Oral adherence monitoring using a breath test to supplement highly active antiretroviral therapy.

A breath-based adherence system to document ingestion of oral medications (e.g., HAART) was investigated. Specifically, the food additive 2-butanol, which can be easily packaged with a drug, is converted via alcohol dehydrogenase to the volatile metabolite 2-butanone that rapidly appears in breath, indicating adherence. In healthy adults using a portable sensor and GC-MS, the following experiments were performed: yield of 2-butanone in breath following ingestion of 2-butanol, adherence system accuracy, and potential interference of the adherence system by food or misplacement of 2-butanol on the tongue. During feasibility testing, every subject exhaled 2-butanone with 6.6 ± 1.5 min to peak concentrations of 548 ± 235 ppb following ingestion of 2-butanol (40 mg). ROC areas at 5 and 10 min were 0.95 (0.86-1.00) and 1.00 (1.00-1.00). Food did not interfere. Tongue application resulted in large concentrations of 2-butanol, but not 2-butanone. A breath test to provide definitive evidence of oral medication adherence appears technically feasible.

Adverse impact of temperature and humidity on blood glucose monitoring reliability: a pilot study.

BACKGROUND: The effect of temperature and humidity on the reliability of glucose monitoring systems (GMS) has not been well reported. We performed a study to determine if the effect of temperature and humidity on glucose values could be accurately predicted. METHODS: Eight GMS, including meter, strips, and glucose control solution (GCS), were placed in an environmental chamber for 50 days. Failure of the environmental chamber allowed for the serendipitous observation of the effect on glucose results of a range of temperature (54-87 degrees F) and humidity (49-100%) typically experienced by patients when performing self-monitoring of blood glucose. GCS was used to generate glucose results in triplicate for each meter daily. Temperature and humidity variations were recorded, and a linear model was generated to explain the variation in glucose results. RESULTS: Both temperature and humidity had significant effects on the reliability of nearly all GMS. The effect of temperature was greater than the effect of humidity. CONCLUSIONS: In this pilot study, GMS were unreliable at temperatures and humidity within the manufacturers' recommended limits. Such variations could result in clinically significant errors in diabetes management. Further studies are needed to confirm the potential inadequacies of GMS with multiple meters and real-time patient blood samples. Glucose meter manufacturers should develop systems that either are less affected by climate or adjust reported values based on ambient temperature and humidity.

Second-hand exposure to aerosolized intravenous anesthetics propofol and fentanyl may cause sensitization and subsequent opiate addiction among anesthesiologists and surgeons.

We hypothesize that aerosolization of anesthetics administered intravenously to patients in the operating room may be an unintended source of exposure to physicians. This may lead to inadvertent sensitization, which is associated with an increased risk for developing addiction. This may contribute to the over-representation of certain specialties among physicians with addiction. We retrospectively reviewed the de-identified demographic information of all licensed physicians treated for substance abuse in the State of Florida since 1980, to determine if medical specialty was associated with addiction in this group of individuals. Then, to identify the potential for exposure, two mass spectrometry assays were developed to detect two intravenously administered drugs, fentanyl and propofol, in air. Since 1980, 7.6% of licensed Florida physicians underwent treatment for addiction. Addiction in anesthesiologists was higher than expected. Opiate abuse was greater in anesthesiologists and surgeons compared to other specialties. Aerosolized fentanyl was detected in the air of the cardiothoracic operating room, in patients' expiratory circuits, and in the headspace above sharps boxes, but not in adjoining hallways. Aerosolized propofol was detected in the expirations of a patient undergoing transurethral prostatectomy. While access and stress may place anesthesiologists and surgeons at greater risk for substance abuse, an additional risk factor may be unintended occupational exposure to addictive drugs. This report provides preliminary evidence of detection of aerosolized intravenous anesthetics using two newly developed analytical methods. We conclude that the potential exists for chronic exposure to low levels of airborne intravenously administered drugs. Further studies are under way to determine the significance of this exposure.

Fentanyl abuse and dependence: further evidence for second hand exposure hypothesis.

We have proposed a novel hypothesis regarding the potential role of occupational or second-hand exposure in physician substance use, abuse, and addiction. While only 5.6% of licensed physicians in Florida are anesthesiologists, nearly 25% of physicians followed for substance abuse/dependence are anesthesiologists. When we sort by drug of choice, anesthesiologists have more opioid abuse and dependence than other physicians and appropriate controls. Abuse of one opioid, fentanyl, appears to be increasing and has been noted among the State of Florida's causes of opioid deaths. Fentanyl and sufentanyl are commonly administered highly potent opioid analgesics, as much as 80-800 times as potent as morphine. We have recent data from the State of Florida impaired physicians database, which has allowed us to categorize all fentanyl abusing and/ or dependent physicians. Just knowing that a physician abuses fentanyl gives you a good clue as to their specialty; 75% are anesthesiologists! While drug abuse researchers, oncologists and others who handle drugs of abuse everyday, have no greater incidence of opioid abuse or dependence, anesthesiologists are at the top of every list. Can this be due to just access and stress? We have proposed an alternative hypothesis of second hand exposure. To test this hypothesis, we developed a sensitive LC/MS/MS assay to measure the intravenous anesthetic and analgesic agents, propofol and fentanyl in air. Not only did we detect propofol and fentanyl in cardiovascular surgery operating room air, we also found the highest concentrations were close to the patient's mouth where anesthesiologists work for hours. Like tobacco, second hand opioid exposure can sensitize and change the brain making abuse, dependence and behavioral disorders more likely. Thus environmental exposure and sensitization may be an important risk factor in physician addiction. Second hand exposure may affect treatment outcome and explain anesthesiologist's inability to return to work in the operating room. We are developing an animal model for second hand exposure and additional studies of the operating room and cardiac anesthesiologists are underway.

Feasibility of a breath test for monitoring adherence to vaginal administration of antiretroviral microbicide gels.

Adherence to microbicide gel use is critical to optimizing effectiveness in preventing human immunodeficiency virus transmission. The authors hypothesized that ester taggants added to vaginal gels would generate exhaled alcohol and ketone metabolites and provide a "breath test" for vaginal gel use. This 2-arm (vaginal and dermal), randomized, participant-blinded, pilot study tested this hypothesis. On 8 visits, healthy women (n = 8) received intravaginal taggant (2-butyl acetate, 2-pentyl acetate, isopropyl butyrate, or 2-pentyl butyrate; 30 mg) formulated in hydroxyethylcellulose or tenofovir placebo gel. A second group (n = 4) of women received the same formulations administered dermally on the forearm to determine if skin administration might confound the system. Breath samples were collected using bags before and after taggant administration for 1 hour. Samples were measured using a miniature gas chromatograph and/or gas chromatography-mass spectroscopy for ester taggant, alcohol, and ketone concentrations. After vaginal administration, 2-butyl acetate, 2-pentyl acetate, and metabolites were observed in breath, whereas isopropyl butyrate, 2-pentyl butyrate, and metabolites were not. Some women reported self-resolving, mild burning (24/64 visits) with vaginal administration or a "bubblegum" taste (7/64 visits). No taggants or metabolites were detected following dermal application. A "breath test" for adherence to antiretroviral vaginal gel application appears physiologically and technically feasible.

Measurement of ethanol in gaseous breath using a miniature gas chromatograph.

We designed and built a novel, miniature gas chromatograph (mGC) to use exhaled breath to estimate blood ethanol concentrations that may offer GC quality sensitivity and specificity, but with portability, reduced size, and decreased cost. We hypothesized that the mGC would accurately estimate the serum ethanol concentration using exhaled breath. Human subjects (n = 8) were dosed with ethanol employing the Widmark criteria, targeting a blood concentration of 0.08 g/dL. Serum and breath samples were collected concurrently over an hour. Ethanol concentrations in serum were measured using a CLIA-approved laboratory. Ethanol concentrations in conventional breath were assayed using a calibrated mGC or Intoxilyzer 400PA. Data were analyzed using Bland-Altman analysis using serum concentrations as a "gold standard". For the mGC, the regression line (correlation coefficient), bias, and 95% limits of agreement were y = 1.013x - 0.009 (r = 0.91), -0.008 g/dL, and -0.031 to 0.016 g/dL, respectively, for 30 specimens. For the Intoxilyzer 400PA, the regression line (correlation coefficient), bias, and 95% limits of agreement were y = 0.599x + 0.008 (r = 0.86), -0.024 g/dL, and -0.049 to 0.002 g/dL, respectively, for 71 specimens with a large magnitude effect. We concluded that the mGC, using exhaled breath, performed well to estimate the serum ethanol concentrations.

Prototype of a breath-based analysis system for medication compliance monitoring.

Poor compliance to prescribed medication regimens in clinical trials continues to be a major obstacle to drug development success and cost reduction, and there is no gold standard technology that is cheap and effective to reliably measure drug compliance. This paper presents a new drug compliance scheme based on the detection of volatile markers in exhaled breath using a commercial off-the-shelf electronic nose (e-nose) system. A mouth air collection system was developed and interfaced with an e-nose for automated sampling and analysis of breath samples. Advanced signal processing techniques were used to develop classifiers for discriminating between blank breath and breaths masked with volatiles. The compliance monitor was able to achieve 100% detection rate in separating a volatile tagged breath from a blank breath, and 98% discrimination rate between volatile types. The proposed compliance monitor demonstrates a cheap and reliable method of measuring drug compliance in clinical trials.

Comparative testing of pulse oximeter probes.

UNLABELLED: The testing of pulse oximeter probes is generally limited to the integrity of the electrical circuit and does not include the optical properties of the probes. Few pulse oximeter testers evaluate the accuracy of both the monitor and the probe. We designed a study to compare the accuracy of nonproprietary probes (OSS Medical) designed for use with Nellcor, Datex-Ohmeda, and Criticare pulse oximeter monitors with that of their corresponding proprietary probes by using a commercial off-the-shelf pulse oximeter tester (Index). The Index pulse oximeter tester does include testing of the optical properties of the pulse oximeter probes. The pulse oximeter tester was given a controlled input that simulated acute apnea. Desaturation curves were automatically recorded from the pulse oximeter monitors with a data-collection computer. Comparisons between equivalent proprietary and nonproprietary probes were performed. Data were analyzed by using univariate and multivariate general linear model analysis. Five OSS Medical probe models were statistically better than the equivalent proprietary probes. The remainder of the probes were statistically similar. Comparative and simulation studies can have significant advantages over human studies because they are cost-effective, evaluate equipment in a clinically relevant scenario, and pose no risk to patients, but they are limited by the realism of the simulation. IMPLICATIONS: We studied the performance of pulse oximeter probes in a simulated environment. Our results show significant differences between some probes that affect the accuracy of measurement.