http://informahealthcare.com/jmt ISSN: 0309-1902 (print), 1464-522X (electronic) J Med Eng Technol, 2014; 38(5): 244–250 ! 2014 Informa UK Ltd. DOI: 10.3109/03091902.2014.902513
INNOVATION
Remote physiological monitoring of acute cocaine exposure J Med Eng Technol 2014.38:244-250. Downloaded from informahealthcare.com by Swinburne University of Technology on 12/31/14. For personal use only.
Jin H. Yoon*1,2, Ravi S. Shah1, Nicholas M. Arnoudse1,3, and Richard De La Garza II1 1
Department of Psychiatry, Baylor College of Medicine, Houston, TX, USA, 2Department of Psychiatry, University of Texas Medical School at Houston, Houston, TX, USA, and 3Texas A&M Health Science Center, College of Medicine, Houston, TX, USA
Abstract
Keywords
Cocaine exposure results in predictable cardiovascular changes. The current study evaluated the utility of BioHarness for assessing cardiovascular and respiratory changes following cocaine exposure (0 and 40 mg, IV) under controlled laboratory conditions. Participants (n ¼ 28) included non-treatment-seeking, cocaine-dependent volunteers. Results showed that BioHarness was able to detect a significant increase in heart rate following cocaine exposure, in comparison to placebo, (p50.0001). Additionally, heart rate values obtained using BioHarness were significantly correlated with those obtained from standard hospital equipment (p50.001). Significantly greater peak effects in breathing rate were also observed (p ¼ 0.04). BioHarness is a promising remote physiological monitoring device that can accurately assess exposure to cocaine in the laboratory and may provide additional advantages when compared to standard hospital equipment.
BioHarness, cardiovascular, cocaine, remote physiological monitoring, respiration
1. Introduction In 2010, 637,000 persons aged 12 or older reported using cocaine for the first time in the last 12 months in the US. Among those 12 or older, cocaine represents 1.5% of illicit drug use in the last month [1]. Despite the relatively low percentage of use, cocaine is a significant public health concern. In 2010, the leading illicit drug involved in emergency room visits was cocaine (488,101 visits or 41.7%) according to Drug Abuse Warning Network (DAWN) reports [2]. Cocaine increases the risk of morbidity and mortality [3,4] and is associated with a host of problems negatively affecting not only users, but society at large. Such consequences include but are not limited to overdose and premature death, crime, incarceration, violence, homelessness, drug-exposed neonates and increased risk of infectious disease [5–9]. When applied locally, cocaine acts as an anaesthetic, but, when applied systemically (i.e. non-medicinal or recreational use), it is a powerful sympathomimetic agent. Indeed, the cardiovascular effects of intravenous (IV) cocaine administered in the laboratory are well documented [10–15], although cardiovascular measures are assessed only at discrete timepoints using standard hospital equipment in these studies. Cocaine blocks the re-uptake and stimulates the release of catecholamines from central and peripheral stores [16–18], producing high levels of norepinephrine and dopamine in the
*Corresponding author. Email: [email protected]
History Received 7 October 2013 Revised 26 February 2014 Accepted 4 March 2014
intra-synaptic milieu and these effects mediate the dosedependent increases in heart rate and blood pressure following cocaine exposure [19]. These effects of cocaine may potentially serve as a biomarker of cocaine use, allowing clinicians and researchers to eventually wirelessly monitor cocaine use in real-time in the natural environment in a manner similar to SCRAMx for alcohol. SCRAMx provides objective measures of recent alcohol use and severity of use by measuring transdermal alcohol concentration. SCRAMx is already widely utilized by the judicial system in the US to monitor alcohol use and in some cases individuals wear it for years. Additionally, both the UK and Australia have begun assessing SCRAMx under similar contexts as well. To our knowledge, no studies have attempted to measure cardiovascular changes in the natural environment as an indicator of cocaine exposure. For example, recent cocaine use is typically assessed by measuring metabolites such as benzylecgonine in urine. However, this outcome do not provide pertinent information regarding how much cocaine was used and for how long. One method to accomplish this may be through remote physiological monitoring. Historically, remote physiological monitoring has been predominately associated with respiratory monitoring of patients with recent heart issues [20,21]. Such devices typically required surgical implantation. However, relatively recent advances in technology now provide access to a variety of non-surgical options in the form of small, portable and unobtrusive remote physiological devices. BioHarness (Zephyr, Annapolis, MD) is one such device and has been used to monitor the health of soldiers in combat,
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DOI: 10.3109/03091902.2014.902513
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emergency first responders and athletes during training. The validity and reliability of BioHarness measures has been evaluated under controlled laboratory conditions [22,23] and field-based assessments [24]. More recently, studies have begun to examine the clinical and research utility of BioHarness in hospital and exercise settings [25–28]. However, to our knowledge, no studies to date have utilized the BioHarness to assess changes associated with illicit exposure. The purpose of the current study was to conduct a preliminary evaluation of BioHarness for assessing cardiovascular and respiratory changes following administration of cocaine (0 and 40 mg, IV) among non-treatment-seeking, cocaine-dependent volunteers under controlled laboratory conditions.
Table 1. Summary of participant socio-demographic and drug-use characteristics (n ¼ 28). Cigarette use characteristics are based on the subset of participants who reported smoking (n ¼ 25). Error represents ± standard error of the mean (SEM).
2. Methods
physical exam and screening laboratory results demonstrating no contraindication to study participation; and (4) provide informed consent. Participants were excluded from the study for meeting any of the following exclusion criteria: (1) a current psychiatric disorder or meet DSM-IV criteria for dependence to drugs other than cocaine or nicotine; and (2) currently pregnant or breastfeeding. Participants tested positive for recent use for cocaine during the screening process (indicating that they were active users) and then provided a negative sample for cocaine in order to be eligible for admission and enrolment into the protocol. Participants were admitted to the Research Commons on an inpatient basis (day 0). Participants who failed to provide a negative sample were re-scheduled for admit on for another day.
2.1. Ethical approval All relevant ethical safeguards have been met in relation to participant protection. The study was conducted in accordance with the Helsinki Declaration for biomedical research involving humans and with the approval of the Bioethical Committees at the Baylor College of Medicine (i.e. Institutional Review Board) and the Michael E. DeBakey Veterans Affairs Medical Center (i.e. Research and Development Committee). Informed consent was obtained from each participant before beginning any study-related procedures. 2.2. Participants Participants (n ¼ 28) represent a sub-set of individuals who were enrolled in an ongoing parent study assessing the effects of rivastigimine and huperzine A on the reinforcing and subjective effects produced by cocaine (data to be presented elsewhere). As part of the parent study, infusion sessions (cocaine 0 and 40 mg, IV) were conducted prior to and after receiving medication. In the current study, we only examined data from the infusion session conducted prior to randomization, in order to eliminate any potential influence of the study medications on BioHarness outcome measures. Further details regarding the infusion session are provided below. As part of the parent study, participants were recruited through local newspaper, radio and internet advertisements. All participants completed an initial telephone screen in order to assess basic eligibility. Eligible candidates completed an in-person assessment at the Research Commons of the Michael E. DeBakey Veterans Affairs Medical Center. During the in-person interview, candidates received an explanation of the study purpose and requirements and were allowed to review, inquire about and sign the informed consent form. Table 1 provides a summary of participant socio-demographic and drug-use characteristics. In order to be enrolled into the study, participants had to meet the following inclusion criteria: (1) be fluent in English and between 18–55 years old; (2) meet DSM-IV criteria for cocaine-dependence as determined using the MINI Neuropsychiatric Interview [29]; (3) a medical history,
Variable Males (%) Caucasian (%) African-American (%) Age (years) Education (years) Cocaine use (years) Use in last 30 days Primary cocaine use is smoking (%) Report smoking cigarettes (%) Cigarette use (years) Cigarettes per day
Mean (±SEM) 78.6 28.6 67.9 41.4 ± 1.4 12.9 ± 0.4 16.8 ± 1.6 12.3 ± 1.4 87.5 89.3 19.6 ± 1.8 10.2 ± 1.3
2.3. Study design A double-blind, placebo-controlled, within-subject design was utilized to assess the cardiovascular and respiratory effects produced by 40 mg IV cocaine or saline/placebo, which were randomly administered on study day 1 as described below; these are the only data included in this manuscript. 2.4. Infusion session Cigarette smoking was not allowed 1 h before or during the infusion sessions. Infusion sessions were conducted at 10 am and 2 pm on the same day. The dose of cocaine (0 and 40 mg) was randomized between the morning and afternoon sessions. Participants were reclined in standard hospital beds for the duration of each infusion session. Electrocardiogram (ECG) readings were taken 15 min prior to the 10 am infusion session (T ¼ 15 min). Both infusions were administered by IV push over 2-min either by a nurse practitioner or study physician. 2.5. Physiological monitoring Cardiovascular and respiratory measures were continuously recorded during both infusion sessions using BioHarness 2. While other devices such as FITBIT are arguably less expensive or Actiheart provided greater battery life, BioHarness is arguably the most advanced device of its kind. BioHarness, which is 85 g and the size of a deck of
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cards (75 57 15 mm), was connected to an adjustable elastic harness that houses the ECG and respiration sensors. The harness was worn around the upper torso. The device itself houses a rechargeable battery, a 3-axis accelerometer and thermistor. Using these sensors, BioHarness is capable of measuring and recording heart rate, respiration, activity, body posture and surface body temperature. Single-lead ECG can also be transmitted via Bluetooth but it is not recorded on the device like the other measures. Given that participants were required to rest in hospital beds in the current study, only heart rate and respiration data are presented. However, the ability of BioHarness to measure these other variables is a benefit for follow-up studies assessing the effects of cocaine under more naturalistic conditions. Data measures were recorded once per second directly to the device and subsequently downloaded to a computer via USB in conjunction with the proprietary data analysis software (Zephyr Technology, Annapolis, MD). In order to ensure session time was synced with data recording, the BioHarness device was activated at the same time that the IV push was initiated. In addition to the BioHarness, heart rate and blood pressure were also assessed 15 min prior to infusions sessions (T ¼ 15 min) and at 5, 10, 15, 20 and 30 min during infusion sessions using standard hospital equipment (GE Medical Systems Information Technologies, Inc., Milwaukee, WI), which is how heart rate is typically monitored in these types of studies. 2.6. Medication Cocaine HCl was provided by a contractor for the National Institutes on Drug Abuse’s Drug Supply Programme (RTI International, Durham, NC). Cocaine, in sterile saline, was used for both IV infusions and prepared by the Michael E. DeBakey Veterans Affairs Medical Center Research Pharmacy. The Research Pharmacy was also responsible for randomizing the dose of cocaine to maintain the double-blind. 2.7. Other measures Cigarette smoking was assessed via self-report and breath carbon monoxide (CO) (Vitalograph Inc, Lenexa, KS) on day 0. Recent alcohol use was evaluated via breath-alcohol monitor (Alco-Sensor FST, Intoximeters, Inc, Saint Louis, MO) and illicit drug use was assessed via 5-Panel Drug Test Kits (Arham International, Inc., Greenville, SC), testing for cocaine, amphetamine, methamphetamine, THC and opiate metabolites. Additionally, cocaine use was assessed via timeline follow-back.
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these data for nine participants. These units were sent back to the manufacturer and replaced with no subsequent problems. Statistical analyses were conducted only on the data collected after the 2-min infusion was complete. Repeatedmeasures ANOVA was used to evaluate changes in heart rate and respiration as a function of cocaine dose (0 and 40 mg) and time (min). Peak effects were also evaluated for heart and respiration rates using paired t-test that compared cocaine to saline. A Pearson’s correlation was conducted to compare heart rate data obtained from standard hospital equipment and BioHarness at corresponding time-points. Data were analysed using StatView 5.0 (SAS Institute Inc., Cary, NC) and results were considered significant at alpha 50.05.
3. Results Importantly, the BioHarness device was well tolerated and there were no complaints reported. Participants were informed that wearing the BioHarness was voluntary, however no participants refused to wear them. Comparisons of heart rate and respiration obtained from BioHarness during infusion sessions are illustrated in Figure 1. Note that some measures required a certain amount of time before an accurate report could be generated by BioHarness. Therefore, all statistical analyses began at 2 min, once the IV push was completed, but all data are graphically presented. For heart rate (top), results from repeated-measures ANOVA revealed a significant effect of Drug (F1,54 ¼ 34.80, p50.001) and Time (F29,1566 ¼ 13.05, p50.0001) and a significant Drug Time interaction (F29,1566 ¼ 9.25, p50.0001). Likewise, peak-effects were greater in the 40 mg vs 0 mg condition (t27 ¼ 6.42, p50.0001). For respiration (bottom), repeated-measures ANOVA revealed no significant effect of Drug (F1,54 ¼ 3.36, p ¼ 0.08) or Time (F29,1044 ¼ 1.21, p ¼ 0.20) and there was no significant Drug Time interaction (F29,1044 ¼ 0.97, p ¼ 0.51). However, a significant increase in peak-effects was observed in the 40 mg vs 0 mg condition (t18 ¼ 2.28, p ¼ 0.04). Heart rate was measured with standard hospital equipment at 5, 10, 15, 20 and 30 min after the infusions. Thus, these data were compared to data measured with BioHarness at corresponding time-points. As revealed in Figure 2, there was a close correspondence between BioHarness and standard hospital equipment measures with few exceptions for both cocaine (top) and saline (bottom) sessions. In particular, correspondence was within 10 beats/min for 90.0% and within 5 beats/min for 68.6% of the values obtained by the two devices. Overall, a high degree of correlation was observed between the values obtained by the two devices (Figure 3; r ¼ 0.91, p50.001).
2.8. Data analyses Descriptive statistics were compiled for socio-demographic and drug use characteristics. In order to make the data obtained from BioHarness more manageable and minimize the influence of occasional spikes observed in the continuous data stream, median values for each of the data outputs were obtained from consecutive 1-min bins during the infusion sessions. Over the course of the study, some BioHarness units failed to record respiration rates, which resulted in a loss of
4. Discussion The primary purpose of the current study was to determine if cocaine-induced cardiovascular and respiratory changes could be accurately detected with a remote physiological monitoring device in a controlled laboratory setting. Our results show that BioHarness was capable of detecting significant differences in heart rate and respiration following acute administration of placebo vs 40 mg of cocaine.
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Figure 1. Changes in heart rate (top) and respiration (bottom) during saline (white) and cocaine (black) infusion sessions. The dashed line indicates when the 2-min IV push was completed (T ¼ 0). Inset bar graphs represent the average peak-effect observed for the cocaine (black) and saline (white) sessions. Astericks (*) indicate significantly higher values compared to saline at p50.05. Error bars represent ±1 SEM.
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Additionally, heart rates obtained via BioHarness were highly correlated with those obtained with standard hospital equipment. Importantly, the effects of cocaine reported here are similar to those previously observed in other laboratory-based studies [10–15]. The BioHarness system has two noteworthy benefits in regards to cardiovascular assessment. First, BioHarness is able to provide continuous measurement of heart rate. To our knowledge, no human studies in cocaine-addicted individuals have presented data using continuous heart rate measurements or, at the very least, presented data as frequently as once per minute as done in the current study. Additionally, these data are digitally recorded, allowing for alternative analyses (e.g. 30-s bins) as needed. This feature of Bioharness provides the ability to capture a clearer, more comprehensive and likely more accurate characterization of cocaine’s cardiovascular effects. These benefits may allow for more effective research designs requiring fewer subjects or the ability to detect more subtle effects. Second, since data is both digitally recorded
and transmitted in real time, researchers and clinicians are able to obtain more data with less effort. Third, BioHarness is significantly less expensive ($450) compared to standard hospital equipment ($7500) used in the current study. Such results speak favourably towards the use of BioHarness for accurately tracking cardiovascular changes in a research setting. In addition to heart rate, the current study also assessed changes in respiration following acute cocaine exposure. While results from repeated-measures ANOVA revealed no significant differences, a comparison of peak-effects showed significantly greater breathing rates following 40 mg vs 0 mg of cocaine. This finding highlights two important advantages of BioHarness. First, the simple fact that respiration was recorded provides additional and pertinent data. Second, we were able to reveal a significant effect that would have likely been missed if respiration was only assessed at discrete timepoints. In regards to the former point, it is worth highlighting that the BioHarness device is also capable of recording other
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Figure 2. Individual heart rates obtained from standard hospital equipment (grey) and BioHarness (white) at corresponding time-points during cocaine (top) and saline (bottom) infusion sessions. Corresponding heart rates between BioHarness and standard hospital equipment are connected by solid lines. In general, very high levels of agreement are observed, with few instances of large discrepancies between devices. Black circles represent mean heart rate values.
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measures such as surface body temperature and activity. These data are not shown since significant effects were not observed, which was expected given that participants were required to lay in standard hospital beds as part of the parent protocol. However, such measures would likely be of interest when assessing the effects of cocaine under more natural conditions. Like heart rate, these measures can also be continuously recorded digitally and be transmitted in realtime using blue-tooth or cellular technology. The ability to monitor additional measures can be used to potentially develop individualized BioHarness profiles that differentiate heart rate increases caused by cocaine exposure vs another activity such as exercise (running or walking on a treadmill) or smoking a cigarette. For example, in an ongoing study, we are currently assessing the effects of varying levels of exercise (sitting, walking and running) on cocaine use among treatment-seeking, cocaine-dependent volunteers. Sessions are conducted 3-times a week for 4 weeks. Our preliminary findings (data not shown) suggest that increased heart rate
caused by 40 mg of IV cocaine is 2.5-times greater than that observed following smoking of a single cigarette and comparable to heart rate increases observed with vigorous walking (despite the difference in activity level) [30]. Additionally, we propose that the BioHarness has the potential to assess cardiovascular changes associated with ad lib cocaine use in the users’ natural environment, which to our knowledge has yet to be done. Presumably, not only could the dose of cocaine used during ad lib conditions be higher, but it would not be uncommon for individuals to repeatedly dose themselves for an extended period of time. This brings up the possibility that a remote physiological monitoring device such as BioHarness may be able to capture medication effects that may not be detected using typical monitoring methods such as urine tests, which usually only indicate recent use. Limitations of the current study are that we only compared heart rate but not respiration with other validated measurement. However, respiration as measured by BioHarness has
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Figure 3. A scatterplot comparing heart rates obtained from BioHarness and standard hospital equipment. The dashed line represents values with perfect, one-to-one, correspondence.
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and the use of facilities at Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX. The current study was approved by the Baylor College of Medicine and Michael E. Debakey Veterans Affairs Medical Center Bioethical Committees. All participants provided informed consent and the study was conducted in accordance with the Declaration of Helsinkii. Jin Yoon developed the study design, conducted data analysis, and wrote the initial full draft of the manuscript. Richard De La Garza provided guidance during the course of the study a extensive feedback on the manuscript, and helped with the final data analysis which was incorporated into the final version. Ravi Shah and Nicholas Arnoudse were critical in conducting study-related procedures and assisted in data analyses. All authors read and provided comments and suggestions for the final version of the manuscript. The authors report no conflicts of interest.
References been observed to be moderately-to-highly correlated with a previously validated system in an exercise study [31]. In another study, BioHarness was observed to have a sensitivity of 91% in detecting tachypnea (420 breaths/min) when compared to criterion standard measurement. This was significantly superior to usual care measurement, which had a sensitivity of 23% [32]. Another limitation is that cocaine is known to increase in locomotor activity [33] and those data were recorded in the current study, but not shown, since no significant differences were observed between cocaine vs saline conditions. As participants in the current study were required to remain in their beds as part of the parent protocol, the data were not reflective to changes in locomotor activity if participants were allowed to move freely. However, the current results do provide a foundation upon which future studies allowing free movement can be compared (as we have done in the exercise study). Likewise, another limitation was that we only assessed one dose of cocaine (40 mg), as was originally proposed in the parent protocol. Therefore, the current study cannot speak to the efficacy of BioHarness in differentiating between different doses of cocaine exposure. Finally, as the current study was conducted in the context of an ongoing clinical trial, the selection and recruitment of participants may be potentially biased. However, the primary purpose of the current study was to assess the effects of cocaine on heart rate and respiration and our findings closely follow results from similar studies in the literature [10–15]. Overall, results of the current study suggest that BioHarness is a promising remote physiological monitoring device that can accurately assess exposure to cocaine in the laboratory and provide additional advantages such as continuous monitoring, ease of use, additional measures (e.g. activity, surface body temperature) and cost-effectiveness relative to standard hospital equipment.
Declaration of interest Grant funding was provided by the National Institute on Drug Abuse to Dr De La Garza (DA023624, DA023624-03S1). This material is the result of work supported with resources
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INNOVATION
Remote physiological monitoring of acute cocaine exposure J Med Eng Technol 2014.38:244-250. Downloaded from informahealthcare.com by Swinburne University of Technology on 12/31/14. For personal use only.
Jin H. Yoon*1,2, Ravi S. Shah1, Nicholas M. Arnoudse1,3, and Richard De La Garza II1 1
Department of Psychiatry, Baylor College of Medicine, Houston, TX, USA, 2Department of Psychiatry, University of Texas Medical School at Houston, Houston, TX, USA, and 3Texas A&M Health Science Center, College of Medicine, Houston, TX, USA
Abstract
Keywords
Cocaine exposure results in predictable cardiovascular changes. The current study evaluated the utility of BioHarness for assessing cardiovascular and respiratory changes following cocaine exposure (0 and 40 mg, IV) under controlled laboratory conditions. Participants (n ¼ 28) included non-treatment-seeking, cocaine-dependent volunteers. Results showed that BioHarness was able to detect a significant increase in heart rate following cocaine exposure, in comparison to placebo, (p50.0001). Additionally, heart rate values obtained using BioHarness were significantly correlated with those obtained from standard hospital equipment (p50.001). Significantly greater peak effects in breathing rate were also observed (p ¼ 0.04). BioHarness is a promising remote physiological monitoring device that can accurately assess exposure to cocaine in the laboratory and may provide additional advantages when compared to standard hospital equipment.
BioHarness, cardiovascular, cocaine, remote physiological monitoring, respiration
1. Introduction In 2010, 637,000 persons aged 12 or older reported using cocaine for the first time in the last 12 months in the US. Among those 12 or older, cocaine represents 1.5% of illicit drug use in the last month [1]. Despite the relatively low percentage of use, cocaine is a significant public health concern. In 2010, the leading illicit drug involved in emergency room visits was cocaine (488,101 visits or 41.7%) according to Drug Abuse Warning Network (DAWN) reports [2]. Cocaine increases the risk of morbidity and mortality [3,4] and is associated with a host of problems negatively affecting not only users, but society at large. Such consequences include but are not limited to overdose and premature death, crime, incarceration, violence, homelessness, drug-exposed neonates and increased risk of infectious disease [5–9]. When applied locally, cocaine acts as an anaesthetic, but, when applied systemically (i.e. non-medicinal or recreational use), it is a powerful sympathomimetic agent. Indeed, the cardiovascular effects of intravenous (IV) cocaine administered in the laboratory are well documented [10–15], although cardiovascular measures are assessed only at discrete timepoints using standard hospital equipment in these studies. Cocaine blocks the re-uptake and stimulates the release of catecholamines from central and peripheral stores [16–18], producing high levels of norepinephrine and dopamine in the
*Corresponding author. Email: [email protected]
History Received 7 October 2013 Revised 26 February 2014 Accepted 4 March 2014
intra-synaptic milieu and these effects mediate the dosedependent increases in heart rate and blood pressure following cocaine exposure [19]. These effects of cocaine may potentially serve as a biomarker of cocaine use, allowing clinicians and researchers to eventually wirelessly monitor cocaine use in real-time in the natural environment in a manner similar to SCRAMx for alcohol. SCRAMx provides objective measures of recent alcohol use and severity of use by measuring transdermal alcohol concentration. SCRAMx is already widely utilized by the judicial system in the US to monitor alcohol use and in some cases individuals wear it for years. Additionally, both the UK and Australia have begun assessing SCRAMx under similar contexts as well. To our knowledge, no studies have attempted to measure cardiovascular changes in the natural environment as an indicator of cocaine exposure. For example, recent cocaine use is typically assessed by measuring metabolites such as benzylecgonine in urine. However, this outcome do not provide pertinent information regarding how much cocaine was used and for how long. One method to accomplish this may be through remote physiological monitoring. Historically, remote physiological monitoring has been predominately associated with respiratory monitoring of patients with recent heart issues [20,21]. Such devices typically required surgical implantation. However, relatively recent advances in technology now provide access to a variety of non-surgical options in the form of small, portable and unobtrusive remote physiological devices. BioHarness (Zephyr, Annapolis, MD) is one such device and has been used to monitor the health of soldiers in combat,
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DOI: 10.3109/03091902.2014.902513
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emergency first responders and athletes during training. The validity and reliability of BioHarness measures has been evaluated under controlled laboratory conditions [22,23] and field-based assessments [24]. More recently, studies have begun to examine the clinical and research utility of BioHarness in hospital and exercise settings [25–28]. However, to our knowledge, no studies to date have utilized the BioHarness to assess changes associated with illicit exposure. The purpose of the current study was to conduct a preliminary evaluation of BioHarness for assessing cardiovascular and respiratory changes following administration of cocaine (0 and 40 mg, IV) among non-treatment-seeking, cocaine-dependent volunteers under controlled laboratory conditions.
Table 1. Summary of participant socio-demographic and drug-use characteristics (n ¼ 28). Cigarette use characteristics are based on the subset of participants who reported smoking (n ¼ 25). Error represents ± standard error of the mean (SEM).
2. Methods
physical exam and screening laboratory results demonstrating no contraindication to study participation; and (4) provide informed consent. Participants were excluded from the study for meeting any of the following exclusion criteria: (1) a current psychiatric disorder or meet DSM-IV criteria for dependence to drugs other than cocaine or nicotine; and (2) currently pregnant or breastfeeding. Participants tested positive for recent use for cocaine during the screening process (indicating that they were active users) and then provided a negative sample for cocaine in order to be eligible for admission and enrolment into the protocol. Participants were admitted to the Research Commons on an inpatient basis (day 0). Participants who failed to provide a negative sample were re-scheduled for admit on for another day.
2.1. Ethical approval All relevant ethical safeguards have been met in relation to participant protection. The study was conducted in accordance with the Helsinki Declaration for biomedical research involving humans and with the approval of the Bioethical Committees at the Baylor College of Medicine (i.e. Institutional Review Board) and the Michael E. DeBakey Veterans Affairs Medical Center (i.e. Research and Development Committee). Informed consent was obtained from each participant before beginning any study-related procedures. 2.2. Participants Participants (n ¼ 28) represent a sub-set of individuals who were enrolled in an ongoing parent study assessing the effects of rivastigimine and huperzine A on the reinforcing and subjective effects produced by cocaine (data to be presented elsewhere). As part of the parent study, infusion sessions (cocaine 0 and 40 mg, IV) were conducted prior to and after receiving medication. In the current study, we only examined data from the infusion session conducted prior to randomization, in order to eliminate any potential influence of the study medications on BioHarness outcome measures. Further details regarding the infusion session are provided below. As part of the parent study, participants were recruited through local newspaper, radio and internet advertisements. All participants completed an initial telephone screen in order to assess basic eligibility. Eligible candidates completed an in-person assessment at the Research Commons of the Michael E. DeBakey Veterans Affairs Medical Center. During the in-person interview, candidates received an explanation of the study purpose and requirements and were allowed to review, inquire about and sign the informed consent form. Table 1 provides a summary of participant socio-demographic and drug-use characteristics. In order to be enrolled into the study, participants had to meet the following inclusion criteria: (1) be fluent in English and between 18–55 years old; (2) meet DSM-IV criteria for cocaine-dependence as determined using the MINI Neuropsychiatric Interview [29]; (3) a medical history,
Variable Males (%) Caucasian (%) African-American (%) Age (years) Education (years) Cocaine use (years) Use in last 30 days Primary cocaine use is smoking (%) Report smoking cigarettes (%) Cigarette use (years) Cigarettes per day
Mean (±SEM) 78.6 28.6 67.9 41.4 ± 1.4 12.9 ± 0.4 16.8 ± 1.6 12.3 ± 1.4 87.5 89.3 19.6 ± 1.8 10.2 ± 1.3
2.3. Study design A double-blind, placebo-controlled, within-subject design was utilized to assess the cardiovascular and respiratory effects produced by 40 mg IV cocaine or saline/placebo, which were randomly administered on study day 1 as described below; these are the only data included in this manuscript. 2.4. Infusion session Cigarette smoking was not allowed 1 h before or during the infusion sessions. Infusion sessions were conducted at 10 am and 2 pm on the same day. The dose of cocaine (0 and 40 mg) was randomized between the morning and afternoon sessions. Participants were reclined in standard hospital beds for the duration of each infusion session. Electrocardiogram (ECG) readings were taken 15 min prior to the 10 am infusion session (T ¼ 15 min). Both infusions were administered by IV push over 2-min either by a nurse practitioner or study physician. 2.5. Physiological monitoring Cardiovascular and respiratory measures were continuously recorded during both infusion sessions using BioHarness 2. While other devices such as FITBIT are arguably less expensive or Actiheart provided greater battery life, BioHarness is arguably the most advanced device of its kind. BioHarness, which is 85 g and the size of a deck of
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cards (75 57 15 mm), was connected to an adjustable elastic harness that houses the ECG and respiration sensors. The harness was worn around the upper torso. The device itself houses a rechargeable battery, a 3-axis accelerometer and thermistor. Using these sensors, BioHarness is capable of measuring and recording heart rate, respiration, activity, body posture and surface body temperature. Single-lead ECG can also be transmitted via Bluetooth but it is not recorded on the device like the other measures. Given that participants were required to rest in hospital beds in the current study, only heart rate and respiration data are presented. However, the ability of BioHarness to measure these other variables is a benefit for follow-up studies assessing the effects of cocaine under more naturalistic conditions. Data measures were recorded once per second directly to the device and subsequently downloaded to a computer via USB in conjunction with the proprietary data analysis software (Zephyr Technology, Annapolis, MD). In order to ensure session time was synced with data recording, the BioHarness device was activated at the same time that the IV push was initiated. In addition to the BioHarness, heart rate and blood pressure were also assessed 15 min prior to infusions sessions (T ¼ 15 min) and at 5, 10, 15, 20 and 30 min during infusion sessions using standard hospital equipment (GE Medical Systems Information Technologies, Inc., Milwaukee, WI), which is how heart rate is typically monitored in these types of studies. 2.6. Medication Cocaine HCl was provided by a contractor for the National Institutes on Drug Abuse’s Drug Supply Programme (RTI International, Durham, NC). Cocaine, in sterile saline, was used for both IV infusions and prepared by the Michael E. DeBakey Veterans Affairs Medical Center Research Pharmacy. The Research Pharmacy was also responsible for randomizing the dose of cocaine to maintain the double-blind. 2.7. Other measures Cigarette smoking was assessed via self-report and breath carbon monoxide (CO) (Vitalograph Inc, Lenexa, KS) on day 0. Recent alcohol use was evaluated via breath-alcohol monitor (Alco-Sensor FST, Intoximeters, Inc, Saint Louis, MO) and illicit drug use was assessed via 5-Panel Drug Test Kits (Arham International, Inc., Greenville, SC), testing for cocaine, amphetamine, methamphetamine, THC and opiate metabolites. Additionally, cocaine use was assessed via timeline follow-back.
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these data for nine participants. These units were sent back to the manufacturer and replaced with no subsequent problems. Statistical analyses were conducted only on the data collected after the 2-min infusion was complete. Repeatedmeasures ANOVA was used to evaluate changes in heart rate and respiration as a function of cocaine dose (0 and 40 mg) and time (min). Peak effects were also evaluated for heart and respiration rates using paired t-test that compared cocaine to saline. A Pearson’s correlation was conducted to compare heart rate data obtained from standard hospital equipment and BioHarness at corresponding time-points. Data were analysed using StatView 5.0 (SAS Institute Inc., Cary, NC) and results were considered significant at alpha 50.05.
3. Results Importantly, the BioHarness device was well tolerated and there were no complaints reported. Participants were informed that wearing the BioHarness was voluntary, however no participants refused to wear them. Comparisons of heart rate and respiration obtained from BioHarness during infusion sessions are illustrated in Figure 1. Note that some measures required a certain amount of time before an accurate report could be generated by BioHarness. Therefore, all statistical analyses began at 2 min, once the IV push was completed, but all data are graphically presented. For heart rate (top), results from repeated-measures ANOVA revealed a significant effect of Drug (F1,54 ¼ 34.80, p50.001) and Time (F29,1566 ¼ 13.05, p50.0001) and a significant Drug Time interaction (F29,1566 ¼ 9.25, p50.0001). Likewise, peak-effects were greater in the 40 mg vs 0 mg condition (t27 ¼ 6.42, p50.0001). For respiration (bottom), repeated-measures ANOVA revealed no significant effect of Drug (F1,54 ¼ 3.36, p ¼ 0.08) or Time (F29,1044 ¼ 1.21, p ¼ 0.20) and there was no significant Drug Time interaction (F29,1044 ¼ 0.97, p ¼ 0.51). However, a significant increase in peak-effects was observed in the 40 mg vs 0 mg condition (t18 ¼ 2.28, p ¼ 0.04). Heart rate was measured with standard hospital equipment at 5, 10, 15, 20 and 30 min after the infusions. Thus, these data were compared to data measured with BioHarness at corresponding time-points. As revealed in Figure 2, there was a close correspondence between BioHarness and standard hospital equipment measures with few exceptions for both cocaine (top) and saline (bottom) sessions. In particular, correspondence was within 10 beats/min for 90.0% and within 5 beats/min for 68.6% of the values obtained by the two devices. Overall, a high degree of correlation was observed between the values obtained by the two devices (Figure 3; r ¼ 0.91, p50.001).
2.8. Data analyses Descriptive statistics were compiled for socio-demographic and drug use characteristics. In order to make the data obtained from BioHarness more manageable and minimize the influence of occasional spikes observed in the continuous data stream, median values for each of the data outputs were obtained from consecutive 1-min bins during the infusion sessions. Over the course of the study, some BioHarness units failed to record respiration rates, which resulted in a loss of
4. Discussion The primary purpose of the current study was to determine if cocaine-induced cardiovascular and respiratory changes could be accurately detected with a remote physiological monitoring device in a controlled laboratory setting. Our results show that BioHarness was capable of detecting significant differences in heart rate and respiration following acute administration of placebo vs 40 mg of cocaine.
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Figure 1. Changes in heart rate (top) and respiration (bottom) during saline (white) and cocaine (black) infusion sessions. The dashed line indicates when the 2-min IV push was completed (T ¼ 0). Inset bar graphs represent the average peak-effect observed for the cocaine (black) and saline (white) sessions. Astericks (*) indicate significantly higher values compared to saline at p50.05. Error bars represent ±1 SEM.
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Additionally, heart rates obtained via BioHarness were highly correlated with those obtained with standard hospital equipment. Importantly, the effects of cocaine reported here are similar to those previously observed in other laboratory-based studies [10–15]. The BioHarness system has two noteworthy benefits in regards to cardiovascular assessment. First, BioHarness is able to provide continuous measurement of heart rate. To our knowledge, no human studies in cocaine-addicted individuals have presented data using continuous heart rate measurements or, at the very least, presented data as frequently as once per minute as done in the current study. Additionally, these data are digitally recorded, allowing for alternative analyses (e.g. 30-s bins) as needed. This feature of Bioharness provides the ability to capture a clearer, more comprehensive and likely more accurate characterization of cocaine’s cardiovascular effects. These benefits may allow for more effective research designs requiring fewer subjects or the ability to detect more subtle effects. Second, since data is both digitally recorded
and transmitted in real time, researchers and clinicians are able to obtain more data with less effort. Third, BioHarness is significantly less expensive ($450) compared to standard hospital equipment ($7500) used in the current study. Such results speak favourably towards the use of BioHarness for accurately tracking cardiovascular changes in a research setting. In addition to heart rate, the current study also assessed changes in respiration following acute cocaine exposure. While results from repeated-measures ANOVA revealed no significant differences, a comparison of peak-effects showed significantly greater breathing rates following 40 mg vs 0 mg of cocaine. This finding highlights two important advantages of BioHarness. First, the simple fact that respiration was recorded provides additional and pertinent data. Second, we were able to reveal a significant effect that would have likely been missed if respiration was only assessed at discrete timepoints. In regards to the former point, it is worth highlighting that the BioHarness device is also capable of recording other
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Figure 2. Individual heart rates obtained from standard hospital equipment (grey) and BioHarness (white) at corresponding time-points during cocaine (top) and saline (bottom) infusion sessions. Corresponding heart rates between BioHarness and standard hospital equipment are connected by solid lines. In general, very high levels of agreement are observed, with few instances of large discrepancies between devices. Black circles represent mean heart rate values.
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measures such as surface body temperature and activity. These data are not shown since significant effects were not observed, which was expected given that participants were required to lay in standard hospital beds as part of the parent protocol. However, such measures would likely be of interest when assessing the effects of cocaine under more natural conditions. Like heart rate, these measures can also be continuously recorded digitally and be transmitted in realtime using blue-tooth or cellular technology. The ability to monitor additional measures can be used to potentially develop individualized BioHarness profiles that differentiate heart rate increases caused by cocaine exposure vs another activity such as exercise (running or walking on a treadmill) or smoking a cigarette. For example, in an ongoing study, we are currently assessing the effects of varying levels of exercise (sitting, walking and running) on cocaine use among treatment-seeking, cocaine-dependent volunteers. Sessions are conducted 3-times a week for 4 weeks. Our preliminary findings (data not shown) suggest that increased heart rate
caused by 40 mg of IV cocaine is 2.5-times greater than that observed following smoking of a single cigarette and comparable to heart rate increases observed with vigorous walking (despite the difference in activity level) [30]. Additionally, we propose that the BioHarness has the potential to assess cardiovascular changes associated with ad lib cocaine use in the users’ natural environment, which to our knowledge has yet to be done. Presumably, not only could the dose of cocaine used during ad lib conditions be higher, but it would not be uncommon for individuals to repeatedly dose themselves for an extended period of time. This brings up the possibility that a remote physiological monitoring device such as BioHarness may be able to capture medication effects that may not be detected using typical monitoring methods such as urine tests, which usually only indicate recent use. Limitations of the current study are that we only compared heart rate but not respiration with other validated measurement. However, respiration as measured by BioHarness has
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Figure 3. A scatterplot comparing heart rates obtained from BioHarness and standard hospital equipment. The dashed line represents values with perfect, one-to-one, correspondence.
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and the use of facilities at Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX. The current study was approved by the Baylor College of Medicine and Michael E. Debakey Veterans Affairs Medical Center Bioethical Committees. All participants provided informed consent and the study was conducted in accordance with the Declaration of Helsinkii. Jin Yoon developed the study design, conducted data analysis, and wrote the initial full draft of the manuscript. Richard De La Garza provided guidance during the course of the study a extensive feedback on the manuscript, and helped with the final data analysis which was incorporated into the final version. Ravi Shah and Nicholas Arnoudse were critical in conducting study-related procedures and assisted in data analyses. All authors read and provided comments and suggestions for the final version of the manuscript. The authors report no conflicts of interest.
References been observed to be moderately-to-highly correlated with a previously validated system in an exercise study [31]. In another study, BioHarness was observed to have a sensitivity of 91% in detecting tachypnea (420 breaths/min) when compared to criterion standard measurement. This was significantly superior to usual care measurement, which had a sensitivity of 23% [32]. Another limitation is that cocaine is known to increase in locomotor activity [33] and those data were recorded in the current study, but not shown, since no significant differences were observed between cocaine vs saline conditions. As participants in the current study were required to remain in their beds as part of the parent protocol, the data were not reflective to changes in locomotor activity if participants were allowed to move freely. However, the current results do provide a foundation upon which future studies allowing free movement can be compared (as we have done in the exercise study). Likewise, another limitation was that we only assessed one dose of cocaine (40 mg), as was originally proposed in the parent protocol. Therefore, the current study cannot speak to the efficacy of BioHarness in differentiating between different doses of cocaine exposure. Finally, as the current study was conducted in the context of an ongoing clinical trial, the selection and recruitment of participants may be potentially biased. However, the primary purpose of the current study was to assess the effects of cocaine on heart rate and respiration and our findings closely follow results from similar studies in the literature [10–15]. Overall, results of the current study suggest that BioHarness is a promising remote physiological monitoring device that can accurately assess exposure to cocaine in the laboratory and provide additional advantages such as continuous monitoring, ease of use, additional measures (e.g. activity, surface body temperature) and cost-effectiveness relative to standard hospital equipment.
Declaration of interest Grant funding was provided by the National Institute on Drug Abuse to Dr De La Garza (DA023624, DA023624-03S1). This material is the result of work supported with resources
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