Analysis of steroid hormones and their conjugated forms in water and urine by on-line solid-phase extraction coupled to liquid chromatography tandem mass spectrometry.

BACKGROUND: In recent years, endocrine disrupting compounds (EDCs) have been found in rivers that receive significant inputs of wastewater. Among EDCs, natural and synthetic steroid hormones are recognized for their potential to mimic or interfere with normal hormonal functions (development, growth and reproduction), even at ultratrace levels (ng L(-1)). Although conjugated hormones are less active than free hormones, they can be cleaved and release the unconjugated estrogens through microbial processes before or during the treatment of wastewater. Due to the need to identify and quantify these compounds, a new fully automated method was developed for the simultaneous determination of the two forms of several steroid hormones (free and conjugated) in different water matrixes and in urine. RESULTS: The method is based on online solid phase extraction coupled with liquid chromatography and tandem mass spectrometry (SPE-LC-MS/MS). Several parameters were assessed in order to optimize the efficiency of the method, such as the type and flow rate of the mobile phase, the various SPE columns, chromatography as well as different sources and ionization modes for MS. The method demonstrated good linearity (R(2) > 0.993) and precision with a coefficient of variance of less than 10 %. The quantification limits vary from a minimum of 3-15 ng L(-1) for an injection volume of 1 and 5 mL, respectively, with the recovery values of the compounds varying from 72 to 117 %. CONCLUSION: The suggested method has been validated and successfully applied for the simultaneous analysis of several steroid hormones in different water matrixes and in urine.

Using a novel sol-gel stir bar sorptive extraction method for the analysis of steroid hormones in water by laser diode thermal desorption/atmospheric chemical ionization tandem mass spectrometry.

A new coating material was used for a stir bar sorptive extraction (SBSE) method coupled to a high throughput sample analysis technique. This allowed for a simple procedure for fast determinations of eight steroid hormones (estriol, estradiol, ethynylestradiol, estrone, progesterone, medroxyprogesterone, levonorgestrel, northindrone) in water. Sample pre-treatment was performed using an in-house SBSE method based on a polydimethylsiloxane/phenyltrimethylsiloxane/ß-cyclodextrin sol-gel material. The analytes were desorbed by liquid extraction prior to their analysis by laser diode thermal desorption/atmospheric pressure chemical ionization coupled to tandem mass spectrometry (LDTD-APCI-MS/MS). Several parameters, including ionic strength, volume and time of extraction as well as volume and time of desorption, were investigated to maximize extraction efficiency by SBSE in aqueous solutions. The in-house stir bar showed good reproducibility and could be used for at least 50 extractions without affecting analytical performance. The recoveries of the spiked steroid hormones ranged from 55% to 96% in all water matrices studied (HPLC grade water, tap water and raw wastewater). Only one compound showed poor recovery values (<2% for estriol) in all matrices. The method detection limits (MDLs) in real matrices were within the range of 0.1-0.3 µg L(-1) except for estriol at 48 µg L(-1). The extraction performance of the in-house SBSE for the eight selected hormones was also compared with that of a commercially-available stir bar coated with polydimethylsiloxane (PDMS). This novel stir bar coating could prove to be useful method for the detection and quantification of trace levels of steroid hormones.

Prevalence and knowledge of transient ischemic attack among US adults.

BACKGROUND: Little information is available about public knowledge of TIA and prevalence of a TIA diagnosis. METHODS: The National Stroke Association sponsored a telephone survey by single-stage random-digit dialing of noninstitutionalized US residents > or =18 years old, which was conducted in 1999. Demographic characteristics of participants were compared to the US population to produce weights for projections. Independent predictors of knowledge and diagnosis of TIA were determined by including all demographic characteristics in logistic regression models. RESULTS: Among 10,112 participants, 2.3% reported having been told by a physician that they had a TIA. Older age, lower income, and fewer years of education were independently associated with a diagnosis of TIA. Of those with TIA, only 64% saw a physician within 24 hours of the event. A physician diagnosis of stroke was reported by 2.3% of participants, of whom 19% recalled having had a TIA before the stroke. An additional 3.2% of participants recalled symptoms consistent with TIA but did not seek medical attention. Only 8.2% correctly related the definition of TIA and 8.6% could identify a typical symptom. Men, nonwhites, and those with lower income and fewer years of education were less likely to be knowledgeable about TIA. CONCLUSIONS: An estimated 4.9 million people in the US report a diagnosis of TIA, and many more recall symptoms consistent with TIA but do not seek medical attention. Reducing stroke risk after TIA could have substantial impact on public health but will require public education about the importance of having stroke symptoms evaluated, even if they resolve.

Stereotactic computed tomographic-guided aspiration and thrombolysis of intracerebral hematoma : protocol and preliminary experience.

BACKGROUND AND PURPOSE: We review preliminary experience with patients harboring intracerebral hematoma (ICH) treated by stereotactic computed tomographic (CT) guided thrombolysis and aspiration and assess procedure feasibility and safety. METHODS: Twelve patients with supratentorial ICH >/=25 mL without suspected underlying structural etiology or coagulopathy and an initial Glasgow Coma Scale (GCS) score of >/=5 were treated. A catheter was directed stereotactically or manually into the ICH through a burr hole under CT guidance. Hematoma aspiration was followed by instillation of urokinase (5 000 to 10 000 IU). This was repeated every 6 to 8 hours at bedside, with interval CT imaging, until the ICH volume diminished to <25 mL, less than half of its initial volume, or after a maximum of 10 aspirations/instillations. RESULTS: Mean age was 69 years (range 55 to 82 years). Median initial GCS was 12 (range 5 to 14). There were 7 ganglionic and 5 lobar ICH, and baseline hematoma size ranged 29 to 70 mL (mean 46 mL). Final ICH volume ranged from 14 to 51 mL (mean 21 mL), with ICH volume reduction by an average of 57% (range 38% to 70%). One patient (8. 3%) suffered hematoma expansion during the procedure. At 6 months after the procedure, 3 patients (25%) had achieved a good recovery (Glasgow Outcome Scale [GOS] score of 5), 5 patients (42%) were dependent (GOS 3), and 1 (8.3%) remained vegetative (GOS 2). Three patients (25%) died in hospital (1 from cardiac arrhythmia and 2 from respiratory failure). CONCLUSIONS: CT-guided thrombolysis and aspiration appears safe and effective in the reduction of ICH volume. Further studies are needed to assess optimal thrombolytic dosage and must include controlled comparisons of mortality, disability outcome, time until convalescence, and cost of care in treated and untreated patients.

Safety and tolerability study of aptiganel hydrochloride in patients with an acute ischemic stroke.

BACKGROUND AND PURPOSE: Aptiganel (CNS 1102) is a selective, noncompetitive antagonist that acts on the ion channel associated with the N-methyl-D-aspartate (NMDA) receptor and is neuroprotective in experimental focal cerebral ischemia models at a plasma concentration of 10 ng/mL. In human volunteers, dose-limiting effects of aptiganel are blood pressure increases and central nervous system (CNS) excitation or depression. This study assessed the safety and tolerability of non-weight-adjusted doses of aptiganel in patients with acute ischemic stroke. METHODS: This was a double-blind, randomized, placebo-controlled multicenter study in patients presenting within 24 hours of acute ischemic stroke. Ascending single intravenous bolus doses of aptiganel (3, 4.5, 6, and 7.5 mg) were assessed in 21 patients with a 3:1 active drug:placebo randomization schedule. In 15 subsequent patients, selected bolus doses were followed by constant intravenous infusion for 6 to 12 hours (6 mg plus 1 mg/h, n=10; then 4.5 mg plus 0.75 mg/h, n=15) in a 4:1 randomization schedule. Prospectively collected pharmacokinetic data guided selection of infusion rates. Neurological and functional status were recorded at entry and after 1 week, although the study was not designed to test efficacy. RESULTS: Forty-six patients were randomized from 4 centers (3 in the United States and 1 in the United Kingdom): 36 received aptiganel HCl, and 10 were given placebo. Hypertension and CNS events were commonly reported after a bolus dose of 7.5 mg and after a 6-mg bolus followed by an infusion of 1 mg/h. The lower regimen of 4.5-mg bolus followed by infusion of 0.75 mg/h achieved plasma aptiganel concentrations of >10 ng/mL and was well tolerated by patients but still raised systolic blood pressure by approximately 30 mm Hg over baseline. CONCLUSIONS: A 4.5-mg intravenous bolus of aptiganel HCl followed by infusion of 0.75 mg/h for 12 hours is a tolerable dose that can produce plasma drug concentrations shown to be neuroprotective in animal models. However, increases in systolic blood pressure and an excess of CNS effects were both observed at this dose.

Surgery for intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) represents 8 to 15% of all strokes in the United States and 20 to 30% of all strokes in Japan and China. Although ICH represents a relatively small fraction of total strokes, it is a formidable disease, with a 30-day mortality rate two- to sixfold higher than that for ischemic stroke. Furthermore, it is a major cause of disability, with only 20% of patients becoming independent at 6 months. The most common risk factors for ICH are age, hypertension, and amyloid angiopathy, which are associated with damage to and weakening of the arterial/arteriolar wall leading to vessel rupture. The pathology is a dynamic one that continues to evolve over the first few days after onset. In 20 to 30% of ICH, clot volume increases over the first 24 hours and is generally associated with neurologic worsening. The final outcome from ICH is related not only to clot volume, compression, and destruction but also to potential neurotoxicity from the blood degradation products and associated neuronal ischemia. The treatment of ICH has been one of the most controversial and least well-studied areas from a medical or surgical perspective. Surgical treatment has evolved over the years and can be grouped into open and stereotactically guided surgery for hematoma evacuation. Seven thousand operations per year are performed in the United States for hematoma evacuation, although this approach has not been adequately investigated. Adjuvant medical therapies with neuroprotective agents require further investigation and may potentially have additive benefits.

Failure of the hypotensive provocative test during temporary balloon test occlusion of the internal carotid artery to predict delayed hemodynamic ischemia after therapeutic carotid occlusion.

BACKGROUND: Extensive experience and critical evaluation of the efficacy of a pharmacologic hypotensive challenge during conventional balloon test occlusion (BTO) of the internal carotid artery (ICA) is lacking. This prompted us to review our institution's most recent experience with this adjunctive provocative test before planned therapeutic balloon occlusion of the ICA. METHODS: Twenty consecutive cases of endovascular therapeutic balloon occlusion of the ICA were retrospectively reviewed. Conventional BTO under normotension and with hypotensive challenge were performed within a standardized protocol. RESULTS: Sixteen patients underwent provocative testing, of which 13 had BTO with hypotensive challenge. All patients in this group tolerated these maneuvers without acute neurologic deficit. Two (15%) of these patients developed delayed permanent neurologic deficits, which seemed to be attributable to hemodynamic ischemia. One of seven patients not undergoing hypotensive challenge also developed transient neurologic deficits after carotid occlusion. CONCLUSIONS: Despite the conceptually attractive and early positive experience of the hypotensive challenge in attempting to increase sensitivity and specificity of risk for developing delayed hemodynamic ischemia, we have found two significant false-negative results. This experience is reviewed in the context of risks of permanent balloon occlusion of the carotid artery after balloon test occlusion.

MR of hereditary hemorrhagic telangiectasia: prevalence and spectrum of cerebrovascular malformations.

PURPOSE: Our goal was to describe the prevalence and types of cerebral vascular malformations (CVMs) seen with MR imaging in patients with hereditary hemorrhagic telangiectasia (HHT). METHODS: We reviewed retrospectively the brain MR images of 184 consecutive patients with HHT. Catheter angiography was performed in 17 patients with CVMs detected on MR images. RESULTS: MR imaging revealed 63 CVMs in 42 patients. Classic arteriovenous malformations (n = 10) had a conspicuous network of vessels with flow voids and enlarged adjacent pial vessels. Apparent venous malformations (n = 5) were best seen after administration of contrast material as a prominent vessel coursing through normal brain parenchyma. Indeterminate vascular malformations (n = 48) had a spectrum of appearances characterized by variable combinations of heterogeneous signal intensity, enhancement, or hemosiderin. Angiography in 17 patients revealed 47 CVMs. Forty-six were arteriovenous malformations (AVMs), including 25 CVMs not seen with MR imaging and 21 CVMs that by MR criteria included 8 AVMs and 13 indeterminate vascular malformations. Angiography confirmed 1 venous malformation seen with MR imaging but failed to detect 3 indeterminate lesions revealed by MR imaging. CONCLUSION: MR imaging of a large cohort of consecutive patients with HHT revealed a CVM prevalence of 23% (42/184). Most CVMs (48/63) have an atypical appearance for vascular malformations on MR images. Angiographic correlation suggests that MR imaging underestimates the prevalence of CVMs and that the majority of indeterminate CVMs, despite their variable MR appearance, are AVMs.

Embolotherapy of large pulmonary arteriovenous malformations: long-term results.

BACKGROUND: The purpose of this study was to document the long-term results of transcatheter embolotherapy of large pulmonary arteriovenous malformations (PAVMs). METHODS: From a data base of 221 consecutive patients with PAVMs treated by embolotherapy between 1978 and 1995, 45 patients with 52 PAVMs, supplied by feeding arteries 8 mm in diameter or larger, were selected for a retrospective investigation. RESULTS: Of 45 patients with 52 large PAVMs, 38 patients (84%) with 44 PAVMs (85%) were cured by the first embolotherapy (mean follow-up, 4.7 years). Acute periprocedural complications included self-limited pleurisy (31%), angina secondary to air embolus (2%), and paradoxical embolization of a device during deployment (4%). None of these events led to short- or long-term sequelae. Seven patients (16%) had persistence of the PAVM attributable to either recanalization (n = 4) or interim accessory artery growth (n = 3). Two of these patients presented with ischemic stroke several years after the initial treatment. Persistent PAVMs (n = 8) were retreated successfully by a second procedure (n = 7), or a third procedure (n = 1) (mean follow-up, 5.9 and 5.3 years, respectively). CONCLUSIONS: Embolotherapy of large PAVMs results in permanent occlusion in an overwhelming majority of patients. Continued patency due to recanalization or accessory artery growth is easily detected and treated.

Exceptional multiplicity of cerebral arteriovenous malformations associated with hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome).

PURPOSE: To describe the clinical and imaging features of seven patients with hereditary hemorrhagic telangiectasia and an exceptional number of cerebral arteriovenous malformations (AVMs). METHODS: One hundred thirty-six patients from a dedicated hereditary hemorrhagic telangiectasia clinic were screened systematically for cerebral AVMs by means of MR imaging. Thirty-one were found to have abnormalities suggestive of a vascular malformation. Eighteen of these 31 patients subsequently underwent diagnostic cerebral angiography. RESULTS: Of the 18 patients who had cerebral angiography, all were found to have at least one AVM and seven were found to have three or more AVMs. The number of cerebral AVMs detected ranged from three to nine. At angiography, the AVMs varied in size from 3 to 25 mm in maximal dimension and consisted of a poorly defined plexiform nidus that typically had a single arterial feeding pedicle and a single draining vein. The two largest AVMs (20- and 25-mm nidus, respectively) contained intranidal aneurysms. Treatment included embolization, surgical excision, or follow-up management. CONCLUSIONS: Multiple cerebral AVMs are associated with hereditary hemorrhagic telangiectasia and further highlight the uniqueness of central nervous system involvement by this systemic angiodysplasia. MR imaging can underestimate the number and size of cerebral AVMs; therefore, catheter angiography is necessary to establish the extent of central nervous system involvement in this disorder.

Effects of a specialized team on stroke care. The first two years of the Yale Stroke Program.

BACKGROUND AND PURPOSE: Strategies have been proposed for stroke care to improve quality or reduce cost. We sought to document the effects of a new program of specialized stroke care. METHODS: In a programmatic review using historical and concurrent control subjects, we evaluated patients discharged with a stroke diagnosis (diagnosis-related group 14) over a 6-year period between January 1987 and December 1992. Patients were from an academic medical center. The intervention was consultation (on university neurology patients) by a specialized multidisciplinary team during the last 2 years of the review period. The main outcome measures were median length of stay and rate of common complications before and after implementation compared with other hospital services (private neurology and medicine). RESULTS: Stroke team involvement was associated with a shortened median length of stay from 10 to 8 days (P < .0001). There was no significant change in the median length of stay for the private neurology or medicine services. After stroke team involvement, there were fewer urinary tract infections (P = .056), and those patients who developed infection had a shorter length of stay (P = .0007). There was no change in the rate of aspiration pneumonia or in length of stay for patients with aspiration pneumonia. Mortality did not change. CONCLUSIONS: A coordinated, multidisciplinary approach to stroke care may reduce length of stay and morbidity in patients hospitalized because of stroke.

Clivus and cervical spinal osteomyelitis with epidural abscess presenting with multiple cranial neuropathies.

A 65-year-old diabetic man with a history of otitis was admitted with headache, neck and shoulder pain and cranial nerve abnormalities including sixth, seventh and twelfth nerve palsies, hearing loss and ptosis. Lumbar puncture revealed an elevated CSF protein and pleocytosis. Imaging procedures demonstrated osteomyelitis of the clivus that involved the epidural space and extended within the prevertebral space to the cervical spine. The patient improved after treatment with antibiotics and immobilization of the neck. This case illustrates the importance of recognizing infections of the clivus in patients with cranial nerve abnormalities.

Ischemic stroke and intracranial multifocal cerebral arteriopathy in Williams syndrome.

We describe an otherwise healthy 2-year-old patient with Williams syndrome who had a stroke as a result of intracranial multivessel focal and segmental stenotic disease. The diagnosis of Williams syndrome was confirmed by elastin gene deletion testing. Combined magnetic resonance imaging and magnetic resonance angiography, and transcranial Doppler flow studies, were used in diagnosing and monitoring the course of the disease.

Clinical correlates of proton magnetic resonance spectroscopy findings after acute cerebral infarction.

BACKGROUND AND PURPOSE: We sought to determine whether lactate and N-acetyl signals measured by proton magnetic resonance spectroscopy (MRS) in the first days after stroke correlate with clinical measures of disability and functional outcome. METHODS: One-dimensional spectroscopic imaging was performed after stroke on 32 patients using a 2.1-T magnet. The Toronto Stroke Scale score at the time of the MRS study and the Barthel Index score at hospital discharge were determined from patient records. Lesion volume was estimated by a tracing algorithm from the scout magnetic resonance image obtained as part of the MRS study. The scaled lactate and N-acetyl signals from the voxel having the highest measured lactate were used to predict the clinical variables and lesion volume, as well as relative perfusion within the lesion, in those patients who underwent single-photon emission computed tomography (SPECT) blood flow imaging, using a multiple regression analysis. The correlation of lesion volume with the clinical variables was also evaluated. RESULTS: Lesion lactate signal was correlated with the Toronto Stroke Scale score, Barthel Index score, lesion volume, and SPECT score, all at P < .01. The N-acetyl level correlated with the Barthel Index score and lesion volume at P < .05. Lesion volume was also strongly correlated with the clinical variables (P < .0001). CONCLUSIONS: This is the first study to document the clinical predictive value of proton MRS measurements in patients after stroke. The association with functional outcome is stronger for lactate than for N-acetyl. Spectroscopic assessment of the metabolic status of cerebral tissues shortly after infarction may have significant clinical utility.

Painless aortic dissection presenting as a progressive myelopathy.

We report a patient with a painless aortic dissection whose neurologic symptoms progressed over 5 days to a complete transverse myelopathy. She did not experience pain as her neurologic deficits evolved. Magnetic resonance imaging revealed a thoracic aortic dissection extending from the arch to the level of the 12th thoracic vertebra and demonstrated ischemic changes in the spinal cord and one thoracic vertebral body. Aortic dissection must be included in the differential diagnosis of spinal cord syndromes even in the absence of pain. Early recognition of aortic dissection as a cause of progressive myelopathy may become increasingly important as new therapies for central nervous system ischemia are developed.

Factors associated with early presentation of acute stroke.

BACKGROUND AND PURPOSE: Patients with stroke symptoms commonly delay many hours before seeking medical attention. We sought to explore the factors associated with early presentation of stroke patients to physicians. METHODS: We prospectively studied 100 consecutive acute stroke patients presenting to three large, urban medical centers. Using a standardized, structured interview and chart review, we assessed patient education about stroke, risk factors, clinical features of the stroke, source of stroke recognition, and timing of presentation. We did not study the distance from the site of stroke onset to the site of physician contact. RESULTS: Stroke onset time was known in 96 of the patients. Mean patient age was 71.3 years, 79% had at least one stroke risk factor, 26% had prior transient ischemic attack, 19% had prior stroke, 74% had some high school education, and 86% had regular physicians. Only 8% had been previously educated about stroke symptoms. Eighty one percent of strokes were ischemic. The mean time to physician contact was 13.4 +/- 2.3 hours (median, 4.0 hours) and to neurologist contact was 21.2 +/- 2.9 hours. A skewed distribution of presentation times accounts for the mean-median differences. A small number of patients presenting very late could have an effect on the correlations between presentation time and the variables studied. Early presentation time was associated with increased age, the sudden onset of a stable deficit, and recognition that the symptoms signified stroke. Only the sudden onset of a stable deficit correlated independently with early presentation time (P = .0048). There was no correlation between presentation time and prior transient ischemic attack or stroke, headache, vomiting, loss of consciousness or seizures at onset, or stroke subtype, but a type II error could not be excluded. CONCLUSIONS: Despite their education level, regular health care, and risk factors, especially prior stroke and transient ischemic attack, these patients were not knowledgeable about stroke and delayed many hours before contacting physicians. The course of symptoms and recognition that they signified stroke were associated with earlier presentation. Patient education focused on groups at risk may hasten the presentation and treatment of acute stroke.

Early temporal variation of cerebral metabolites after human stroke. A proton magnetic resonance spectroscopy study.

BACKGROUND AND PURPOSE: Proton magnetic resonance spectroscopy has documented declines in normal metabolites and long-term elevation of lactate signal after stroke in humans. Within days of stroke, leukocytes infiltrating the infarct zone may produce much of the lactate seen in the subacute and chronic periods. METHODS: We examined 10 patients by localized proton magnetic resonance spectroscopy with one-dimensional spectroscopic imaging within the first 60 hours after acute nonhemorrhagic cerebral infarction, a period before abundant leukocyte infiltration. Follow-up studies on day 8 to 17 after stroke were performed on 7 of these patients. RESULTS: Initially, the lactate magnetic resonance signal was elevated in all patients. The N-acetyl-aspartate peak within the lesion was reduced below contralateral normal brain in all but two. At subsequent examination, significant declines had occurred in lesion maximum lactate and N-acetyl-aspartate signals, with average changes of -36 +/- 11% per week and -29 +/- 9% per week, respectively. Declines in lesion creatine/phosphocreatine and in choline-containing compound peaks occurred in some patients but did not attain statistical significance for the group as a whole. Estimated lesion volume correlated positively with both total (r = .75, P = .012) and lesion maximum (r = .74, P = .015) lactate signal. CONCLUSIONS: Elevated lactate signal is reliably detectable by magnetic resonance spectroscopy after acute cerebral infarction in humans. Clearance of lactate occurs despite the potential contribution of lactate-producing leukocytes in the subacute stage. Delayed loss of N-acetyl-aspartate signal in second examinations suggests that late death of viable cells may occur within the first 2 weeks after cerebral infarction.

Transcranial Doppler validation pilot study.

The use of transcranial Doppler sonography (TCD) for the evaluation of patients with ischemic cerebrovascular disease remains controversial. This study was organized to gather preliminary data regarding the sensitivity and specificity of TCD when compared to cerebral angiography in detecting stenosing lesions and collateral flow patterns of the anterior cerebral circulation. Forty-two patients from six medical centers were prospectively enrolled. Each received cerebral angiography and TCD testing within 24 hours of each other. Based on TCD criteria established a priori, the results were first analyzed by a blinded investigator and then by computer. Computerized analyses were then repeated with modified criteria. Collateral flow through the anterior communicating and ophthalmic arteries was detected with sensitivities of 62% and 100%, and specificities of 98% and 92%, respectively. Internal carotid artery proximal and distal severe ( greater than 70%) stenoses were detected with sensitivities of 79% and 100% and specificities of 88% and 97%. Middle and anterior cerebral artery stenoses and middle cerebral artery occlusion were detected with specificities exceeding 98%; however, the data were insufficient to determine sensitivity. Computerized analyses did not permit improvement of sensitivity and specificity of the baseline criteria. The selected TCD criteria are highly specific in detecting intracranial stenoses and collateral flow patterns of the anterior circulation. The criteria have limited but acceptable sensitivity and specificity in detecting internal carotid artery origin severe stenoses, and are highly sensitive in detecting ophthalmic artery retrograde flow. A study with a larger sample is necessary to provide definitive guidelines for diagnosis.

Effect of caffeine on the recognition of and responses to hypoglycemia in humans.

OBJECTIVE: To determine whether two effects of acute caffeine ingestion--decrease in cerebral blood flow and increase in brain glucose use--alter the recognition of and physiologic responses to hypoglycemia. DESIGN: On two occasions, a hyperinsulinemic glucose clamp technique (2 mU/kg body weight per minute) was used to maintain plasma glucose at 5 mmol/L for 90 minutes, followed by 60 minutes at 3.8 mmol/L, and then 2.8 mmol/L. After 30 minutes at 5 mmol/L, participants consumed, using a randomized, double-blind design, caffeine-free cola with or without caffeine (400 mg) added. SETTING: Yale Clinical Research Center. PARTICIPANTS: Eight healthy, nonobese volunteers (5 men; age range, 20 to 33 years). MEASUREMENTS: Middle cerebral artery velocity (V MCA), counter-regulatory hormone levels, hypoglycemic symptoms, and cognitive function (P300 evoked potentials). RESULTS: Caffeine caused an immediate and sustained 23% decrease in VMCA from 64 to 49 cm/s (point estimate of difference, +15 cm/s [95% CI, 10 to 21 cm/s], P < 0.001). At a glucose level of 3.8 mmol/L, only the participants given caffeine had warning symptoms and "felt hypoglycemic." Moreover, the level of epinephrine was 118% ([CI of point difference, 76% to 158%] [CI, P < 0.001]) higher after caffeine consumption compared with placebo. Similarly, levels of norepinephrine (41% [CI, 26% to 60%], P < 0.002), cortisol (65% [CI, 26% to 78%], P < 0.008), and growth hormone (60% [CI, 16% to 143%], P < 0.05) were higher after caffeine consumption compared with placebo. At 2.8 mmol/L, epinephrine (40% [point estimate of the percentage difference], P < 0.05), norepinephrine (27%, P < 0.05), and cortisol (24%, P < 0.05) levels were higher, participants were more aware (P < 0.02) of hypoglycemia, and P300 latency was prolonged in the group that consumed caffeine (7.2%, P < 0.05). CONCLUSIONS: Acute ingestion of caffeine is associated with sympathoadrenal activation and awareness of hypoglycemia at a glucose level not usually considered hypoglycemic. Our data suggest that individuals who ingest moderate amounts of caffeine may develop hypoglycemic symptoms if plasma glucose levels fall into the "low-normal" range, as might occur in the late postprandial period after ingestion of a large carbohydrate load.