obtained a clinical history, performed a physical examination, and evaluated the patients eligibility for the study. Eligible patients who gave informed consent were then managed according to the study protocol (Figure 1). Patients were ineligible if compression ultrasonography could not be done because of physical or technical limitations, if the patients were unable to return for repeated testing in 5 to 7 days, if long-term follow-up was not possible because of geographic inaccessibility, if the patients had received therapeutic doses of heparin for more than 24 hours before their referral, or if the patients were pregnant. The institutional review board approved the study protocol. Figure 1. Study protocol and outcomes. Objective Testing for Venous Thrombosis at Study Entry Real-time B-mode ultrasonography was performed immediately after the clinical assessment. The simplified compression technique described by Lensing and colleagues [14] was used, with a minor modification as described below. Ultrasonography was performed by using an Acuson 128 scanner (Acuson Corp., Mountain View, California) equipped with a 7.5-MHz linear-array transducer. Both the common femoral and popliteal veins were imaged in gray scale and were assessed for compressibility [14]. The common femoral vein was imaged from the inguinal line to its bifurcation into the superficial femoral vein and profunda femoris. The popliteal vein was imaged from the proximal popliteal fossa to a point 10 cm distal from the mid-patella. This point was chosen to provide a reproducible method with which to approximate the most distal popliteal vein because the calf-vein trifurcation is often difficult to identify by ultrasonography. Vein anatomy in the popliteal fossa, as well as the formation of the popliteal vein itself, greatly varies; the classic trifurcation pattern is found in only a minority of patients [25-27]. Compressibility of the veins was assessed only in the transverse plane [14]. The results were categorized as normal if all imaged venous segments were fully compressible, as abnormal if a noncompressible segment was identified, or as inadequate for interpretation. If the result of initial compression ultrasonography was normal, anticoagulation was withheld and testing was repeated 5 to 7 days later. Anticoagulation was withheld from all patients whose results remained normal on compression ultrasonography (the normal cohort), regardless of their symptoms. If the result of initial or repeated testing was abnormal (the abnormal cohort), venography was done to confirm the extent of thrombosis. The venographic results were categorized as normal, positive for proximal venous thrombosis (thrombosis of the popliteal, femoral, or iliac vein with or without thrombosis of the calf vein), positive for isolated thrombosis of the calf vein, or inadequate for interpretation. The diagnostic criterion for the presence of deep venous thrombosis was an intraluminal filling defect that was constant on all films [28]. If the venogram was abnormal or inadequate for interpretation, anticoagulation was given unless contraindicated. If the venogram was normal, anticoagulation was not given and the abnormal ultrasonography result was considered falsely abnormal. Long-Term Follow-up All patients were instructed to immediately return to our clinic or emergency department if they had symptoms or signs of venous thrombosis or pulmonary embolism. They were also assessed routinely at 3 months either in the clinic or by telephone. At this follow-up assessment, an interval history was taken that addressed general health, specific symptoms (including leg pain, tenderness and swelling, chest pain, dyspnea, hemoptysis, and syncope), hospitalization, and use of anticoagulants. For all patients who died, the cause of death was determined either from autopsy or by independent clinical review. The primary outcome measure was a diagnosis of venous thrombosis or pulmonary embolism during follow-up confirmed by objective testing. The 3-month follow-up period was chosen because inadequate management of proximal venous thrombosis results in a high rate of recurrent venous thromboembolism during the subsequent 3 months [19-21]. All patients in either cohort who returned during 3-month follow-up with clinically suspected deep venous thrombosis underwent objective testing with impedance plethysmography, which was performed serially according to published protocols [7-929, 30]. Serial impedance plethysmography is highly sensitive and specific for proximal venous thrombosis in symptomatic patients [7-9]. Venography was indicated in patients with abnormal results on impedance plethysmography. If venography could not be done or the results of venography were inadequate, deep venous thrombosis was diagnosed if impedance plethysmography yielded abnormal results in the absence of conditions known to produce false-positive results [7-9, 29-31]. Patients suspected of having pulmonary embolism underwent objective testing with lung scanning and, if indicated, pulmonary angiography, according to published protocols and diagnostic criteria [32-34]. Methodologic Issues and Avoidance of Bias Care was taken to avoid bias. Selection bias was avoided by entering consecutive patients into the study. Bias during the initial testing period was avoided by defining criteria for normal and abnormal ultrasonography results a priori; by prohibiting venography or other objective leg testing in patients with normal ultrasonography results; and by withholding anticoagulation from all patients with normal ultrasonography results, regardless of their symptoms. Diagnostic suspicion bias [35] was avoided by objectively testing all patients who re

Effects of caffeine on vascular resistance, cardiac output and myocardial contractility in young men☆

Background: Patients undergoing hip or knee joint replacement are at risk for venous thromboembolic complications for up to twelve weeks postoperatively. We evaluated the efficacy and safety of a prolonged post-hospital regimen of enoxaparin, a low-molecular-weight heparin, in this patient population. Methods: Following elective total hip or knee replacement, 968 patients received subcutaneous enoxaparin (30 mg twice daily) for seven to ten days, and 873 were then randomized to receive three weeks of double-blind outpatient treatment with either enoxaparin (40 mg once daily) or a placebo. The primary efficacy end point was the prevalence of objectively confirmed venous thromboembolism or symptomatic pulmonary embolism during the double-blind phase of treatment. Results: Of the 873 randomized patients, 435 underwent elective total hip replacement and 438 underwent elective total knee replacement. Enoxaparin was superior to the placebo in reducing the prevalence of venous thromboembolism in patients treated with hip replacement: 8.0% (eighteen) of the 224 patients treated with enoxaparin had venous thromboembolism compared with 23.2% (forty-nine) of the 211 patients treated with the placebo (p < 0.001; odds ratio, 3.62; 95% confidence interval, 2.00 to 6.55; relative risk reduction, 65.5%). Enoxaparin had no significant benefit in the patients treated with knee replacement: thirty-eight (17.5%) of the 217 patients treated with enoxaparin had venous thromboembolism compared with forty-six (20.8%) of the 221 patients treated with the placebo (p = 0.380; odds ratio, 1.24; 95% confidence interval, 0.76 to 2.02; relative risk reduction, 15.9%). Symptomatic pulmonary embolism developed in three patients, one with a hip replacement and two with a knee replacement; all had received the placebo. There was no significant difference in the prevalence of hemorrhagic episodes or other types of toxicity between the enoxaparin and placebo-treated groups. Conclusions: Prolonging enoxaparin thromboprophylaxis following hip replacement for a total of four weeks provided therapeutic benefit, by reducing the prevalence of venous thromboembolism, without compromising safety. A similar benefit was not observed in patients treated with knee replacement.

Hypertension Risk Status and Effect of Caffeine on Blood Pressure

This study evaluated the cardiovascular effects and elimination kinetics of coffee and caffeine in 54 volunteers selected according to 3 gradations of daily caffeine consumption, cigarette smoking status and the presence of caffeine intolerance. After 24 hours of caffeine abstinence, subjects received coffee and 2.2 mg/kg of caffeine (equivalent to 2 cups of coffee). Blood pressure, heart rate, systolic time intervals and plasma concentrations of caffeine were measured before and at timed intervals after coffee and caffeine. There were no differences in response to coffee and caffeine. The average systolic/diastolic blood pressure increased 9/10 mm Hg. The maximal decrease in heart rate averaged 10 beats/min, and there were small increases in the systolic time intervals. There were no cardiovascular differences among the various groups. Caffeine in the smokers and heavy caffeine users had a shorter half-life (3.2 and 4.1 hours) than that in nonsmokers and nonusers (5.1 and 5.3 hours). In the caffeine-intolerant group it had a longer half-life, while the cardiovascular effects were similar to those of the other groups. Thus, irrespective of the amount of daily caffeine consumption, smoking status or caffeine intolerance, the cardiovascular responses were similar and tolerance, if present, was gone by 24 hours.

Blood Pressure Response to Caffeine Shows Incomplete Tolerance After Short-Term Regular Consumption

The mechanisms by which caffeine typically elevates blood pressure (BP) in humans have not been previously examined using a placebo-controlled design. Accordingly, oral caffeine (3.3 mg/kg body weight, equivalent to 2 to 3 cups of coffee) was given on 2 days and a placebo was given on 1 day to 15 healthy young men using a double-blind, crossover procedure. All 3 test sessions were held during a week of caffeine abstinence. Multiple measurements were made on subjects at rest (baseline values) and over a 45-minute interval after ingestion of caffeine for BP, heart rate, systolic time intervals and thoracic impedance measures of ventricular function. Baseline measurements were highly reliable for each subject across all sessions and yielded means for placebo vs caffeine days that were not different. Caffeine increased systolic and diastolic BP (p less than 0.01) and decreased heart rate (p less than 0.05). The pressor effect was due to progressively increased systemic vascular resistance and resulted in greater stroke work (p less than 0.01). There was no indication that caffeine increased cardiac output or contractility. These actions of caffeine were replicable when each caffeine day was tested separately against the placebo day. These results suggest that caffeine use by persons with cardiovascular diseases should be examined to determine whether caffeines enhancement of vascular resistance may contribute to systematic hypertension and/or create excessive demands for cardiac work.

Caffeine Stimulation of Cortisol Secretion Across the Waking Hours in Relation to Caffeine Intake Levels

We compared the acute effects of caffeine on arterial blood pressure (BP) in 5 hypertension risk groups composed of a total of 182 men. We identified 73 men with optimal BP, 28 with normal BP, 36 with high-normal BP, and 27 with stage 1 hypertension on the basis of resting BP; in addition, we included 18 men with diagnosed hypertension from a hypertension clinic. During caffeine testing, BP was measured after 20 minutes of rest and again at 45 to 60 minutes after the oral administration of caffeine (3.3 mg/kg or a fixed dose of 250 mg for an average dose of 260 mg). Caffeine raised both systolic and diastolic BP (SBP and DBP, respectively; P<0.0001 for both) in all groups. However, an ANCOVA revealed that the strongest response to caffeine was observed among diagnosed men, followed by the stage 1 and high-normal groups and then by the normal and optimal groups (SBP F(4),(175)=5.06, P<0.0001; DBP F(4,175)=3.02, P<0.02). Indeed, diagnosed hypertensive men had a pre-to-postdrug change in BP that was >1.5 times greater than the optimal group. The potential clinical relevance of caffeine-induced BP changes is seen in the BPs that reached the hypertensive range (SBP >/=140 mm Hg or DBP >/=90 mm Hg) after caffeine. During the predrug baseline, 78% of diagnosed hypertensive men and 4% of stage 1 men were hypertensive, whereas no others were hypertensive. After caffeine ingestion, 19% of the high-normal, 15% of the stage 1, and 89% of the diagnosed hypertensive groups fell into the hypertensive range. All subjects from the optimal and normal groups remained normotensive. We conclude that hypertension risk status should take priority in future research regarding pressor effects of dietary intake of caffeine.

Negative d-dimer Result To Exclude Recurrent Deep Venous Thrombosis: A Management Trial

Abstract—Caffeine acutely raises blood pressure (BP). The clinical significance of this effect depends on whether BP responses persist in persons who consume caffeine on a daily basis. Accordingly, the ability of caffeine to raise BP after 5 days of regular daily intake was tested in a randomized controlled trial. Individual differences in tolerance formation were then examined. Men (n=49) and women (n=48) completed a double-blind, crossover trial conducted over 4 weeks. During each week, subjects abstained for 5 days from dietary caffeine and instead used capsules totaling 0 mg, 300 mg, and 600 mg of caffeine per day in 3 divided doses. On day 6, in the laboratory, they used capsules with either 0 mg or 250 mg of caffeine at 9:00 am and 1:00 pm. Systolic/diastolic BP increases as a result of 250 mg of caffeine remained significant (P <0.006/0.001) at all levels of previous daily consumption. Individual difference comparisons found that although half the subjects had complete loss of systolic and diastolic BP responses to the challenge doses, the other half showed no loss in BP response, even after using 600 mg of caffeine per day for the previous 5 days (F >7.90, P <0.001). The sexes did not differ in degree of tolerance formation. Daily caffeine consumption failed to eliminate the BP response to repeated challenge doses of caffeine in half of the healthy adults who were tested. Caffeine may therefore cause persistent BP effects in persons who are regular consumers, even when daily intake is at moderately high levels.

Stress-like adrenocorticotropin responses to caffeine in young healthy men

Objective: Caffeine increases cortisol secretion in people at rest or undergoing mental stress. It is not known whether tolerance develops in this response with daily intake of caffeine in the diet. We therefore tested the cortisol response to caffeine challenge after controlled levels of caffeine intake. Methods: Men (N = 48) and women (N = 48) completed a double-blind, crossover trial conducted over 4 weeks. On each week, subjects abstained for 5 days from dietary caffeine and instead took capsules totaling 0 mg, 300 mg, and 600 mg/day in 3 divided doses. On day 6, they took capsules with either 0 mg or 250 mg at 9:00 AM, 1:00 PM, and 6:00 PM, and cortisol was sampled from saliva collected at 8 times from 7:30 AM to 7:00 PM. Results: After 5 days of caffeine abstinence, caffeine challenge doses caused a robust increase in cortisol across the test day (p < .0001). In contrast, 5 days of caffeine intake at 300 mg/day and 600 mg/day abolished the cortisol response to the initial 9:00 AM caffeine dose, although cortisol levels were again elevated between 1:00 PM and 7:00 PM (p = .02 to .002) after the second caffeine dose taken at 1:00 PM. Cortisol levels declined to control levels during the evening sampling period. Conclusion: Cortisol responses to caffeine are reduced, but not eliminated, in healthy young men and women who consume caffeine on a daily basis. ANOVA = analysis of variance; C = caffeine; HPAC = hypothalamic-pituitary-adrenocortical axis; P = placebo; ACTH = adrenocorticotropin.