U.S. patent application number 13/246436 was filed with the patent office on 2012-01-19 for system and method for monitoring health using exhaled breath.
Invention is credited to David G. Bjoraker, Richard J. Melker.
Application Number | 20120016252 13/246436 |
Document ID | / |
Family ID | 38327829 |
Filed Date | 2012-01-19 |
United States Patent
Application |
20120016252 |
Kind Code |
A1 |
Melker; Richard J. ; et
al. |
January 19, 2012 |
SYSTEM AND METHOD FOR MONITORING HEALTH USING EXHALED BREATH
Abstract
The present invention includes systems and methods for
monitoring endogenous compound concentration in blood by detecting
markers, such as odors, upon exhalation by a patient, wherein such
markers are the endogenous compound itself or result from the
endogenous compound. In the case of olfactory markers, the
invention preferably utilizes electronic sensor technology, such as
the commercial devices referred to as "artificial" or "electronic"
noses or tongues, to non-invasively monitor endogenous compound
levels in blood. The invention further includes a reporting system
capable of tracking endogenous compound concentrations in blood
(remote or proximate locations) and providing the necessary alerts
with regard to emergent or harmful conditions in a patient.
Inventors: |
Melker; Richard J.;
(Gainesville, FL) ; Bjoraker; David G.;
(Gainesville, FL) |
Family ID: |
38327829 |
Appl. No.: |
13/246436 |
Filed: |
September 27, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11301911 |
Dec 13, 2005 |
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13246436 |
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PCT/US05/06355 |
Feb 28, 2005 |
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11301911 |
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10788501 |
Feb 26, 2004 |
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PCT/US05/06355 |
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10178877 |
Jun 24, 2002 |
6981947 |
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10788501 |
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10054619 |
Jan 22, 2002 |
7104963 |
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10178877 |
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Current U.S.
Class: |
600/532 |
Current CPC
Class: |
A61B 5/082 20130101;
A61M 16/0841 20140204; A61M 16/026 20170801; A61M 2016/1035
20130101; A61M 2230/435 20130101; A61M 2016/0036 20130101; A61M
16/01 20130101; A61M 2230/437 20130101; A61B 5/14532 20130101; A61B
5/14546 20130101; G16H 20/17 20180101; A61M 16/22 20130101; A61M
2202/0486 20130101; A61M 2205/80 20130101; G01N 33/497 20130101;
A61M 16/18 20130101; A61M 2230/43 20130101; G16H 20/40 20180101;
A61M 2205/3584 20130101; A61M 2205/3561 20130101; A61B 5/411
20130101; A61M 2205/18 20130101; A61M 2202/0275 20130101; A61B
5/4821 20130101; A61M 16/1045 20130101; A61M 16/0051 20130101; A61B
5/7267 20130101; A61M 2205/3553 20130101; A61M 2205/52 20130101;
G16H 40/63 20180101; A61M 16/0808 20130101; A61M 2230/432
20130101 |
Class at
Publication: |
600/532 |
International
Class: |
A61B 5/08 20060101
A61B005/08 |
Claims
1-19. (canceled)
20. A method for detecting an anesthetic agent in the breath of a
subject receiving said anesthetic agent intravenously which
comprises: capturing at least one breath sample or a portion of a
breath sample of said subject and subjecting said breath sample or
portion thereof to analysis by a breath analyzer for analyzing the
patient's breath for concentration of at least one substance,
selected from the group consisting of the active anesthetic agent
itself or a metabolite thereof.
21. The method according to claim 20 wherein said breath analyzer
comprises a collector for sampling the patient's expired breath, a
sensor for analyzing the breath for concentration of at least one
substance indicative of the anesthetic agent concentration, a
processor for calculating the effect of the agent based on the
concentration and determining depth of anesthesia.
22. The method according to claim 21 wherein the sensor is selected
from semiconductor gas sensor technology, surface acoustic wave gas
sensor technology or conductive polymer gas sensor technology.
23. The method according to claim 20, further comprising
respiratory phase sensor technology for determining a specific
phase of the respiratory cycle from which the sample of breath is
collected.
24. The method according to claim 23 wherein said respiratory phase
sensor technology is selected from the group consisting of:
viscosity sensors; flow sensors; pressure sensors; humidity
sensors; temperature sensors; and gas sensors.
25. The method of claim 24, wherein said respiratory phase sensor
technology is selected from the group consisting of: CO.sub.2
sensors; O.sub.2 sensors; and NO sensors.
26. The method of claim 24, wherein the sample of breath is
collected from the initial phase or end-tidal phase.
27. The method of claim 20 wherein said anesthetic agent is
propofol.
Description
CROSS-REFERENCE TO A RELATED APPLICATION
[0001] This application is a continuation application of co-pending
U.S. patent application Ser. No. 11/301,911, filed Dec. 13, 2005;
which is a continuation-in-part of co-pending International
Application No. PCT/US2005/006355, filed Feb. 28, 2005, which is a
continuation-in-part of co-pending U.S. patent application Ser. No.
10/788,501, filed Feb. 26, 2004, which is a continuation-in-part of
co-pending U.S. patent application Ser. No. 10/178,877, filed Jun.
24, 2002, which is a continuation-in-part of co-pending U.S. patent
application Ser. No. 10/054,619, filed Jan. 22, 2002. All of the
afore-mentioned applications are hereby incorporated by reference
herein in their entirety, including any figures, tables, or
drawings.
FIELD OF INVENTION
[0002] The present invention relates to non-invasive monitoring of
substance/compound concentrations in blood; and more particularly,
to a system and method for the determination of drug concentrations
and endogenous compounds in blood utilizing a breath detection
system.
BACKGROUND INFORMATION
[0003] Breath is a unique bodily fluid. Unlike blood, urine, feces,
saliva, sweat and other bodily fluids, it is available on a breath
to breath and therefore continuous basis. It is readily available
for sampling non-invasively and because the lung receives all of
the blood flow from the right side of the heart, measurements of
analytes/compounds in breath correlate strongly and reproducibly
with blood concentration. It is less likely to be associated with
the transfer of serious infections than other bodily fluids and
collection of samples is straightforward and painless.
[0004] Further, exhaled breath contains 100% humidity at 37.degree.
C. (body temperature), thus it can be considered an aerosol. If the
temperature of the collected sample is maintained at 37.degree. C.
or higher it will remain in this state and can be treated as a gas
for compounds that are insoluble in water or readily diffuse out of
water. In this instance, sensors designed to work with gaseous
media would be preferable. For compounds that are highly water
soluble and likely to remain in solution, the exhaled breath sample
can be collected as a condensate when cooled. This liquid can then
be analyzed with sensors that are designed for liquid-based
analyses. Compounds likely to be detectable in the gas phase
typically are lipophilic (hydrophobic) such as the intravenous
anesthetic agent, propofol, while compounds likely to be detected
in the liquid phase are hydrophilic, such as glucose, lactic acid
and perhaps even electrolytes. Thus an exhaled breath sample can be
handled to produce a gaseous matrix for certain compounds and
sensors, and a liquid matrix for others. In instances where it is
desirable to detect more than one compound (e.g., detection of
hydrophilic and hydrophobic molecules in the breath), the sample
can be split and a portion maintained as a gas and a portion
condensed as a liquid.
[0005] An example of the unique characteristic of breath is the
correlation between blood concentrations of drugs, both licit and
illicit, and their concentration in the breath. The concentration
of a drug in a patient's body is generally regulated both by the
amount of drug ingested by the patient over a given time period, or
the dosing regimen, and the rate at which the drug is metabolized
and eliminated by the body.
[0006] Historically, pharmaceutical compositions were delivered to
patients according to standard doses based on the patient's weight.
In the early 1970s, it was discovered with epileptic patients that
pharmaceutical treatment with dosages adjusted according to blood
concentration of the drug was far more efficient and demonstrated
better seizure control and fewer side effects than with dosages
adjusted according to patient weight.
[0007] It is now generally accepted that with many medications, it
is necessary to monitor the concentration in the blood stream in
order to ensure optimal, therapeutic drug effect (therapeutic drug
monitoring [TDM]). Medications are ineffective if blood
concentration levels are too low. Moreover, certain medications are
toxic to the body when concentration levels in the blood are too
high. It would also be valuable to have a means for monitoring drug
concentration in blood for medications that do not require constant
monitoring. By monitoring blood serum drug levels, medication
dosage can be individualized within a therapeutically effective
range.
[0008] For example, patients prescribed tricyclic (or tetracyclic)
antidepressants (TCAs) require frequent monitoring of blood levels.
TCAs work by inhibiting serotonin and norepinephrine reuptake into
the synaptic cleft. This group includes among its members the
tricyclics: amitriptyline, imipramine, nortriptyline, and
clomipramine, and the tetracyclics maprotiline and amoxapine.
Although highly effective for the treatment of depression, TCAs
have a high incidence of side effects, some of which may be
life-threatening, especially when blood concentrations are too
high. Consequently, TCAs have been largely replaced by serotonin
reuptake inhibitors (SSRIs) for treatment of depression. In
addition to the toxic effects of TCAs due to inhibition of sodium
and potassium channels, which occurs primarily in the heart and
brain, TCAs can also cause side effects due inhibition of
norepinephrine reuptake and elevated norepinephrine levels. The
latter can cause sedation, manic episodes, profuse sweating,
palpitations, increased blood pressure, tachycardia, twitches and
tremors of the tongue or upper extremities, and weight gain.
[0009] Although SSRIs are no more, or may actually be slightly less
effective than TCAs, TCAs are less attractive because they are more
toxic than SSRIs and pose a greater threat of overdose. A TCA
overdose results in central nervous system and cardiovascular
toxicity making the relative risk of death by overdose with a TCA
2.5 to 8.5 times that with the commercially available SSRI
fluoxetine. The greater danger with TCA is that side effects, as
well as constant blood sampling, will persuade the patient to
discontinue treatment. Studies indicate that patients taking a
classical antidepressant (TCA or MAOI) are three times as likely to
drop out of treatment due to side effects and constant monitoring
as patients taking SSRIs. Interestingly, recent studies have shown
that some SSRIs (and a similar group of drugs--selective
norepinephrine uptake inhibitors [SNRIs]) have a "cut-off" below
which the drugs are far less effective than at doses above the
"cut-off", but that this can only be determined by blood
concentrations, not dosage due to large inter-patient variability.
Thus, although drug manufacturers have tried to develop medications
so "one dose fits all", TDM might be applied more readily and
improve drug effectiveness while reducing side effects and overdose
if a simple and efficacious method of determining blood
concentrations were available. Exhaled breath drug monitoring holds
such promise.
[0010] Thus, many therapeutically effective medications that
require TDM are less likely to be prescribed by physicians in view
of inconvenience in constant blood sampling and lack of patient
compliance. Further, in the present era of cost-effective
healthcare, considerations of prescription costs have become the
primary issue for all aspects of laboratory operation.
Individualization of drug therapy contributes to cost-effective
patient management through detection and elimination of drug side
effects; detection of unusual metabolism and adjustment of dosage
based on individual metabolism; and detection of unusual metabolism
and adjustment of dosage based on the effects on disease.
[0011] Drug level testing is especially important in patients being
administered medications where the margin of safety between
therapeutic effectiveness and toxicity is narrow (low therapeutic
index). In addition to TCAs, other drugs such as procainamide or
digoxin, which are used to treat arrhythmias and heart failure;
dilantin or valproic acid, which are used to treat seizures;
gentamicin or amikacin, which are antibiotics used to treat
infections and lithium which is a mainstay of treatment for dipolar
disease, are examples of medications having a narrow margin of
safety and therapeutic effectiveness with administration.
[0012] Currently available tests for TDM are invasive, difficult to
administer, frequently require the patient to be in a health care
setting (versus home), and/or require an extended period of time
for analysis. Such tests are generally complex, requiring a
laboratory to perform the analysis. Healthcare providers' offices
rarely possess appropriate testing technology to analyze blood
samples and must therefore send the samples to an off-site
laboratory or refer the patient to the laboratory to have their
blood drawn, which results in an extended time period for analysis.
In the process of transfer to and from a laboratory, there is a
greater likelihood that samples will be lost or mishandled, or that
the incorrect results are provided to the healthcare provider,
which could be detrimental to the patient's health and well-being.
Further, those on-site test devices that are presently available
for assessing drug concentration levels in blood are expensive.
Reference laboratories using sophisticated techniques such as gas
chromatography-mass spectrometry typically conduct complex and
expensive toxicological analyses to determine the quantity of a
medication.
[0013] A further problem with present methods of TDM is that the
concentration in the blood may not correlate with the concentration
at the "effect site". It has been found that the concentration of
drug in the blood may not directly reflect the concentrations at
the cellular or receptor level, where drugs exert their biological
effects. The pharmacodynamics and pharmacokinetics (PD/PK) of many
drugs also exhibit wide inter- and intra-individual variation. The
drug concentration at the site of action relates best with clinical
responses; however, it is typically difficult or impossible to
measure. Although plasma drug concentrations often provide an
informative and feasible measurement for defining the
pharmacodynamics of medications, they do not consistently provide
an accurate report of drug disposition in a patient.
[0014] For medications appearing in breath, it appears that the
concentration that appears in breath correlates best with the
"free" drug in the body, that is, the drug available for the
therapeutic effect, thus the concentration in exhaled breath is an
excellent measure of the drug fraction that is most important for
the healthcare provider to know in order to make informed decisions
about dose regimens. Although the fraction of drug bound to protein
and whole blood is essentially constant over a wide range of plasma
and blood concentrations (i.e., free drug concentrations can be
deduced from plasma and whole blood concentrations under normal
circumstances) for the vast majority of subjects, various
pathological circumstances can arise that make this correlation in
a patient problematic (e.g., drug-drug interactions, massive blood
loss and transfusion, protein losing syndromes, etc).
[0015] There are generally four processes by which drug disposition
takes place: absorption, distribution, metabolism, and excretion.
Absorption of a drug is generally dictated by route of drug
administration (i.e., intravenous (IV), intramuscular (IM),
subcutaneous (SC), topical, inhalation, oral, rectal, sublingual,
etc.); drug factors (i.e., lipid solubility); as well as host
factors (i.e., gastric emptying time). Alterations in drug
absorption may affect the therapeutic effectiveness of the
drug.
[0016] Factors related to drug distribution include body fat,
protein binding, and membranes. Because lipid soluble drugs tend to
dissolve in fat, drugs can build up to very high, potentially
toxic, levels in a patient with a high percentage of body fat.
There are several drugs available that have a high affinity for
serum proteins. Protein binding limits the therapeutic
effectiveness of the drug. Membranes such as the blood brain
barrier (BBB) sometimes make it difficult for the drug to be
properly distributed.
[0017] All tissues in the body can contribute to the metabolism of
a drug. For example, the liver, kidney, lungs, skin, brain, and gut
can all be involved in metabolizing a drug, although it most cases
metabolism in the liver predominates. Physiologically, metabolism
can increase the activity, decrease the activity, or have no effect
on the activity of a drug. Because metabolism of a drug differs
from one patient to another, the dosage required for a drug can
differ from patient to patient.
[0018] Routes of drug elimination include the kidney, liver,
gastrointestinal tract, lungs, sweat, lacrimal fluid, and milk. All
of these processes (absorption, distribution, metabolism, and
excretion), which can occur at varying times after drug
administration, affect the level of pharmacologically effective
drug in a patient. Thus, current methods for analyzing a blood
sample to assess plasma drug concentrations only provides a
snapshot for defining the pharmacodynamics of a drug and does not
consistently provide an accurate report of drug disposition in a
patient.
[0019] An example of the value of continuous or frequent breath
monitor of drug concentrations is during anesthesia.
Anesthesiologists use many sophisticated and expensive devices to
monitor the vital signs of and to provide respiratory and
cardiovascular support for patients undergoing surgical procedures.
Such monitors provide the anesthesiologist with information about
the patient's physiologic status and verify that the appropriate
concentrations of delivered gases are administered.
[0020] Anesthesia can be achieved by using either inhalational or
intravenous (IV) anesthetics, or combination of both. Inhalation
anesthetics are substances that are brought into the body via the
lungs and are distributed with the blood into the different
tissues. The main target of inhalation anesthetics (or so-called
volatile anesthetics) is the brain. Some commonly used inhalational
anesthetics include enflurane, halothane, isoflurane, sevoflurane,
desflurane, and nitrous oxide. Older volatile anesthetics include
ether, chloroform, and methoxyflurane. Intravenous (IV) anesthetics
frequently used clinically are barbiturates, opioids,
benzodiazepines, ketamine, etomidate, and propofol. Currently,
however, volatile anesthetics are seldom used alone. Rather, a
combination of inhalation anesthetics and intravenous drugs are
administered, in a process known as "balanced anesthesia." During
administration of balanced anesthesia, for example, opioids are
administered for analgesia, along with neuromuscular blockers for
relaxation, anesthetic vapors for unconsciousness and
benzodiazepines for amnesia.
Inhalational Anesthetics
[0021] With inhalation agents, the concentration of drug delivered
is metered and the variation between patients in the depth of
anesthesia resulting from known inhaled concentrations of agents is
relatively narrow, permitting the anesthesiologist to confidently
assume a particular level of anesthesia based on the concentration
of anesthetic gas delivered.
[0022] Monitors used during the administration of inhalational
anesthesia generally display inspired and exhaled gas
concentrations. Most use side-stream monitoring wherein gas samples
are aspirated from the breathing circuit through long tubing lines.
A water trap, desiccant and/or filter may be used to remove water
vapor and condensation from the sample. Gas samples are aspirated
into the monitor at a low rate to minimize the amount of gas
removed from the breathing circuit and, therefore, the patient's
tidal volume. These gas monitors continuously sample and measure
inspired and exhaled (end-tidal) concentrations of respiratory
gases. The monitored gases are both the physiologic gases found in
the exhaled breath of patients (oxygen, carbon dioxide, and
nitrogen), as well as those administered to the patient by the
anesthesiologist in order to induce and maintain analgesia and
anesthesia.
[0023] There are a number of techniques to monitor respiratory
gases, including mass spectroscopy, Raman spectroscopy, IR--light
spectroscopy, IR--photo acoustics, piezoelectric (U.S. Pat. No.
4,399,686 to Kindlund), resonance, polarography, fuel cell,
paramagnetic analysis, and magnetoacoustics. Infrared detector
systems are most commonly used systems to monitor gas
concentrations.
[0024] A major disadvantage of conventional gas monitors is that
they only determine the concentrations of certain types of gases or
a limited number of gases and most do not measure N.sub.2 nor any
medications delivered by other routes (i.e., intravenously). These
monitors are also fragile, expensive and require frequent
calibration and maintenance. For this reason, not all purchasers of
anesthesia machines buy anesthesia gas monitors and therefore, rely
on anesthesia gas vaporizers to control anesthetic gas
concentration. Unfortunately, these vaporizers frequently go out of
calibration and the anesthesiologist may administer too much or too
little anesthesia.
Intravenous (IV) Anesthetics
[0025] Another method of providing anesthesia includes IV
anesthetics. At present, a major impediment to the wider use of IV
anesthetics, rather than inhaled anesthetics, has been the
inability to precisely determine the quantity of drug required to
provide a sufficient "depth of anesthesia" without accumulating an
excessive amount.
[0026] Propofol, for example, is an agent that is widely used as a
short acting IV anesthetic. Its physiochemical properties are
hydrophobic and volatile. It is usually administered as a constant
IV infusion in order to deliver and maintain a specific plasma
concentration. Although the metabolism is mainly hepatic and rapid,
there is significant inter-patient variability in the plasma
concentration achieved with a known dose. However, the depth of
anesthesia for a known plasma concentration is far less variable
and it is therefore highly desirable to be able to evaluate plasma
(or ideally free, unbound drug) concentrations in real time to
accurately maintain anesthetic efficacy. ["A Simple Method for
Detecting Plasma Propofol," Akihiko Fujita, MD, et al., Feb. 25,
2000, International Anesthesia Research Society]. The authors
describe a means to measure plasma (free) rather than total
propofol using headspace -GC with solid phase microextraction. This
is preferable since plasma (free) propofol is responsible for the
anesthetic effect. Prior methods of monitoring propofol
concentration in blood include high-performance liquid
chromatography (HPLC) and gas chromatography (GC). It has been
reported that 97%-99% of propofol is bound with albumin and red
blood cells after IV injection, and the remainder exists in blood
as a free type. HPLC and GC detect the total propofol
concentration, which does not correlate as well with the anesthetic
effect as the plasma propofol level. Studies of exhaled breath
propofol concentrations show an excellent correlation with plasma
(free) concentration and therefore are likely to better predict the
effect of the drug.
[0027] Propofol may also be monitored in urine. Metabolic processes
control the clearance of propofol from the body, with the liver
being the principal eliminating organ. ["First-pass Uptake and
Pulmonary Clearance of Propofol," Jette Kuipers, et al.,
Anesthesiology, V91, No. 6, December 1999]. In a study, 88% of the
dose of propofol was recovered in urine as hydroxylated and
conjugated metabolites.
[0028] The aim of any dosage regimen in anesthesia is to titrate
the delivery rate of a drug to achieve the desired pharmacologic
effect for any individual patient while minimizing the unwanted
toxic side effects. Certain drugs such as propofol, alfentanil and
remifentanil have a close relationship between free blood
concentration and effect; thus, the administration of the drug can
be improved by basing the dosage regimen on the pharmacokinetics of
the agent. [Kenny, Gavin, Target-Controlled
Infusions--Pharmacokinetics and Pharmacodynamic Variations,
http://www.anaesthesiologie.med.unierlangen.de/esctaic97/a_Kenny.htm].
Target controlled infusion (TCI) is one means for administering an
IV anesthesia agent using a computer to control the infusion pump.
Using a computer with a pharmacokinetic program permits control of
a desired plasma concentration of an agent, such as propofol. The
systems do not sample the blood in real-time, but use previously
acquired population PD/PK parameters to provide a best estimate of
the predicted blood concentration. However, even if TCI systems
produced the exact target concentrations of blood concentration, it
would not be possible to know if that concentration was
satisfactory for each individual patient and for different points
during the surgical procedure.
[0029] Among the technologies used to process and monitor
electrical brain signal is BIS (Bispectral Index Monitor)
monitoring of the EEG. It is an indirect monitor of depth of
anesthesia. The BIS monitor translates EEG waves from the brain
into a single number--depicting the depth of anesthesia on a scale
from 1 to 100. In addition, neural networks have been used to
classify sedation concentration from the power spectrum of the EEG
signal. However, these technologies are costly and not entirely
predictive.
[0030] Artificial neural networks have also been developed which
use the patient's age, weight, heart rate, respiratory rate, and
blood pressure to predict depth of anesthesia. The networks
integrate physiological signals and extract meaningful information.
Certain systems use mid-latency auditory evoked potentials (MLAEP)
which are wavelet transformed and fed into an artificial neural
network for classification in determining the anesthesia depth.
[Depth of Anesthesia Estimating & Propofol Delivery System, by
Johnnie W. Huang, et al., Aug. 1, 1996,
http://www.rpi.edu/.about.royr/roy_descpt.html].
[0031] An apparatus and method for total intravenous anesthesia
delivery is also disclosed in U.S. Pat. No. 6,186,977 to Andrews.
This patent describes a method in which the patient is monitored
using at least one of electrocardiogram (EKG), a blood oxygen
monitor, a blood carbon dioxide monitor, inspiration/expiration
oxygen, inspiration/expiration carbon dioxide, a blood pressure
monitor, a pulse rate monitor, a respiration rate monitor, and a
patient temperature monitor.
Combination Inhalational and Intravenous (IV) Anesthetics
[0032] As previously stated, anesthesia can be achieved by using
either inhalational or IV anesthetics, or combination of both
("balanced anesthesia"). Monitoring techniques for inhalational and
IV anesthesia differ because of the nature of the drug delivery.
Monitors for inhalational anesthesia delivery generally comprise
systems that monitor the breathing circuit. Monitors for IV
anesthesia generally comprise physiologic monitoring of the patient
rather than monitoring the concentration of the drug in the blood.
Based on this bifurcation of monitoring systems, anesthesiologists
must utilize separate systems when switching between drug delivery
methods or when utilizing a combination of methods.
[0033] Accordingly, there is a need in the art for methods to
improve therapeutic drug monitoring (such as IV and/or inhalational
delivered anesthetics) and the monitoring of endogenous compounds
related to health conditions that are non-invasive, speedy, and
inexpensive in administration. There is also a need for a
monitoring system capable of continuously monitoring drug
concentration levels (to assess drug disposition) and of
continuously monitoring endogenous compound levels (such as glucose
levels in exhaled breath). Further, there is a need for
non-invasive monitoring systems capable of being used at remote
locations and/or non-laboratory settings to monitor the therapeutic
efficacy of the drug or to assess patient health by monitoring
endogenous compounds present in exhaled breath.
Other Applications for Intermittent or Continuous Breath
Monitoring
[0034] In addition to monitoring blood concentrations of licit
medications using exhaled breath either intermittently or
continuously, exhaled breath measurements can be used to monitor a
wide range of other compounds and correlate them with blood
concentrations. For instance, breath can be used to determine
whether an individual has used an illicit drug. Likewise, breath
can be used to determine blood glucose concentrations, thus freeing
diabetics from having to perform frequent blood sticks to determine
their glucose concentrations. Breath glucose can also be measured
continuously in the operating room during surgery and/or the
intensive care units since tight glucose control has been shown to
improve wound healing and reduce the incidence of post-operative
infection.
[0035] The breath may also be an excellent media to diagnose acute
and/or chronic "stress" in humans, which can occur in various
settings (e.g., injured humans stressed due to disease, accidents,
or military actions, etc.; or non-injured humans stressed due to
extreme/excessive exercise or environments that require an
extremely high level of vigilance such as the longterm operation of
military aircraft under battlefield conditions). Various stress
markers including those suggesting inflammation, which may appear
in the breath, include but are not limited to concentrations of
lactic acid, ketones, cortisol, testosterone, ATP, ADP, AMP,
adenosine, prostaglandins (e.g., PGF2a), leukotrienes, cytokines,
interleukins, melatonin, 6-sulfatoxymelatonin, HIF-1.alpha., HSP70
and myogenic regulatory factors.
[0036] For example, lactic acid in blood is an indicator of the
severity of shock (hypoperfusion) and numerous disease states. It
is usually measured intermittently by drawing blood samples.
Intermittent or continuous breath measurements of lactic acid could
revolutionize the care of critically ill patients in the operating
room or intensive care unit. Numerous other compounds can also
indicate disease states appear in breath. The ability to monitor
these compounds in real-time, either intermittently or continuously
without the delay of having to send specimens to a laboratory,
could dramatically improve the care of hospitalized or even home
care or ambulatory patients.
SUMMARY OF THE INVENTION
[0037] The present invention solves the needs in the art by
providing a method and apparatus for non-invasive monitoring of
substance/compound concentration in blood, and, more particularly
to systems and methods for non-invasive monitoring of endogenous
compound and/or therapeutic drug concentration in blood. The
systems and methods of the present invention utilize sensors that
can analyze a patient's exhaled breath components to detect,
quantify, and/or trend concentrations of endogenous compound
markers in exhaled breath, which correlate to the endogenous
compound concentration in the patient's body, in particular in
blood. Endogenous compound markers detectable in exhaled breath can
be the endogenous compounds themselves or substances derived from
the endogenous compounds (such as metabolites of endogenous
compounds).
[0038] In other embodiments, systems and methods are provided for
the detection, quantification, and trending of delivered
therapeutic drug concentration utilizing sensors that can analyze a
patient's exhaled breath components. Such systems and methods
include: at least one supply of at least one therapeutic drug for
delivery to a patient; and an expired gas sensor for analyzing the
patient's breath for concentration of at least one drug or marker
indicative of therapeutic drugs in the patient's bloodstream,
wherein the sensor provides a signal to indicate marker
concentration that corresponds to therapeutic drug concentration in
the patient's bloodstream. The methods of the subject invention
include the steps of measuring the concentration of one or more
therapeutic markers in a patient's exhaled breath. These measured
markers can then be used to quantify the concentration of
therapeutic drug(s) in the patient's blood as well as trend the
delivered drug, and ultimately determine the PD/PK of the drug.
[0039] In one embodiment, the subject invention contemplates
administering to a patient a therapeutic drug, wherein the
therapeutic drug contains a therapeutic drug marker that is
detectable in exhaled breath by a sensor of the subject invention.
In certain embodiments of the invention, the therapeutic drug
marker is the therapeutic drug itself or a metabolite of the drug,
which is detectable in exhaled breath. As contemplated herein, the
blood concentration of the therapeutic drug and the exhaled
concentration of the therapeutic drug marker are substantially
proportional. By using a sensor of the subject invention for
analyzing the concentration of a therapeutic drug marker in exhaled
breath, which substantially corresponds to the blood concentration
of a therapeutic drug, the present invention enables non-invasive,
continuous monitoring of therapeutic drug blood concentration.
[0040] One particular application of the present invention is for
predicting the depth of anesthesia utilizing a breath detection
system. It has been shown that there is a good correlation between
blood concentration of anesthetic agents (e.g., propofol) and depth
of anesthesia. In a related embodiment, the present invention
provides methods and apparatuses for the detection, quantitation,
and trending of intravenous (IV) and/or inhalational delivered drug
concentration utilizing a breath detection system.
[0041] Since there is no direct on-line method to continuously
monitor blood concentration of agents, in that the blood and
exhaled concentration are relatively proportional, the method of
the present invention will provide a more predictive method to
monitor depth of anesthesia by monitoring breath rather than
blood.
[0042] In one embodiment, the method of the invention includes
measuring both exhaled breath concentrations of IV and inhalational
anesthetics, and also the circuit concentration of inhalational
anesthetic gases. The method includes the steps of both measuring
the circuit concentration and measuring the concentration of one or
more components in the patient's exhaled breath. These measured
components can then be used to quantitate the concentration of
anesthetics in the circuit (such as halothane, isoflurane,
sevoflurane, desflurane and enflurane) and to detect, quantitate,
and trend the delivered drug, and ultimately determine depth of
anesthesia.
[0043] The method of the present invention may also be used to
monitor perflubron concentration. Emulsified perflubron is one of a
class of compounds used to deliver oxygen in anemic patients as a
substitute for hemoglobin.
[0044] In a preferred embodiment of the subject invention, a
specific phase of the respiratory cycle, namely the end-tidal
portion of exhaled breath, is sampled to detect the concentration
of a therapeutic drug marker as a measure of drug concentration
levels in blood.
[0045] In accordance with the subject invention, a sensor can be
selected from a variety of systems that have been developed for use
in collecting and monitoring exhaled breath components,
particularly specific gases. For example, the sensor of the subject
invention can be selected from those described in U.S. Pat. Nos.
6,010,459; 5,081,871; 5,042,501; 4,202,352; 5,971,937, and
4,734,777. Further, sensor systems having computerized data
analysis components can also be used in the subject invention
(i.e., U.S. Pat. No. 4,796,639).
[0046] Sensors of the subject invention can also include commercial
devices commonly known as "artificial" or "electronic" noses or
tongues to non-invasively monitor therapeutic drug blood
concentration. Sensors of the subject invention can include, but
are not limited to, metal-insulator-metal ensemble (MIME) sensors,
cross-reactive optical microsensor arrays, fluorescent polymer
films, corona devices, surface enhanced Raman spectroscopy (SERS),
semiconductor gas sensor technology, conductive polymer gas sensor
technology, surface acoustic wave gas sensor technology,
functionalized microcantilevers and immunoassays.
[0047] In certain embodiments, the systems of the subject invention
include a reporting system capable of tracking marker concentration
(remote or proximate) and providing the necessary outputs,
controls, and alerts.
[0048] In one example, a sensor of the subject invention would be
used either in a clinical setting or patient-based location during
delivery of a therapeutic drug to monitor drug concentration in
blood by measuring therapeutic drug marker concentration in patient
exhaled breath. Moreover, exhaled breath detection using the
systems and methods of the present invention may enable accurate
evaluation of PD/PK for drug studies and/or in individual
patients.
[0049] The preferred device of the present invention includes two
parts: 1) the breathing circuit sensor and 2) the expired breath
sensor. The breathing circuit sensor includes a sensor having a
surface exposed to the gas stream and comprises a material
selectively absorptive of a chemical vapor or group of vapors. The
expired breath sensor includes a sensor having a surface exposed to
the patient's breath and/or airway and also comprises a material
selectively absorptive of a chemical vapor or group of vapors.
These sensors are coupled to an analyzer(s) for producing an
electrical signal indicative of the presence of the vapors. The
analyzer is further operative to determine the approximate
concentration of the vapors, display results, signal alarms,
etc.
[0050] In one embodiment, the device detects a target substance
(anesthetic gases and/or physiologic gases) in both the breathing
circuit and in expired breath using the following components: (a)
surface-acoustic wave sensor(s) capable of detecting the presence
of the target substance, wherein the sensor responds to the target
substance by a shift in the resonant frequency; (b) oscillator
circuit(s) having the sensor as an active feedback element; (c)
frequency counter(s) in communication with the oscillator
circuit(s) to measure oscillation frequency which corresponds to
resonant frequency of the sensor(s); and (d) a processor for
comparing the oscillation frequency with a previously measured
oscillation frequency of the target substance and determining
presence and concentration of the target substance therefrom.
[0051] In another embodiment, the device detects a target marker
(anesthetic gases and/or physiologic gases) in both the breathing
circuit and in expired breath using the following components: (a)
sensor(s) having an array of polymers capable of detecting the
presence of the target substance, wherein the sensor(s) responds to
the target substance by changing the resistance in each polymer
resulting in a pattern change in the sensor array; (b) a processor
for receiving the change in resistance, comparing the change in
resistance with a previously measured change in resistance, and
identifying the presence of the target substance from the pattern
change and the concentration of the substance from the amplitude.
The processor can include a neural network for comparing the change
in resistance with a previously measured change in resistance to
find a best match.
[0052] In another embodiment, the invention includes a method of
monitoring a patient during administration of anesthesia wherein
the patient is connected to a breathing circuit. In the method, a
first sensor is exposed to inspired gases, wherein at least one
inspired gas is an anesthetic agent; a second sensor is exposed to
expired gases; one or more target substances is detected with the
sensors; and concentration of the target substances is
determined.
[0053] In another embodiment, the invention includes an anesthetic
agent delivery system for delivering balanced anesthesia to a
patient through a breathing circuit and an IV which includes: (1)
an anesthetic gas supply having a controller for controlling the
amount of volatile anesthetic agent provided by the supply to the
breathing circuit; (2) an IV anesthetic agent supply having a
controller for controlling the amount of IV anesthetic agent
administered to the patient intravenously; (3) an inspired gas
analyzer for analyzing the concentration of anesthetic gas in the
breathing circuit; (4) an expired gas analyzer for analyzing the
patient's breath for concentration of at least one substance
indicative of anesthetic agent concentrations in the patient's
bloodstream that provides at least one signal to indicate the
anesthetic agent concentration delivered to the patient; and (5) a
system controller connected to each of the anesthetic supplies
which receives the signal and controls the amount of anesthetic
agents administered based on the signal.
[0054] In still a further embodiment, the invention includes an
apparatus for administering balanced anesthesia to a patient
including: (1) at least one supply of at least one intravenous
anesthetic agent; (2) intravenous delivery means for controllably
delivering the intravenous anesthetic agent to the patent; (3) at
least one supply of at least one inhalational anesthetic agent; (4)
a breathing circuit for delivery of said inhalational anesthetic
agent; (5) an inspired gas analyzer for analyzing gas in the
breathing circuit for the inhalational agent; (6) an expired gas
analyzer for analyzing the patient's breath for concentration of at
least one substance indicative of anesthetic agents in the
patient's bloodstream that provides a signal to indicate anesthetic
agent concentration delivered to the patient; (7) a system
controller connected to the intravenous delivery means which
receives the signal and controls the amount of anesthetic agent
based on the signal; and (8) a system controller connected to the
breathing circuit which receives the signal and controls the amount
of anesthetic agent based on the signal.
[0055] Another embodiment includes a device for detecting target
substances in a breathing circuit including: (1) at least one
surface-acoustic wave sensor capable of detecting the presence of
the target substance in inspired and/or expired gas, wherein the
sensor responds to the target substance by a shift in the resonant
frequency; (2) an oscillator circuit having the sensor as an active
feedback element; (3) a frequency counter in communication with the
oscillator circuit to measure oscillation frequency which
corresponds to resonant frequency of the sensor; and (4) a
processor for comparing the oscillation frequency with a previously
measured oscillation frequency of the target substance and
determining presence and concentration of the target substance
therefrom.
[0056] Another embodiment includes a device for detecting target
substances in a breathing circuit including: (1) a sensor having an
array of polymers capable of detecting the presence of the target
substance in inspired and/or expired gas, wherein the sensor
responds to the target substance by changing the resistance in each
polymer resulting in a pattern change in the sensor array; (2) a
processor for receiving the change in resistance, comparing the
change in resistance with a previously measured change in
resistance, and identifying the presence of the target substance
from the pattern change and the concentration of the substance from
the amplitude.
[0057] Moreover, sensing antibiotics with the exhaled breath
detection method of the present invention, would allow for use of
the method as a surrogate for blood antibiotic concentration. This
would also be true for a wide range of medications for which blood
concentration would be valuable. Exhaled breath detection using the
method of the present invention may also evaluate PD/PK for both
drug studies and in individual patients. Moreover, it may be used
to sense endogenous compounds such as glucose, ketones, lactic acid
and electrolytes, which are normally found in blood.
[0058] The invention also includes a method of determining the rate
of washout of a target substance (such as anesthetic gases or other
drugs) by (a) obtaining a sample of expired breath at a first
interval; (b) analyzing the sample with sensor technology to
determine the concentration of the substance; (c) obtaining at
least one additional sample of expired breath at a later interval;
(d) analyzing said additional sample with sensor technology to
determine the concentration of said substance; and (e) comparing
the concentration of the first sample with the concentration of
additional samples to determine rate of washout of the target
substance.
[0059] Therefore, it is an object of the present invention to
non-invasively monitor therapeutic drug blood or endogenous
compound concentration by monitoring the concentration of
therapeutic drug marker or endogenous compound marker,
respectively, present in exhaled breath using sensors that analyze
markers in exhaled breath.
[0060] In one embodiment of the invention, monitoring of
therapeutic drug marker and/or endogenous compound marker
concentration is conducted continuously using a system of the
invention. In another embodiment of the invention, monitoring of
therapeutic drug marker and/or endogenous compound marker
concentration is conducted intermittently using a system of the
invention.
[0061] Another object of the present invention is to non-invasively
monitor substance concentration (such as endogenous compound blood
concentration) by monitoring substance or substance marker
concentrations in exhaled breath using sensors that analyze exhaled
breath components. Exhaled breath detection using the method of the
present invention may be used to sense endogenous compounds such as
glucose, ketones, lactic acid, and electrolytes that are normally
found in blood. These compounds could be monitored intermittently
or continuously in a wide range of environments. Small handheld
portable equipment could be used by patients in the home, at work,
in nursing homes or while they are ambulatory, while other devices
could be designed for continuous monitoring in the operating room,
intensive care units and in other areas of hospitals or other
healthcare facilities such as clinics, doctors offices where this
capability would be valuable.
[0062] A resulting advantage of the subject invention is the
ability to monitor such substance and/or therapeutic drug
concentration in a more cost effective and frequent manner than
current methods, which involve drawing blood samples and
transferring the blood samples to a laboratory facility for
analysis. In addition, the subject invention enables the user to
immediately and continuously monitor therapeutic drug and/or
endogenous compound concentration levels in a patient's blood
stream to monitor patient health, whether in a clinical setting or
via known forms of communication if the patient is located at a
remote location. The systems and methods of the subject invention
can be used in place of the invasive practice of drawing blood to
measure concentration.
[0063] The invention will now be described, by way of example and
not by way of limitation, with reference to the accompanying sheets
of drawings and other objects, features and advantages of the
invention will be apparent from the following detailed disclosure
and from the appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0064] FIG. 1 shows a capnogram of a single respiratory cycle and a
capnogram of several breaths from a patient with obstructive lung
disease.
[0065] FIG. 2 shows a gas sensor chip, which may be utilized as the
sensor for the present invention.
[0066] FIG. 3 shows the FT-IR signal for propofol.
[0067] FIG. 4 shows an example of measuring expired breath of a
patient utilizing a sensor.
[0068] FIG. 5a shows the characteristic signature of propofol.
[0069] FIG. 5b shows a propofol relative breath concentration
profile of a patient.
[0070] FIG. 6a shows the unique signature of Isoflurane derived
from a SAW sensor.
[0071] FIG. 6b shows the unique signature of Sevoflurane derived
from a SAW sensor.
[0072] FIGS. 7a and 7b illustrate the blood (7a) and breath (7b)
concentrations of glucose over time after the ingestion of a 100 gm
glucose solution.
DETAILED DESCRIPTION OF THE INVENTION
[0073] The present invention provides systems and methods for
non-invasive monitoring of substances in blood by analyzing a
patient's exhaled breath components. Substances in blood that can
be monitored by analyzing exhaled breath components include, but
are not limited to, endogenous compounds, such as glucose, ketones,
lactic acid, prostaglandins, leukotrienes, cortisol, and
electrolytes, and therapeutic drugs, including IV and/or inhalation
anesthetics for detecting the depth of anesthesia and a wide range
of licit and illicit drugs.
[0074] In certain embodiments, the breath concentration of at least
one endogenous compound marker is analyzed using sensor technology.
The endogenous compound marker can be the endogenous compound
itself or derived from the endogenous compound, such as a
metabolite of the endogenous compound. According to the present
invention, the concentration of an endogenous compound marker in
breath is proportionate to the concentration of the corresponding
endogenous compound in blood. Thus, based on the breath
concentration of endogenous compound markers, the concentration of
the corresponding endogenous compounds in a patient can be
non-invasively and efficiently assessed.
DEFINITIONS
[0075] As used herein, the term "therapeutic drug" or "drug" refers
to a substance used in the diagnosis, treatment, or prevention of a
disease or condition, wherein the concentration of the therapeutic
drug in a patient's blood stream must be monitored to ensure the
therapeutic drug level is within a clinically effective range. A
therapeutic drug of the present invention includes anesthetic
agents.
[0076] Throughout this disclosure, a "marker" is defined as a
substance that is detected by means of its physical or chemical
properties using a sensor of the subject invention. According to
the subject invention, an endogenous compound marker is either the
endogenous compound itself or a compound derived directly from the
endogenous compound (such as a metabolite of the endogenous
compound). Therapeutic drug markers are the therapeutic drug
itself, or derived either directly from the therapeutic drug (such
as a metabolite) or from an additive combined with the therapeutic
drug prior to administration. Such therapeutic drug markers
preferably include olfactory markers (odors) as well as other
substances and compounds, which may be detectable by sensors of the
subject invention.
[0077] Halogenated compounds (i.e. fluorinated drugs or markers)
hold particular promise as they are readily highly volatile, safe
for human consumption at doses required, and are readily detected
in exhaled breath with several types of portable Freon leak
detectors. Some of these compounds are used as propellants for
delivery of drugs via the pulmonary route, such as metered dose
inhalers and therefore are known to be safe and are FDA approved.
The technologies most often used to detect Freon leaks include:
Negative Ion Capture, Heated Sensor/Ceramic Semiconductor, Infrared
Absorption, and TIF TIFXP-1A Negative Corona Leak Detector. Many
drugs are fluorinated and metabolites are often extremely volatile
and detectable in exhaled breath. Numerous such compounds are
available that could be used as markers and could be added as
excipients during the manufacture of drugs
[0078] A "patient," as used herein, describes an organism,
including mammals, from which exhaled breath samples are collected
in accordance with the present invention. Mammalian species that
benefit from the disclosed systems and methods for therapeutic drug
monitoring include, and are not limited to, apes, chimpanzees,
orangutans, humans, monkeys; and domesticated animals (e.g., pets)
such as dogs, cats, mice, rats, guinea pigs, and hamsters.
[0079] According to the subject invention, substances detectable in
exhaled breath using the systems and methods of the invention
include those that may be found in breath gas, breath condensate
(liquid phase), respiratory droplet, breath evaporate, water vapor,
and/or bronchial or alveolar aerosols.
[0080] The term "pharmacodynamics," as used herein, refers to the
interaction (biochemical and physiological) of a therapeutic drug
with constituents of a patient body as well as the mechanisms of
drug action on the patient body (i.e., drug effect on body).
[0081] As used herein, the term "pharmacokinetics" refers to the
mathematical characterization of interactions between normal
physiological processes and a therapeutic drug over time (i.e.,
body effect on drug). Certain physiological processes (absorption,
distribution, metabolism, and elimination) will affect the ability
of a drug to provide a desired therapeutic effect in a patient.
Knowledge of a drug's pharmacokinetics aids in interpreting drug
blood stream concentration and is useful in determining
pharmacologically effective drug dosages.
[0082] "Concurrent" administration, as used herein, refers to the
administration of a therapeutic drug marker suitable for use with
the systems and methods of the invention (administration of a
therapeutic drug) for monitoring therapeutic drug levels in blood
stream. By way of example, a therapeutic drug marker can be
provided in admixture with a therapeutic drug, such as in a
pharmaceutical composition; or the marker and therapeutic drug can
be administered to a patient as separate compounds, such as, for
example, separate pharmaceutical compositions administered
consecutively, simultaneously, or at different times. Preferably,
if the marker and the therapeutic drug are administered separately,
they are administered within sufficient time from each other so
that the concentration of the marker in exhaled breath is an
accurate indicator of the concentration of therapeutic drug in the
blood stream.
[0083] The term "aptamer," as used herein, refers to a
non-naturally occurring oligonucleotide chain that has a specific
action on a therapeutic drug marker. Aptamers include nucleic acids
that are identified from a candidate mixture of nucleic acids. In a
preferred embodiment, aptamers include nucleic acid sequences that
are substantially homologous to the nucleic acid ligands isolated
by the SELEX method. Substantially homologous is meant a degree of
primary sequence homology in excess of 70%, most preferably in
excess of 80%.
[0084] The "SELEX.TM." methodology, as used herein, involves the
combination of selected nucleic acid ligands, which interact with a
target marker in a desired action, for example binding to an
olfactory marker, with amplification of those selected nucleic
acids. Optional iterative cycling of the selection/amplification
steps allows selection of one or a small number of nucleic acids,
which interact most strongly with the target marker from a pool,
which contains a very large number of nucleic acids. Cycling of the
selection/amplification procedure is continued until a selected
goal is achieved. The SELEX methodology is described in the
following U.S. patents and patent applications: U.S. patent
application Ser. No. 07/536,428 and U.S. Pat. Nos. 5,475,096 and
5,270,163.
[0085] As used herein, the term "pharmaceutically acceptable
carrier" means a carrier that is useful in preparing a
pharmaceutical composition that is generally compatible with the
other ingredients of the composition, not deleterious to the
patient, and neither biologically nor otherwise undesirable, and
includes a carrier that is acceptable for veterinary use as well as
human pharmaceutical use. "A pharmaceutically acceptable carrier"
as used in the specification and claims includes both one and more
than one such carrier.
Breath Sampling
[0086] Generally, the exhalation gas stream comprises sequences or
stages. At the beginning of exhalation there is an initial stage,
the gas representative thereof coming from an anatomically inactive
(deadspace) part of the respiratory system, in other words, from
the mouth and upper respiratory tracts. This is followed by a
plateau stage. Prior to the plateau stage, the gas is a mixture of
deadspace and metabolically active gases. During the plateau phase,
which comprises the last portion of the exhaled breath, nothing but
deep lung gas, so-called alveolar gas is present. This gas, which
comes from the alveoli, is termed end-tidal gas.
[0087] According to the present invention, exhaled gas from any
specific phase of the respiratory cycle can be sampled to detect
for the presence of target markers as indicators of therapeutic
drug and/or endogenous compound concentration in the patient. For
example, sensor technology as described herein can be applied to
exhalation samples drawn from the initial phase, or the end-tidal
(late plateau) phase.
[0088] Technology used for end-tidal component monitoring (such as
CO.sub.2 sensors, O.sub.2 sensors, and NO sensors) can be used to
determine when or at what stage the sample is collected. Known
methods for airway pressure measurements or for monitoring gas flow
afford other means of collecting samples at the appropriate phase
of the respiratory cycle. In a preferred embodiment, the exhaled
breath sample is collected at end-tidal breathing.
[0089] Single or multiple samples collected by the known in-line
(or mainstream) sampling method are preferable, but if sensor
acquisition time is reduced, side stream sampling may be used. With
in-line sampling, a sensor of the subject invention is placed
proximal to the ET tube directly in the gas stream. In the latter,
samples are collected through an adapter at the proximal end of an
endotracheal (ET) tube and drawn through thin bore tubing to a
sensor of the subject invention. In certain embodiments that use
in-line sampling, the sensor is placed in a sampling chamber
positioned within the patient's gas stream. Alternatively to sample
end-tidal gas, samples can be taken throughout the exhalation phase
of respiration and an average value determined and correlated with
blood concentration. Depending on the sample size and sensor
response time, exhaled gas may be collected on successive
cycles.
[0090] Referring now to FIG. 1, the upper frame demonstrates a
capnogram of a single respiratory cycle. For accurate blood level
correlation, samples are taken at the point labeled "end-tidal
PCO.sub.2" which reflects the CO.sub.2 concentration in the lung.
The lower frame shows a capnogram of several breaths from a patient
with obstructive lung disease. Again the end-tidal sample
correlated best with blood concentration.
[0091] In one embodiment, a VaporLab.TM. brand instrument is used
to collect and analyze exhaled breath samples. The VaporLab.TM.
instrument is a hand-held, battery powered SAW-based chemical vapor
identification instrument suitable for detecting components in
exhaled breath samples in accordance with the present invention.
This instrument is sensitive to volatile and semi-volatile
compounds using a high-stability SAW sensor array that provides
orthogonal vapor responses for greater accuracy and discrimination.
In a related embodiment, this instrument communicates with
computers to provide enhanced pattern analysis and report
generation. In a preferred embodiment, this instrument includes
neural networks for "training" purposes, i.e., to remember chemical
vapor signature patterns for fast, "on-the-fly" analysis.
[0092] In another embodiment, samples are collected at the distal
end of an ET tube through a tube with a separate sampling port.
This may improve sampling by allowing a "cleaner--(less deadspace)"
sample during each respiratory cycle.
[0093] In certain instances, the concentration of a therapeutic
drug in a patient body is regulated by the amount of the drug
administered over a given time period and the rate at which the
agent is eliminated from the body (metabolism). The present
invention provides the steps of administering a therapeutic drug to
a patient and analyzing patient exhaled breath for concentration of
therapeutic drug markers such as unbound substances, active
metabolites, or inactive metabolites associated with the
therapeutic drug, after a suitable time period. In certain
embodiments of the subject invention, the marker concentration
indicates a characteristic of metabolism of the drug in the
patient.
[0094] Methods of the subject invention may further include the use
of a flow sensor to detect starting and completion of exhalation.
The method further includes providing results from the analysis and
communicating to the user or patient the blood concentration of the
therapeutic drug. In a preferred embodiment, results from analysis
can be communicated immediately upon sampling exhaled gases.
[0095] In certain embodiments, the subject invention enables the
immediate monitoring of therapeutic drug levels in a patient's
blood stream. As contemplated herein, immediate monitoring refers
to sampling and analysis of exhaled gases from a patient for target
markers substantially completely within a short time period
following administration of a therapeutic drug (i.e., generally
within a few minutes to about 24 hours).
[0096] Alternatively, in certain instances, a specific period of
time must progress before a therapeutic drug concentration level in
the blood stream can be detected. Accordingly, a system and/or
method of the invention can be provided to a patient taking a
therapeutic drug for intermittent or continuous monitoring of
therapeutic drug concentrations (or endogenous compound markers) in
the blood stream. In certain embodiments, the monitoring system and
method of the subject invention can be administered to a patient
taking a therapeutic drug on an hourly, daily, weekly, monthly, or
even annual basis. Further, additional monitoring can be
administered to a patient when an additional therapeutic drug is
prescribed.
[0097] Moreover, a CPU may be provided as a data processing/control
unit for automatically detecting the signal from the flow sensor to
control sampling of exhaled breath. The CPU may further provide to
the user/patient the appropriate dosage of the therapeutic drug to
be delivered based on analysis of trends in therapeutic drug blood
concentration. In certain embodiments, where the depth of
anesthesia is to be monitored and controlled, the CPU may further
provide the analysis and control of the infusion pump or other
administering means for anesthetic agents.
[0098] Depending on the mode of therapeutic drug administration,
the present invention provides means for automatically adjusting
and administering the appropriate dosage of a therapeutic drug,
based on blood concentration levels, to a patient. In certain
embodiments, a CPU is provided for analysis and control of dosage
adjusting and administering means. In one embodiment in which a
therapeutic drug is delivered intravenously, an infusion pump is
used, wherein the CPU provides analysis and control of the infusion
pump.
[0099] Concentration in the blood of therapeutic drug markers, as
measured by breath analysis in accordance with the present
invention, may indicate when the patient is receiving a high dose
(i.e., toxic dose), a low dose (i.e., ineffective dose), or
effective (i.e., appropriate) dose of the therapeutic drug. Even if
there is wide variation in the metabolism or response to the
therapeutic drug, knowledge of the exhaled breath concentration
allows the user to know if the drug is accumulating in the blood,
possibly leading to dangerously toxic levels of the drug, or that
the concentration is falling, possibly leading to an inadequate
dose of the drug. Monitoring changes in therapeutic drug blood
concentration in accordance with the subject invention are,
therefore, useful.
[0100] In another embodiment, the exhalation air is measured for
marker (such as endogenous compound, therapeutic drug, free agent,
and/or metabolite) concentration either continuously or
intermittently/periodically. From the exhalation air is extracted
at least one measured marker concentration value. Numerous types of
breath sampling apparatuses can be used to carry out the method of
the present invention.
[0101] In one embodiment, the breath sampling apparatus includes a
conventional flow channel through which exhalation air flows. The
flow channel is provided with a sensor of the subject invention for
measuring marker concentration. Furthermore, necessary output
elements may be included with the breath sampling apparatus for
delivering at least a measured concentration result to the user, if
necessary.
[0102] An alarm mechanism may also be provided. An instrument of
similar type is shown in FIGS. 1 and 2 of U.S. Pat. No. 5,971,937
incorporated herein by reference.
[0103] In another embodiment, once the level of concentration is
measured, it is given numerical value (for example, 50 on a scale
of 1 to 100). Should the concentration fall below that value, the
new value would be indicative of a decrease in concentration.
Should the concentration increase beyond that value, the new value
would be indicative of an increase in concentration. This numerical
scale would allow for easier monitoring of changes in
concentration. The numerical scale would also allow for easier
translation into control signals for alarms, outputs, charting, and
control of external devices (e.g., infusion pump). The upper and
lower limits could be set to indicate thresholds such as from
ineffective to dangerous therapeutic drug levels.
Sensor Technology
[0104] The invention preferably utilizes gas sensor technology,
such as commercial devices known as "artificial" or "electronic"
tongues or noses, to non-invasively monitor marker concentration in
exhaled breath (FIG. 2). Electronic noses have been used mostly in
the food, wine, and perfume industry where their sensitivity makes
it possible to distinguish between odorous compounds. For example,
electronic noses have been useful in distinguishing between
grapefruit oil and orange oil in the perfume industry and identify
spoilage in perishable foods before the odor is evident to the
human nose.
[0105] In the past, there was little medical-based research and
application of these artificial/electronic tongues and noses.
However, recent use has demonstrated the power of this non-invasive
technique. For example, electronic noses have been used to
determine the presence of bacterial infection in the lungs by
analyzing the exhaled gases of patients for odors specific to
particular bacteria (Hanson C W, Steinberger H A, "The use of a
novel electronic nose to diagnose the presence of intrapulmonary
infection," Anesthesiology, 87(3A):Abstract A269, (1997)). Also, a
genitourinary clinic has utilized an electronic nose to screen for,
and detect bacterial vaginosis, with a 94% success rate after
training (Chandiok S, et al., "Screening for bacterial vaginosis: a
novel application of artificial nose technology," Journal of
Clinical Pathology, 50(9):790-1 (1997)). Specific bacterial species
can also be identified with the electronic nose based on special
odors produced by the organisms (Parry A D et al., "Leg ulcer odor
detection identifies beta-haemolytic streptococcal infection,"
Journal of Wound Care, 4:404-406 (1995)).
[0106] A number of patents which describe gas sensor technology
that can be used in the subject invention include, but are not
limited to, the following: U.S. Pat. Nos. 5,945,069; 5,918,257;
4,938,928; 4,992,244; 5,034,192; 5,071,770; 5,145,645; 5,252,292;
5,605,612; 5,756,879; 5,783,154; and 5,830,412. Other sensors
suitable for the present invention include, but are not limited to,
metal-insulator-metal ensemble (MIME) sensors, cross-reactive
optical microsensor arrays, fluorescent polymer films, surface
enhanced raman spectroscopy (SERS), diode lasers, selected ion flow
tubes, metal oxide sensors (MOS), non-dispersive infrared
spectrometer, bulk acoustic wave sensors, colorimetric tubes,
functionalized microcantilevers and infrared spectroscopy.
[0107] Recent developments in the field of detection that can also
be used as sensor for the subject invention include, but are not
limited to, gas chromatography, semiconductive gas sensors, mass
spectrometers (including proton transfer reaction mass
spectrometry), and infrared (IR) or ultraviolet (UV) or visible or
fluorescence spectrophotometers (i.e., non-dispersive infrared
spectrometer). For example, with semiconductive gas sensors,
markers cause a change in the electrical properties of
semiconductor(s) by making their electrical resistance vary, and
the measurement of these variations allows one to determine the
concentration of marker(s). In another example, gas chromatography,
which consists of a method of selective detection by separating the
molecules of gas compositions, may be used as a means for analyzing
markers in exhaled breath samples.
[0108] In accordance with the subject invention, sensors for
detecting/quantifying markers utilize a relatively brief detection
time of around a few seconds. Other recent gas sensor technologies
contemplated by the present invention include apparatuses having
conductive-polymer gas-sensors ("polymeric"), aptamer biosensors,
amplifying fluorescent polymer (AFP) sensors, and apparatuses
having surface-acoustic-wave (SAW) gas-sensors.
[0109] The conductive-polymer gas-sensors (also referred to as
"chemoresistors") have a film made of a conductive polymer
sensitive to the molecules of odorous substances. On contact with
target marker molecules, the electric resistance of the sensors
changes and the measurement of the variation of this resistance
enables the concentration of the markers to be determined. An
advantage of this type of sensor is that it functions at
temperatures close to room temperature. Different sensitivities for
detecting different markers can be obtained by modifying or
choosing an alternate conductive polymer.
[0110] Polymeric gas sensors can be built into an array of sensors,
where each sensor is designed to respond differently to different
markers and augment the selectivity of the therapeutic drug
markers. For example, a sensor of the subject invention can
comprise of an array of polymers, (i.e., 32 different polymers)
each exposed to a marker. Each of the individual polymers swells
differently to the presence of a marker, creating a change in the
resistance of that membrane and generating an analog voltage in
response to that specific marker ("signature"). The normalized
change in resistance can then be transmitted to a processor to
identify the type, quantity, and quality of the marker based on the
pattern change in the sensor array. The unique response results in
a distinct electrical fingerprint that is used to characterize the
marker. The pattern of resistance changes of the array is
diagnostic of the marker in the sample, while the amplitude of the
pattern indicates the concentration of the marker in the
sample.
[0111] Responses of polymeric gas sensors to target markers can be
fully characterized using a combination of conventional gas sensor
characterization techniques. For example, the sensor can be
attached to a computer. The results can be displayed on the
computer screen, stored, transmitted, etc. A data analyzer can
compare a pattern of response to previously measured and
characterized responses from known substances. The matching of
those patterns can be performed using a number of techniques,
including neural networks. By comparing the analog output from each
of the 32 polymers to a "blank" or control, for example, a neural
network can establish a pattern that is unique to that substance
and subsequently learns to recognize that substance. The particular
resistor geometries are selected to optimize the desired response
to the particular substance being sensed. In one embodiment, the
sensor of the present invention is a self-calibrating polymer
system suitable for liquid or gas phase biological solutions for
detecting a variety of target markers simultaneously.
[0112] Another sensor of the invention can be provided in the form
of an aptamer. In one embodiment, the SELEX.TM. (Systematic
Evolution of Ligands by EXponential enrichment) methodology is used
to produce aptamers that recognize therapeutic drug markers with
high affinity and specificity. Aptamers produced by the SELEX
methodology have a unique sequence and the property of binding
specifically to a desired marker. The SELEX methodology is based on
the insight that nucleic acids have sufficient capacity for forming
a variety of two- and three-dimensional structures and sufficient
chemical versatility available within their monomers to act as
ligands (form specific binding pairs) with virtually any chemical
compound, whether monomeric or polymeric. According to the subject
invention, therapeutic drug markers of any size or composition can
thus serve as targets for aptamers. See also Jayasena, S.,
"Aptamers: An Emerging Class of Molecules That Rival Antibodies for
Diagnostics," Clinical Chemistry, 45:9, 1628-1650 (1999).
[0113] Aptamer biosensors can be utilized in the present invention
for detecting the presence of markers in exhaled breath samples. In
one embodiment, aptamer sensors are composed of resonant
oscillating quartz sensors that can detect minute changes in
resonance frequencies due to modulations of mass of the oscillating
system, which results from a binding or dissociation event (i.e.,
binding with a target therapeutic drug marker).
[0114] Similarly, molecular beacons (MB) and molecular beacon
aptamers (MBA) employ fluorescence resonance energy transfer based
methods to provide fluorescence signal increases in the presence of
particular target sequences. See also, Stojanovic, Milan N., de
Prada, Paloma, and Landry, Donald W., "Aptamer-Based Folding
Fluorescent Sensor for Cocaine" J. Am. Chem. Soc. 2001, 123,
4928-4931 (2001); Jayasena, Sumedha D., "Aptamers: An Emerging
Class of Molecules That Rival Antibodies of Diagnostics, Clinical
Chemistry 45:9, 1628-1650 (1999).
[0115] Amplifying fluorescent polymer (AFP) sensors may be utilized
in the present invention for detecting the presence of therapeutic
drug markers and/or endogenous compound markers in exhaled breath
samples. AFP sensors are extremely sensitive and highly selective
chemosensors that use amplifying fluorescent polymers. When target
markers bind to thin films of the polymers, the fluorescence of the
film decreases. A single molecule binding event quenches the
fluorescence of many polymer repeat units, resulting in an
amplification of the quenching. The binding of markers to the film
is reversible, therefore the films can be reused.
[0116] Surface-acoustic-wave (SAW) sensors oscillate at high
frequencies and generally have a substrate, which is covered by a
chemoselective material. In SAW sensors, the substrate is used to
propagate a surface acoustic wave between sets of interdigitated
electrodes (i.e., to form a transducer). The chemoselective
material is coated on the transducer. When a marker interacts with
the chemoselective material coated on the substrate, the
interaction results in a change in the SAW properties, such as the
amplitude of velocity of the propagated wave. The detectable change
in the characteristic wave is generally proportional to the mass
load of the marker(s) (i.e., concentration of the marker in exhaled
breath, which corresponds to the concentration of the therapeutic
drug and/or endogenous compound in the blood stream).
[0117] Certain embodiments of the invention use known SAW devices,
such as those described in U.S. Pat. Nos. 4,312,228 and 4,895,017,
and Groves W. A. et al., "Analyzing organic vapors in exhaled
breath using surface acoustic wave sensor array with
preconcentration: Selection and characterization of the
preconcentrator adsorbent," Analytica Chimica Acta, 371:131-143
(1988). Other types of chemical sensors known in the art that use
chemoselective coating applicable to the operation of the present
invention include bulk acoustic wave (BAW) devices, plate acoustic
wave devices, interdigitated microelectrode (IME) devices, optical
waveguide (OW) devices, electrochemical sensors, and electrically
conducting sensors.
[0118] In one embodiment, the sensor of the invention is based on
surface acoustic wave (SAW) sensors. The SAW sensors preferably
include a substrate with piezoelectric characteristics covered by a
polymer coating, which is able to selectively absorb target
markers. SAW sensors oscillate at high frequencies and respond to
perturbations proportional to the mass load of certain molecules.
This occurs in the vapor phase on the sensor surface.
[0119] In a related embodiment, the sensor of the invention is
based on a SAW sensor of Stubbs, D. et al. (see Stubbs, D. et al.,
"Investigation of cocaine plumes using surface acoustic wave
immunoassay sensors," Anal Chem., 75(22):6231-5 (November 2003) and
Stubbs, D. et al., "Gas phase activity of anti-FITC antibodies
immobilized on a surface acoustic wave resonator device," Biosens
Bioelectron, 17(6-7):471-7 (2002)). For example, the sensor of the
subject invention can include a two-port resonator on ST-X quartz
with a center frequency of 250 MHz. On the cut quartz, a
temperature compensated surface acoustic wave (SAW) is generated
via an interdigital transducer. Antibodies specific to a target
marker are then attached to the electrodes (i.e., 1.5 micron wide)
on the sensor device surface via protein cross linkers. In the
vapor phase on the sensor surface, when target markers are present,
a change in frequency occurs to alert the user that a target marker
has been recognized.
[0120] In a related embodiment, the SAW sensor is connected to a
computer, wherein any detectable change in frequency can be
detected and measured by the computer. In a preferred embodiment,
an array of SAW sensors (4-6) is used, each coated with a different
chemoselective polymer that selectively binds and/or absorbs vapors
of specific classes of molecules. The resulting array, or
"signature" identifies specific compounds.
[0121] The operating performance of most chemical sensors that use
a chemoselective film coating is greatly affected by the thickness,
uniformity and composition of the coating. For these sensors,
increasing the coating thickness, has a detrimental effect on the
sensitivity. Only the transducer senses the portion of the coating
immediately adjacent to the transducer/substrate.
[0122] For example, if the polymer coating is too thick, the
sensitivity of a SAW device to record changes in frequency will be
reduced. These outer layers of coating material compete for the
marker with the layers of coating being sensed and thus reduce the
sensitivity of the sensor. Uniformity of the coating is also a
critical factor in the performance of a sensor that uses a
chemoselective coating since changes in average surface area
greatly affect the local vibrational signature of the SAW device.
Therefore, films should be deposited that are flat to within 1 nm
with a thickness of 15-25 nm. In this regard, it is important not
only that the coating be uniform and reproducible from one device
to another, so that a set of devices will all operate with the same
sensitivity, but also that the coating on a single device be
uniform across the active area of the substrate.
[0123] If a coating is non-uniform, the response time to marker
exposure and the recovery time after marker exposure are increased
and the operating performance of the sensor is impaired. The thin
areas of the coating respond more rapidly to a target marker than
the thick areas. As a result, the sensor response signal takes
longer to reach an equilibrium value, and the results are less
accurate than they would be with a uniform coating.
[0124] Most current technologies for creating large area films of
polymers and biomaterials involve the spinning, spraying, or
dipping of a substrate into a solution of the macromolecule and a
volatile solvent. These methods coat the entire substrate without
selectivity and sometimes lead to solvent contamination and
morphological inhomogeneities in the film due to non-uniform
solvent evaporation. There are also techniques such as microcontact
printing and hydrogel stamping that enable small areas of
biomolecular and polymer monolayers to be patterned, but separate
techniques like photolithography or chemical vapor deposition are
needed to transform these films into microdevices.
[0125] Other techniques such as thermal evaporation and pulsed
laser ablation are limited to polymers that are stable and not
denatured by vigorous thermal processes. More precise and accurate
control over the thickness and uniformity of a film coating may be
achieved by using pulsed laser deposition (PLD), a physical vapor
deposition technique that has been developed recently for forming
ceramic coatings on substrates. By this method, a target comprising
the stoichiometric chemical composition of the material to be used
for the coating is ablated by means of a pulsed laser, forming a
plume of ablated material that becomes deposited on the
substrate.
[0126] Polymer thin films, using a new laser based technique
developed by researchers at the Naval Research Laboratory called
Matrix Assisted Pulsed Laser Evaporation (MAPLE), have recently
been shown to increase sensitivity and specificity of
chemoselective Surface Acoustic Wave vapor sensors. By providing
improved SAW biosensor response by eliminating film imperfections
induced by solvent evaporation and detecting molecular attachments
to specific target markers, high sensitivity and specificity is
possible.
[0127] Certain extremely sensitive, commercial off-the-shelf (COTS)
electronic noses, such as those provided by Cyrano Sciences, Inc.
("CSI") (i.e., CSI's Portable Electronic Nose and CSI's Nose-Chip
integrated circuit for odor-sensing, see U.S. Pat. No.
5,945,069--FIG. 1), may be used in the system and method of the
present invention to monitor the exhaled breath from a patient.
These devices offer minimal cycle time, can detect multiple
markers, can work in almost any environment without special sample
preparation or isolation conditions, and do not require advanced
sensor design or cleansing between tests.
[0128] In other embodiments, competitive binding immunoassays can
be used to test a bodily fluid sample for the presence of signaling
agents. Immunoassay tests generally include an absorbent, fibrous
strip having one or more reagents incorporated at specific zones on
the strip. The bodily fluid sample is deposited on the strip and by
capillary action the sample will migrate along the strip, entering
specific reagent zones in which a chemical reaction may take place.
At least one reagent is included which manifests a detectable
response, for example a color change, in the presence of a minimal
amount of a signaling agent of interest. Patents that describe
immunoassay technology include the following: U.S. Pat. Nos.
5,262,333 and 5,573,955, both of which are incorporated herein by
reference in their entirety.
[0129] In one embodiment, the device of the present invention may
be designed so that patients can exhale via the mouth or nose
directly onto a sensor of the invention, without needing a breath
sampling apparatus. For example, a mouthpiece or nosepiece will be
provided for interfacing a patient with the device to readily
transmit the exhaled breath to the sensor (See, i.e., U.S. Pat. No.
5,042,501). In a related embodiment, wherein the sensor is
connected to a neural network, the output from the neural network
is similar when the same patient exhales directly into the device
and when the exhaled gases are allowed to dry before the sensor
samples them.
[0130] In another embodiment, a patient's breath sample can be
captured in a container (vessel) for later analysis using a sensor
of the subject invention (i.e., mass spectrometer).
[0131] The humidity in the exhaled gases represents a problem for
certain electronic nose devices (albeit not SAW sensors) that only
work with "dry" gases. When using such humidity sensitive devices,
the present invention may adapt such electronic nose technology so
that a patient can exhale directly into the device with a means to
dehumidify the samples. This is accomplished by including a
commercial dehumidifier or a heat moisture exchanger (HME), a
device designed to prevent desiccation of the airway during
ventilation with dry gases.
[0132] Alternatively, the patient may exhale through their nose,
which is an anatomical, physiological dehumidifier to prevent
dehydration during normal respiration. Alternatively, the sensor
device can be fitted with a preconcentrator, which has some of the
properties of a GC column. The gas sample is routed through the
preconcentrator before being passed over the sensor array. By
heating and volatilizing the gases, humidity is removed and the
marker being measured can be separated from potential
interferents.
[0133] The results from the sensor technology analysis of the
bodily fluid samples are optionally provided to the user (or
patient) via a reporting means. In one embodiment, the sensor
technology includes the reporting means. Contemplated reporting
means include a computer processor linked to the sensor technology
in which electronic or printed results can be provided.
Alternatively, the reporting means can include a digital display
panel, transportable read/write magnetic media such as computer
disks and tapes which can be transported to and read on another
machine, and printers such as thermal, laser or ink-jet printers
for the production of a printed report.
[0134] The reporting means can provide the results to the user (or
patient) via facsimile, electronic mail, mail or courier service,
or any other means of safely and securely sending the report to the
patient. Interactive reporting means are also contemplated by the
present invention, such as an interactive voice response system,
interactive computer-based reporting system, interactive telephone
touch-tone system, or other similar system. The report provided to
the user (or patient) may take many forms, including a summary of
analyses performed over a particular period of time or detailed
information regarding a particular bodily fluid sample analysis.
Results may also be used to populate a financial database for
billing the patient, or for populating a laboratory database or a
statistical database.
[0135] A data monitor/analyzer can compare a pattern of response to
previously measured and characterized responses from known markers.
The matching of those patterns can be performed using a number of
techniques, including neural networks. By comparing the analog
output from each of the 32 polymers to a "blank" or control, for
example, a neural network can establish a pattern that is unique to
that marker and subsequently learns to recognize that marker. The
particular resistor geometries are selected to optimize the desired
response to the target marker being sensed. The sensor of the
subject invention is preferably a self-calibrating polymer system
suitable for detecting and quantifying markers in gas phase
biological solutions to assess and/or monitor a variety of
therapeutic drug markers simultaneously.
[0136] According to the subject invention, the sensor can include a
computer that communicates therewith, which can also notify the
medical staff and/or the patient as to any irregularities in
dosing, dangerous drug interactions, and the like. This system will
enable determination as to whether a patient has been administered
a pharmacologically effective amount of a therapeutic drug. The
device could also alert the patient (or user) as to time intervals
and/or dosage of therapeutic drug to be administered. Accordingly,
it is contemplated herein that a sensor of the subject invention
can be portable.
[0137] Preferably, in operation, the sensor will be used to
identify a baseline spectrum for the patient prior to drug
administration, if necessary. This will prove beneficial for the
detection of more than one therapeutic drug if the patient receives
more than one drug at a time and possible interference from
different foods and odors in the stomach, mouth, esophagus and
lungs.
Remote Communication System
[0138] A further embodiment of the invention includes a
communications device in the home (or other remote location) that
will be interfaced to the sensor. The home communications device
will be able to transmit immediately or at prescribed intervals
directly or over a standard telephone line (or other communication
transmittal means) the data collected by the data monitor/analyzer
device. The communication of the data will allow the user (i.e.,
physician) to be able to remotely verify if the appropriate dosage
of a therapeutic drug is being administered to the patient. The
data transmitted from the home can also be downloaded to a computer
where the drug blood levels are stored in a database, and any
deviations outside of pharmacological efficacy would be
automatically flagged (i.e., alarm) so that a user (i.e., patient,
physician, nurse) could appropriately adjust the drug dosage per
suggestions provided by a computer processing unit connected to the
sensor or per dosage suggestions provided by health care personnel
(i.e., physician).
Endogenous Compounds
[0139] According to the present invention, the blood concentration
of endogenous compounds can be monitored by utilizing breath sensor
technology to detect and/or quantify endogenous compound markers
present in exhaled breath. It has been shown that blood and exhaled
concentration of certain therapeutic agents (such as propofol) are
proportional. However, there has been no indication to date that
endogenous compound markers are present in exhaled breath, let
alone that the concentration of endogenous compounds in a human's
body, specifically in patient blood, are proportional to those
present in exhaled breath.
[0140] The present inventors have surprisingly discovered that
endogenous compounds and/or their markers are present in exhaled
breath and can be detected using the sensor technology described
herein. In particular, endogenous compounds that are hydrophilic
are likely to be measured in the liquid (exhaled breath condensate)
phase of breath whereas those that are hydrophobic (lipophilic) are
likely to be measured in the gas phase of breath. Further, the
present inventors have discovered certain endogenous compounds,
such as glucose, to be present in exhaled breath and that the
concentration of the endogenous compounds in exhaled breath is
proportional to the concentration in patient blood.
[0141] For example, a researcher ingested a 100 gm glucose solution
and sampled breath and blood glucose levels 40 and 20 minutes
before ingestion and multiple times for 120 minutes after
ingestion. Glucose was readily detectable in the exhaled breath,
which was condensed into a liquid. The concentration of both the
breath and blood glucose rose and fell at the same rates.
Correlation would be even tighter if only end-tidal breath samples
were collected.
[0142] This and several other experiments suggest that the ratio of
exhaled breath to blood glucose concentration is 1:10,000 and that
this ratio is predictable and reproducible. In accordance with the
present invention, a more predictive method is provided to monitor
endogenous compound concentration in a patient by monitoring breath
rather than blood. The systems and methods of the invention may be
used to monitor such endogenous compounds as, but not limited to,
glucose; proteins (e.g., heat shock proteins HSP70); urobilinogen;
urobilirubin; bilirubin; hormones including cortisol, testosterone,
estrogens, and pregnancy markers (e.g., hCG and its subunits);
oligonucleotides (e.g., DNA, RNA); adenosine; adenosine
triphosphate (ATP); adenosine diphosphate (ADP); adenosine
monophosphate (AMP); prostaglandins (e.g., PGF2.alpha.);
leukotrienes; cytokines; interleukins; melatonin;
6-sulfoxymelatonin; hypoxia-inducible factor 1.alpha.
(HIF-1.alpha.); myogenic regulatory factors; 2,3-diphosphoglycerate
(2,3-DPG); ketones; nitrite; electrolytes (e.g., sodium, chlorine,
potassium, magnesium, calcium, bicarbonate, sulfates, phosphates);
urea (blood urea nitrogen); uric acid; ammonia; lactic acid;
cholesterol; triglycerides (and other "fats" such as high density
and low density lipoproteins); lactate dehydrogenase (LDH); cancer
"markers" such as PSA (prostate specific antigen); and liver (SGOT,
SGPT) and cardiac (and other muscle) enzymes: creatinine
phosphokinase (CPK), troponin.
[0143] In view of the above, the present invention provides the
capability of non-invasively, and in certain instances
continuously, measuring a wide variety of endogenous compound
concentrations in blood using exhaled breath as a surrogate,
providing a physician with the ability to monitor and diagnose a
variety of ailments, such as renal, hepatic, pancreatic,
gastrointestinal, and cardiovascular problems via breath
collection.
[0144] Where endogenous compound levels are continuously monitored,
healthcare workers need only intervene if the sensor technology
described herein indicates that a medical concern exists, which can
be relayed in the form of an alarm system triggered if abnormal
endogenous compound concentration levels exceed a predetermined
limit over a given period of time. Electrical output signal(s) that
can be produced by a sensor device of the invention can enable
remote computer monitoring of endogenous compound concentrations in
a patient to provide early indicators of ailments, which is
especially important for diabetic and disabled patients and can
greatly reduce the cost of long-term health care.
[0145] In one embodiment, a system of the invention comprises a
sensor device, a computing/processor device, a system controller,
and a controlled supply means for automated delivery of a
therapeutic drug. The sensor device preferably detects endogenous
compound marker concentration in breath and is connected to
communicate the results to the computing/processor device.
[0146] The computing/processor device runs under control of a
program stored in the memory of the computing/processor device and
determines a desired therapeutic drug and/or dosage of a
therapeutic drug in response to the results provided by the sensor.
Preferably, the computing/processor device comprises a data
monitor/analyzer that can compare a pattern of results communicated
from the sensor device to previously measured and characterized
results, where the results are indicative of patient condition. The
computing/processor device preferably utilizes a trainable neural
network to determine the therapeutic drug and/or therapeutic drug
dosage to be administered to the patient based on the patient's
condition and generates a response signal. In one embodiment,
responsive to the response signal of the computing/processor
device, the system controller directs the controlled supply means
to dispense a dosage or adjust a dosage for a therapeutic drug.
[0147] In operation, upon detection of the target marker, the
concentration of the endogenous compound in blood can be determined
by the computing/processor device for use in establishing
clinically relevant data regarding the patient's condition and,
when appropriate, deriving the appropriate type of therapeutic drug
and dosage amount to be delivered to the patient to address the
patient's condition. In certain embodiments, such information
regarding appropriate drug and dosage is communicated to the
user.
[0148] In a preferred embodiment, an automated system is provided
for monitoring the concentration of glucose present in breath,
where the concentration of glucose is indicative of blood glucose
concentration, which can be used to derive diabetic patient
condition. Specifically, patient exhaled breath is applied to a
sensor (such as an electronic nose), which continuously or
intermittently communicates results to a computing/processor device
to derive the concentration of glucose present in breath (and
corresponding level of glucose in blood). Based on the monitored
glucose concentration in breath, the computing/processor device
communicates with the system controller of the invention, which
will direct the controlled supply means (e.g., IV bag) to dispense
(or refrain from dispensing) an appropriate dosage of a therapeutic
drug, such as insulin, to address the patient's condition. For
example, where the computing/processor device assesses that the
glucose levels in the patient's blood are too high, the system of
the invention can automatically deliver insulin to the patient to
lower blood glucose levels.
Pharmacodynamics and Pharmacokinetics of Therapeutic Drugs
[0149] When a therapeutic drug is administered to a patient in
accordance with the subject invention, there are many factors which
effect drug pharmacodynamics and pharmacokinetics. For example,
drug affinity (i.e., degree of attraction between a drug and a
target receptor in the patient body), drug distribution (i.e.,
binding of drug to proteins circulating in the blood, absorption of
drug into fat), drug metabolism and elimination (i.e., renal
clearance), or existence of a drug in a "free" form may affect drug
pharmacodynamics and pharmacokinetics (PD/PK) in a patient.
[0150] A drug bound to protein or absorbed into fat does not
produce a desired pharmacological effect and exists in equilibrium
with unbound drug. Numerous factors, including competition for
binding sites on the protein from other drugs, the amount of fat in
the body, and the amount of protein produced, determine the
equilibrium between bound and unbound drug.
[0151] An unbound drug can participate directly in the
pharmacological effect or be metabolized into a drug that produces
a desired effect. Metabolism of the active drug often leads to its
removal from the bloodstream and termination of its effect. The
drug effect can also be terminated by the excretion of the free
drug. Free drug or a metabolite can be excreted in the urine or the
digestive tract or in exhaled breath. The concentration in the
blood (or plasma or serum) of such therapeutic drugs is related to
the clinical effect of the agent.
[0152] As described above, blood concentration testing for a
therapeutic drug may or may not provide an accurate indication of
the effect of the therapeutic drug on a patient, since measurement
of blood concentration does not account for the quantity of drug
bound to protein or membranes, or the interaction and competition
between drugs. For this reason, it would be advantageous to measure
only the free drug in the plasma. The concentration of free drug in
plasma is usually low and requires sophisticated and expensive
analytical techniques for measurement. By contrast, the marker that
appears in breath, in accordance with the subject invention, is an
indication of the concentration of free drug in blood. Thus, using
the systems and methods of the subject invention to measure exhaled
breath for marker concentration can provide an effective indicator
of the actual concentration of free drug responsible for PK
effect.
[0153] Further, testing blood directly (i.e., drawing blood for
sample analysis) is invasive, time consuming, expensive, and prone
to inaccuracies. In contrast, by analyzing therapeutic drug markers
in patient exhaled breath, the systems and methods of the subject
invention are non-invasive, speedy, and accurate and can be
performed intermittently or continuously. When a therapeutic drug
marker (such as the therapeutic drug or its metabolite) is excreted
in the breath, the concentration in expired breath is proportional
to the free therapeutic drug (or metabolite) concentration in the
blood and, thus, indicative of the rate of drug absorption,
distribution, metabolism, and/or elimination.
[0154] In certain embodiments, the metabolite measured in exhaled
breath may be the active metabolite or a breakdown product of the
active therapeutic drug. As long as there is equilibrium between
the active drug and a metabolite (such as an inactive metabolite)
excreted in the breath, the activity of the active drug can be
analyzed in accordance with the subject invention.
[0155] The method of the present invention takes into account such
proportional concentrations and allows for the determination of the
rate of absorption, distribution, metabolism, and elimination of a
therapeutic drug by measuring concentration of unbound substances,
markers, and/or active metabolites associated with the drug in a
patient's breath. The proper dosing regimen can thus be determined
therefrom.
Therapeutic Drug Markers
[0156] In accordance with the present invention, therapeutic drug
markers useful as an indication of therapeutic drug concentration
in blood include the following olfactory markers, without
limitation: dimethyl sulfoxide (DMSO), acetaldehyde, acetophenone,
trans-Anethole (1-methoxy-4-propenyl benzene) (anise), benzaldehyde
(benzoic aldehyde), benzyl alcohol, benzyl cinnamate, cadinene,
camphene, camphor, cinnamaldehyde (3-phenylpropenal), garlic,
citronellal, cresol, cyclohexane, eucalyptol, and eugenol, eugenyl
methyl ether; butyl isobutyrate (n-butyl 2, methyl propanoate)
(pineapple); citral (2-trans-3,7-dimethyl-2,6-actadiene-1-al);
menthol (1-methyl-4-isopropylcyclohexane-3-ol); and .alpha.-Pinene
(2,6,6-trimethylbicyclo-(3,1,1)-2-heptene). These markers are
preferred since they are used in the food industry as flavor
ingredients and are permitted by the Food and Drug Administration.
As indicated above, olfactory markers for use in the present
invention can be selected from a vast number of available compounds
(see Fenaroli's Handbook of Flavor Ingredients, 4.sup.th edition,
CRC Press, 2001) and use of such other applicable markers is
contemplated herein.
[0157] The markers of the invention also include additives that
have been federally approved and categorized as GRAS ("generally
recognized as safe"), which are available on a database maintained
by the U.S. Food and Drug Administration Center for Food Safety and
Applied Nutrition. Markers categorized as GRAS that are readily
detectable in exhaled breath include, but are not limited to,
sodium bisulfate, dioctyl sodium sulfosuccinate, polyglycerol
polyricinoleic acid, calcium casein peptone-calcium phosphate,
botanicals (i.e., chrysanthemum; licorice; jellywort, honeysuckle;
lophatherum, mulberry leaf; frangipani; selfheal; sophora flower
bud), ferrous bisglycinate chelate, seaweed-derived calcium, DHASCO
(docosahexaenoic acid-rich single-cell oil) and ARASCO (arachidonic
acid-rich single-cell oil), fructooligosaccharide, trehalose, gamma
cyclodextrin, phytosterol esters, gum arabic, potassium bisulfate,
stearyl alcohol, erythritol, D-tagatose, and mycoprotein.
[0158] Halogenated compounds (i.e. fluorinated drugs or markers)
hold particular promise as they are readily highly volatile, safe
for human consumption, and are readily detected in exhaled breath
with portable Freon leak detectors. Some of these compounds are
used as propellants for delivery of drugs via the pulmonary route,
such as metered dose inhalers and therefore are known to be safe
and are FDA approved, some are GRAS compounds as well. The
technologies most often used to detect Freon leaks include:
Negative Ion Capture, Heated Sensor/Ceramic Semiconductor, Infrared
Absorption, and TIF TIFXP-1A Negative Corona Leak Detector. Many
drugs are fluorinated and metabolites are often extremely volatile
and detectable in exhaled breath. Numerous such compounds are
available that could be used as markers and could be added as
excipients during the manufacture of drugs.
[0159] As described above, therapeutic drug markers are detected by
their physical and/or chemical properties, which does not preclude
using the desired therapeutic drug itself as its own marker.
Therapeutic drug markers, as contemplated herein, also include
products and compounds that are administered to enhance detection
using sensors of the invention. Moreover, therapeutic drug markers
can include a variety of products or compounds that are added to a
desired therapeutic drug regimen to enhance differentiation in
detection/quantification. Generally, in accordance with the present
invention, therapeutic drug markers are poorly soluble in water,
which enhances their volatility and detection in the breath.
[0160] According to the subject invention, upon administering a
therapeutic drug (wherein the therapeutic drug is the marker) or
upon concurrent administration of a therapeutic drug and a
detectable additive, the detection of the marker (such as the
therapeutic drug, a metabolite of the therapeutic drug, or
additive) can occur under several circumstances. In one example
where the drug is administered orally, the marker can "coat" or
persist in the mouth, esophagus and/or stomach upon ingestion and
be detected with exhalation (similar to the taste or flavor that
remains in the mouth after eating a breath mint).
[0161] In a second instance where the drug (and, when present,
detectable additive) is administered orally, the drug may react in
the mouth or stomach with acid or enzymes to produce or liberate
the marker that can then be detected upon exhalation. Thirdly, the
drug and/or marker can be absorbed in the gastrointestinal tract
and be excreted in the lungs (i.e. alcohol is rapidly absorbed and
detected with a Breathalyzer). Generally, a therapeutic drug marker
of the invention provides a means for determining the
pharmacodynamics and pharmacokinetics of the drug.
[0162] In one embodiment, a detectable additive (marker) is
concurrently administered with a therapeutic drug (i.e., detectable
additive is provided in a pharmaceutically acceptable carrier,
detectable additive is provided in medication coating composed of
rapidly dissolving glucose and/or sucrose). In a preferred
embodiment, the therapeutic drug is provided in the form of a pill,
whose coating includes at least one marker in air-flocculated sugar
crystals. This would stimulate salivation and serve to spread the
marker around the oral cavity, enhancing the lifetime in the
cavity. Since the throat and esophagus could also be coated with
the marker as the medication is ingested, detection of the marker
is further enhanced.
[0163] Thus, when a drug is administered to a patient, the
preferred embodiment of the invention detects and quantifies a
therapeutic drug marker almost immediately in the exhaled breath of
the patient (or possibly by requesting the patient to deliberately
produce a burp) using a sensor (i.e., electronic nose). Certain
drug compositions might not be detectable in the exhaled breath.
Others might have a coating to prevent the medication from
dissolving in the stomach. In both instances, as an alternate
embodiment, a non-toxic olfactory marker (i.e., volatile organic
vapors) can be added to the pharmaceutically acceptable carrier
(i.e., the coating of a pill, in a separate fast dissolving
compartment in the pill, or solution, if the drug is administered
in liquid or suspension form) to provide a means for
identifying/quantifying the marker in exhaled breath and thus
determine the drug concentration in blood.
[0164] Preferably the marker will coat the oral cavity or esophagus
or stomach for a short while and be exhaled in the breath (or in a
burp). For drugs administered in the form of pills, capsules, and
fast-dissolving tablets, the markers can be applied as coatings or
physically combined or added to therapeutic drug. Markers can also
be included with therapeutic drugs that are administered in liquid
form (i.e., syrups, via inhalers, or other dosing means).
[0165] The therapeutic drug markers of the invention could be used
for indicating specific drugs or for a class of drugs. For example,
a patient may be taking an anti-depressant (tricyclics such as
nortriptyline), antibiotic, an antihypertensive agent (i.e.,
clonidine), pain medication, and an anti-reflux drug. One marker
could be used for antibiotics as a class, or for subclasses of
antibiotics, such as erythromycins. Another marker could be used
for antihypertensives as a class, or for specific subclasses of
antihypertensives, such as calcium channel blockers. The same would
be true for the anti-reflux drug. Furthermore, combinations of
marker substances could be used allowing a rather small number of
markers to specifically identify a large number of medications.
Therapeutic Drugs
[0166] As contemplated herein, therapeutic drugs to be monitored in
accordance with the subject invention include, but are not limited
to, anesthetic agents, psychiatric drugs (i.e., antidepressants,
anti-psychotics, anti-anxiety drugs, depressants), analgesics,
stimulants, biological response modifiers, NSAIDs, corticosteroids,
disease-modifying antirheumatic drugs (DMARDs), anabolic steroids,
antacids, antiarrhythmics, antibacterials, antibiotics,
anticoagulants and thrombolytics, anticonvulsants, antidiarrheals,
antiemetics, antihistamines, antihypertensives,
anti-inflammatories, antineoplastics, antipyretics, antivirals,
barbiturates, .beta.-blockers, bronchodilators, cough suppressants,
cytotoxics, decongestants, diuretics, expectorants, hormones,
immunosuppressives, hypoglycemics, laxatives, muscle relaxants,
sedatives, tranquilizers, and vitamins.
[0167] For example, the subject invention can effectively monitor
concentrations of the following non-limiting list of therapeutic
drugs in blood: drugs for the treatment of rheumatoid arthritis or
symptoms thereof, systemic lupus erythematosus or symptoms thereof,
degenerative arthritis, vasculitis, inflammatory diseases, angina,
coronary artery disease, peripheral vascular disease; ulcerative
colitis, and Crohn's disease; anti organ rejection drugs;
antiepilepsy medication; and anti-anxiety drugs.
[0168] Therapeutic drugs whose concentration levels in blood can be
monitored in accordance with the subject invention include, but are
not limited to, the following: .alpha.-Hydroxy-Alprazolam;
Acecamide (NAPA); Acetaminophen (Tylenol); Acetylmorphine;
Acetylsalicylic Acid (as Salicylates); .alpha.-hydroxy-alprazolam;
Alprazolam (Xanax); Amantadine (Symmetrel); Ambien (Zolpidem);
Amikacin (Amikin); Amiodarone (Cordarone); Amitriptyline (Elavil)
& Nortriptyline; Amobarbital (Amytal); Anafranil (Clomipramine)
& Desmethylclomipramine; Ativan (Lorazepam); Aventyl
(Nortriptyline); Benadryl (Dephenhydramine); Benziodiazepines;
Benzoylecgonine; Benztropine (Cogentin); Bupivacaine (Marcaine);
Bupropion (Wellbutrin) and Hydroxybupropion; Butabarbital
(Butisol); Butalbital (Fiorinal) Carbamazepine (Tegretol); Cardizem
(Diltiazem); Carisoprodol (Soma) & Meprobamate; and Celexa
(Citalopram & Desmethylcitalopram).
[0169] Additional therapeutic drugs whose blood concentration
levels can be monitored in accordance with the subject invention
include Celontin (Methsuximide) (as desmethylmethsuximide); Centrax
(Prazepam) (as Desmethyldiazepam); Chloramphenicol (Chloromycetin);
Chlordiazepoxide; Chlorpromazine (Thorazine); Chlorpropamide
(Diabinese); Clonazepam (Monopin); Clorazepate (Tranxene);
Clozapine; Cocaethylene; Codeine; Cogentin (Benztropine); Compazine
(Prochlorperazine) Cordarone (Amiodarone); Coumadin (Warfarin);
Cyclobenzaprine (Flexeril); Cyclosporine (Sandimmune); Cylert
(Pemoline); Dalmane (Flurazepam) & Desalkylflurazepam;
Darvocet; Darvon (Propoxyphene) & Norpropoxyphene; Demerol
(Meperidine) & Normeperidine; Depakene (Valproic Acid);
Depakote (Divalproex) (Measured as Valproic Acid); Desipramine
(Norpramin); Desmethyldiazepam; Desyrel (Trazodone); Diazepam &
Desmethyldiazepam; Diazepam (Valium) Desmethyldiazepam; Dieldrin;
Digoxin (Lanoxin); Dilantin (Phenytoin); Disopyramide (Norpace);
Dolophine (Methadone); Doriden (Glutethimide); Doxepin (Sinequan)
and Desmethyldoxepin; Effexor (Venlafaxine); Ephedrine; Equanil
(Meprobamate) Ethanol; Ethosuximide (Zarontin); Ethotoin
(Peganone); Felbamate (Felbatol); Fentanyl (Innovar); Fioricet;
Fipronil; Flunitrazepam (Rohypnol); Fluoxetine (Prozac) &
Norfluoxetine; Fluphenazine (Prolixin); Fluvoxamine (Luvox);
Gabapentin (Neurontin); Gamma-Hydroxyhutyric Acid (GHB); Garamycin
(Gentamicin); Gentamicin (Garamycin); Halazepam (Paxipam); Halcion
(Triazolam); Haldol (Haloperidol); Hydrocodone (Hycodan);
Hydroxyzine (Vistaril); Ibuprofen (Advil, Motrin, Nuprin, Rufen);
Imipramine (Tofranil) and Desipramine; Inderal (Propranolol);
Keppra (Levetiracetam); Ketamine; Lamotrigine (Lamictal); Lanoxin
(Digoxin); Lidocaine (Xylocaine); Lindane (Gamma-BHC); Lithium;
Lopressor (Metoprolol); Lorazepam (Ativan); and Ludiomil.
[0170] Blood level concentrations of the following therapeutic
drugs that can be monitored in accordance with the subject
invention include, but are not limited to, Maprotiline; Mebaral
(Mephobarbital) & Phenobarbital; Mellaril (Thioridazine) &
Mesoridazine; Mephenytoin (Mesantoin); Meprobamate (Miltown,
Equanil); Mesantoin (Mephenyloin); Mesoridazine (Serentil);
Methadone; Methotrexate (Mexate); Methsuximide (Celontin) (as
desmethsuximide); Mexiletine (Mexitil); Midazolam (Versed);
Mirtazapine (Remeron); Mogadone (Nitrazepam); Molindone (Mohair);
Morphine; Mysoline (Primidone) & Phenobarbital; NAPA &
Procainamide (Pronestyl); NAPA (N-Acetyl-Procainamide); Navane
(Thiothixene); Nebcin (Tobramycin); Nefazodone (Serzone); Nembutal
(Pentobarbital); Nordiazepam; Olanzapine (Zyprexa); Opiates;
Orinase (Tolbutamide); Oxazepam (Serax); Oxcarbazepine (Trileptal)
as 10-Hydroxyoxcarbazepine; Oxycodone (Percodan); Oxymorphone
(Numorphan); Pamelor (Nortriptyline); Paroxetine (Paxil); Paxil
(Paroxetine); Paxipam (Halazepam); Peganone (Ethotoin);
(Phenylethylmalonamide); Pentothal (Thiopental); Perphenazine
(Trilafon); Phenergan (Promethazine); Phenothiazine; Phentermine;
Phenylglyoxylic Acid; Procainamide (Pronestyl) & NAPA;
Promazine (Sparine); Propafenone (Rythmol); Protriptyline
(Vivactyl); Pseudoephedrine; Quetiapine (Seroquel); Restoril
(Temazepam); Risperdal (Risperidone) and Hydroxyrisperidone;
Secobarbital (Seconal); Sertraline (Zoloft) Desmethylsertraline;
Stelazine (Trifluoperazine); Surmontil (Trimipramine); Tocamide
(Tonocard); and Topamax (Topiramate).
[0171] Therapeutic drugs of the subject invention can be formulated
according to known methods for preparing pharmaceutically useful
compositions. Formulations are described in a number of sources,
which are well known and readily available to those skilled in the
art. For example, Remington's Pharmaceutical Science (Martin E W
[1995] Easton Pa., Mack Publishing Company, 19.sup.th ed.)
describes formulations that can be used in connection with the
subject invention. Formulations suitable for parenteral
administration include, for example, aqueous sterile injection
solutions, which may contain antioxidants, buffers, bacteriostats,
and solutes, which render the formulation isotonic with the blood
of the intended recipient; and aqueous and nonaqueous sterile
suspensions, which may include suspending agents and thickening
agents.
[0172] Formulations may be presented in unit-dose or multi-dose
containers, for example sealed ampoules and vials, and may be
stored in a freeze dried (lyophilized) condition requiring only the
condition of the sterile liquid carrier, for example, water for
injections, prior to use. Extemporaneous injection solutions and
suspensions may be prepared from sterile powder, granules, tablets,
etc. It should be understood that in addition to the ingredients
particularly mentioned above, the formulations of the subject
invention can include other agents conventional in the art having
regard to the type of formulation in question.
[0173] Administration of a therapeutic drug, in accordance with the
subject invention, can be accomplished by any suitable method and
technique presently or prospectively known to those skilled in the
art. In a preferred embodiment, a therapeutic drug is formulated in
a patentable and easily consumed oral formulation such as a pill,
lozenge, tablet, gum, beverage, etc.
[0174] According to the subject invention, a therapeutic drug can
be delivered from a controlled supply means (i.e., pill dispenser,
IV bag, etc.). Upon delivery of the therapeutic drug to a patient,
a sensor of the invention analyzes a patient's expired gases to
detect at least one target marker of the therapeutic drug. Upon
detection of the target marker, the concentration of the
therapeutic drug in blood can be determined for use in deriving the
appropriate dosage amount of the therapeutic drug to next be
delivered to the patient. In one embodiment, a system controller
utilizes the derived appropriate dosage based on exhaled breath
analysis to dispense an appropriate dosage from the supply means to
the patient.
[0175] Additional embodiments are also envisioned herein. Pulmonary
delivery of medications is well known, especially for conditions
such as asthma and chronic obstructive pulmonary disease. In these
instances, medication (i.e. corticosteroids, bronchodilators,
anticholinergics, etc.) is often nebulized or aerosolized and
inhaled through the mouth directly into the lungs. This allows
delivery directly to the affected organ (the lungs) and reduces
side effects common with enteral (oral) delivery. Metered dose
inhalers (MDIs) or nebulizers are commonly used to deliver
medication by this route. Recently dry powder inhalers have become
increasingly popular, as they do not require the use of propellants
such as CFCs. Propellants have been implicated in worsening asthma
attacks, as well as depleting the ozone layer. Dry power inhalers
are also being used for drugs that were previously given only by
other routes, such as insulin, peptides, and hormones.
[0176] Olfactory markers can be added to these delivery systems as
well. Since the devices are designed to deliver medication by the
pulmonary route, the sensor array can be incorporated into the
device and the patient need only exhale back through the device for
documentation to occur.
[0177] Lastly, devices are available to deliver medication by the
intranasal route. This route is often used for patients with viral
infections or allergic rhinitis, but is being increasing used to
deliver peptides and hormones as well. Again, it would be simple to
incorporate a sensor array into these devices, or the patient can
exhale through the nose for detection by a marker sensing
system.
[0178] Following are examples which illustrate procedures for
practicing the invention. These examples should not be construed as
limiting. All percentages are by weight and all solvent mixture
proportions are by volume unless otherwise noted.
Example 1
Intravenous IV Anesthesia Delivery
[0179] During intravenous anesthesia, anesthetic agents are
administered directly into a patient's bloodstream rather than
administering gases through a breathing circuit. The administered
drug may bind to proteins circulating in the blood, be absorbed
into fat or exist in a "free" form. Drug bound to protein or
absorbed in fat does not produce a pharmacological effect and
exists in equilibrium with unbound drug. Numerous factors,
including competition for binding sites on the protein from other
drugs, the amount of fat in the body and the amount of protein
produced, determine the equilibrium between bound and unbound drug.
Unbound drug may participate directly in the pharmacological effect
or be metabolized into a drug that produces the effect. Metabolism
of the active drug often leads to its removal from the bloodstream
and termination of its effect. The drug effect can also be
terminated by the excretion of the free drug. Free drug or a
metabolite can be excreted in the urine or the digestive tract or
in exhaled breath. The concentration in the blood (or plasma or
serum) of such agents (e.g., propofol, alfentanil and remifentanil)
is related to the clinical effect of the agent.
[0180] FIG. 3 represents the FT-IR signal for propofol
(2,6-diisopropylphenol). It has been specifically shown that there
is a good correlation between blood concentration of anesthetic
agents (e.g., propofol) and depth of anesthesia. Therefore, testing
blood concentration is a good indicator of the effect of the agent
(depth of anesthesia). Unfortunately, testing blood directly is
invasive and time consuming. When a drug or its metabolite is
excreted in the breath, the concentration in expired breath is
proportional to the free drug or metabolite concentration in the
blood and, thus, indicative of depth of anesthesia and/or the rate
of drug metabolism. The metabolite measured in exhaled breath may
be the active metabolite or a breakdown product of the active drug.
As long as there is equilibrium between the active drug and an
inactive metabolite excreted in the breath, the activity of the
active drug will be known. The method of the present invention
takes into account such proportional concentrations and allows for
the determination of depth of anesthesia and/or the rate of
metabolism of the drug by measuring concentration of unbound
substances, agents and/or active metabolites in a patient's breath,
see FIG. 4. The proper dosing regimen can thus be determined
therefrom.
[0181] Generally, the exhalation gas stream comprises sequences or
stages. At the beginning of exhalation there is an initial stage,
the gas representative thereof coming from an anatomically inactive
(deadspace) part of the respiratory system, in other words, from
the mouth and upper respiratory tracts. This is followed by a
plateau stage. Early in the plateau stage, the gas is a mixture of
deadspace and metabolically active gases. The last portion of the
exhaled breath comprises nothing but deep lung, so-called alveolar
gas. This gas, which comes from the alveoli, is termed end-tidal
gas. In one embodiment, the exhaled breath sample is collected at
end-tidal breathing. Technology similar to that used for end-tidal
carbon dioxide monitoring can be used to determine when the sample
is collected. Airway pressure measurements afford another means of
collecting samples at the appropriate phase of the respiratory
cycle. Single or multiple samples collected by the side stream
method are preferable, but if sensor acquisition time is reduced,
in-line sampling may be used. In the former, samples are collected
through an adapter at the proximal end of the endotracheal tube and
drawn through thin bore tubing to the sensor chamber. Depending on
the sample size and detector response time, gas may be collected on
successive cycles. With in-line sampling, the sensor is placed
proximal to the ET tube directly in the gas stream. Alternatively
to sampling end-tidal gas, samples can be taken throughout the
exhalation phase of respiration and average value determined and
correlated with blood concentration.
[0182] Referring now to FIG. 5a, the characteristic signature of
propofol from a four (4) sensor polymer coated SAW array is shown.
In this example, 1 cc of propofol was placed in a "headspace" gas
chromatography vial. A 19-gauge hypodermic needle attached to a
VaporLab.TM. gas detector containing the sensor array was inserted
into the vial, which was heated to 37.degree. C., and the
"signature" was recorded. The VaporLab.TM. brand instrument is a
hand-held, battery powered SAW based chemical vapor identification
instrument suitable for detecting vapors in accordance with the
present invention. This instrument is sensitive to volatile and
semi-volatile compounds and has a high-stability SAW sensor array
that provides orthogonal vapor responses for greater accuracy and
discrimination. The device communicates with computers to provide
enhanced pattern analysis and report generation. The device can be
easily "trained" to remember chemical vapor signature patterns for
fast, "on-the-fly" analysis. Note that the "signature" has both
amplitude and temporal resolution. In the present invention, vapor
concentration measurements of vapors are made by detecting the
adsorption of molecules onto the surface of a SAW sensor coated
with a polymer thin film. This thin film is specifically coated to
provide selectivity and sensitivity to specific vapors. The SAW is
inserted as an active feedback element in an oscillator circuit. A
frequency counter measures the oscillation frequency, which
corresponds to the resonant frequency of the SAW sensor. The
response of the SAW sensor to the vapor is measured as a shift in
the resonant frequency of the SAW sensor. This configuration
requires an oscillator circuit, the coated SAW sensor, and a
frequency counter, all of which can be housed on a small printed
circuit board.
[0183] FIG. 5b shows an example of a Propofol relative breath
concentration profile in a patient.
[0184] In another embodiment, samples are collected at the distal
end of the endotracheal tube (ETT) through a tube with a separate
sampling port. This may improve sampling by allowing a larger
sample during each respiratory cycle.
[0185] The concentration of an anesthetic agent in the body is
regulated both by the amount of the agent administered over a given
time period and the rate at which the agent is eliminated from the
body (metabolism). The present invention provides the steps of
administering an agent to the subject and analyzing exhaled breath
of the subject for concentration of unbound substances, active
metabolites, or inactive metabolites after a suitable time period;
the concentration indicates a characteristic of metabolism of the
agent in the subject. The method may further include using a flow
sensor to detect starting and completion of exhalation. The method
further includes providing results from the analysis and
controlling the infusion pump for delivering the intravenous
anesthesia agent based on the results. Moreover, a CPU may be
provided as a data processing/control unit for automatically
detecting the signal from the flow sensor to control sampling of
exhaled breath. The CPU may further provide the analysis and
control of the infusion pump or other administering means.
[0186] Methods for administering the agent are readily understood
by those skilled in the art. For example, an infusion pump may be
used. Compounds may be also administered parenterally,
sublingually, transdermally, by i.v. bolus, and by continuous
infusion. A number of suitable agents are available for
administration as also known by those skilled in the art
(Remifentanil--Glaxo Wellcome, Propofol--Zeneca). Agents may also
be those of amnesia, analgesia, muscle relaxation, and sedation
agents or a combination thereof. Agents may be administered in an
amount for analgesia, conscious sedation, or unconsciousness as
known in the art. Patient characteristics may also be monitored
during administration of the agent.
[0187] Concentration in the blood as measured by the breath
analysis of the present invention for free agents or metabolites
may indicate when the patient is receiving an anesthetic
concentration (a high dose), an analgesic concentration (a low
dose), or emerging from anesthesia as a result of a level that
allows for full recovery. Even if there is wide variation in the
metabolism or response to an anesthetic agent, knowledge of the
exhaled breath concentration allows the anesthesiologist to know if
the drug is accumulating in the blood, possibly leading to a
dangerously deep level of anesthesia and/or a prolonged recovery
time: or, the concentration is falling, possibly leading to
inadequate anesthesia and premature emergence. Monitoring changes
in concentration are, therefore, useful.
[0188] In another embodiment, the exhalation air is measured for
free agent and/or metabolite concentration either continuously or
periodically. From the exhalation air is extracted at least one
measured free agent or metabolite concentration value. Numerous
types of apparatus may be used to carry out the method of the
present invention. In one embodiment, the apparatus includes a
conventional flow channel through which exhalation air flows. The
flow channel is provided with sensor elements for measuring free
agent or metabolite concentration. Furthermore, the apparatus
includes necessary output elements for delivering at least a
measured concentration result to the operator, if necessary. An
alarm mechanism may also be provided. An instrument of similar type
is shown in FIGS. 1 and 2 of U.S. Pat. No. 5,971,937 incorporated
herein by reference.
[0189] In one embodiment, the device of the present invention may
be designed so that patients can exhale via the mouth or nose
directly into the device, FIG. 4.
[0190] Preferably, in operation, the sensor will be used to
identify a baseline spectrum for the patient prior to delivery, if
necessary. This will prove beneficial for the detection of more
than one drug if the patient receives more than one drug at a time
and possible interference from different foods and odors in the
stomach, mouth, esophagus and lungs.
Example 2
Inhalational Anesthesia
[0191] Inhalation agents are generally administered through a
breathing system. A breathing system is an assembly of components
which connects the patient's airway to the anesthetic machine, from
and into which the patient breathes. As known in the art, such
systems generally include a fresh gas entry port/delivery tube
through which the gases are delivered from the machine; a port to
connect it to the patient's airway (oral airway, mask, endotracheal
tube); a reservoir for gas; a expiratory port/valve through which
the expired gas is vented to the atmosphere; a carbon dioxide
absorber (for rebreathing); and tubes for connecting these
components. Flow directing valves may or may not be used.
[0192] The sensors of the present invention are in communication
with the delivered (inspired) gas and/or the expired gas of the
breathing circuit to appropriately monitor the target substance(s).
Preferably, the sensors are in flow communication with the
appropriate tubes, valves, etc. of the circuit. FIGS. 6a and 6b
show the unique signatures of the inhalational anesthetics
Isoflurane and Sevoflurane, respectively, sampled from a breathing
circuit. Sensors may be placed throughout the breathing circuit to
obtain readings for target substances. Inspired gases are monitored
by connecting the sensor(s) of the present invention to the
appropriate location(s) in the breathing circuit. Similarly,
expired gases are monitored by connecting the sensor(s) of the
present invention to the appropriate location(s) in the breathing
circuit. In an embodiment, samples are collected at the distal end
of the endotracheal tube (ETT) through a tube with a separate
sampling port. This may improve sampling by allowing a larger
sample during each respiratory cycle. Monitored expired gases
include, for example, physiologic gases and anesthetic gases. If IV
anesthesia is also administered, as in "balanced anesthesia,"
monitoring expired gases will also include measuring concentration
in the blood by the breath analysis of the present invention.
[0193] In an embodiment, side-stream monitoring is used. Moreover,
a water trap, desiccant and/or filter may be used to remove water
vapor and condensation from the sample. The device of the present
invention continuously samples and measures inspired and exhaled
(end-tidal) concentrations of respiratory gases. The monitored
gases are both the physiologic gases found in the exhaled breath of
patients (oxygen, carbon dioxide, and nitrogen), as well as those
administered to the patient by the anesthesiologist in order to
induce and maintain analgesia and anesthesia.
[0194] The sensors of the present invention may also monitor purity
of gases at the entry port (fresh gas entry) and/or carrier gases.
If multiple volatile anesthetic agents are connected to the
circuit, an appropriate number of sensors may be included to detect
each of such agents at the respective entry points as well as prior
to inspiration.
[0195] Any number of sensors may be used at various points in the
circuit to accomplish the desired monitoring. All of the sensors
may connect to a single processor for analysis or use multiple
processors. Similarly, the results of the monitoring may be
displayed through a single display device or multiple display
devices as desired. The method and apparatus of the present
invention will detect and quantitate the concentration of the
target substances.
Example 3
Selection of Sensors
[0196] The following are examples of various sensor technologies
that may be utilized in practicing the method of the present
invention:
Microgravimetric Sensors
[0197] Microgravimentric sensors are based on the preparation of
polymeric- or biomolecule-based sorbents that are selectively
predetermined for a particular substance, or group of structural
analogs. A direct measurement of mass changes induced by binding of
a sorbent with a target marker can be observed by the propagation
of acoustic shear waves in the substrate of the sensor. Phase and
velocity of the acoustic wave are influenced by the specific
adsorption of target markers onto the sensor surface. Piezoelectric
materials, such as quartz (SiO.sub.2) or zinc oxide (ZnO), resonate
mechanically at a specific ultrasonic frequency when excited in an
oscillating field. Electromagnetic energy is converted into
acoustic energy, whereby piezoelectricity is associated with the
electrical polarization of materials with anisotropic crystal
structure. Generally, the oscillation method is used to monitor
acoustic wave operation. Specifically, the oscillation method
measures the series resonant frequency of the resonating sensor.
Types of sensors derived from microgravimetric sensors include
quartz crystal microbalance (QCM) devices that apply a
thickness-shear mode (TSM) and devices that apply surface acoustic
wave (SAW) detection principle. Additional devices derived from
microgravimetric sensors include the flexural plate wave (FPW), the
shear horizontal acoustic plate (SH-APM), the surface transverse
wave (STW) and the thin-rod acoustic wave (TRAW).
Conducting Polymers
[0198] Conducting polymer sensors promise fast response time, low
cost, and good sensitivity and selectivity. The technology is
relatively simple in concept. A conductive material, such as
carbon, is homogeneously blended in a specific non-conducting
polymer and deposited as a thin film on an aluminum oxide
substrate. The films lie across two electrical leads, creating a
chemoresistor. As the polymer is subjected to various chemical
vapors, it expands, increasing the distance between carbon
particles, and thereby increasing the resistance. The polymer
matrix swells because analyte vapor absorbs into the film to an
extent determined by the partition coefficient of the analyte. The
partition coefficient defines the equilibrium distribution of an
analyte between the vapor phase and the condensed phase at a
specified temperature. Each individual detector element requires a
minimum absorbed amount of analyte to cause a response noticeable
above the baseline noise. Selectivity to different vapors is
accomplished by changing the chemical composition of the polymer.
This allows each sensor to be tailored to specific chemical vapors.
Therefore, for most applications an array of orthogonal responding
sensors is required to improve selectivity. Regardless of the
number of sensors in the array, the information from them must be
processed with pattern recognition software to correctly identify
the chemical vapors of interest. Sensitivity concentrations are
reportedly good (tens of ppm). The technology is very portable
(small and low power consumption), relatively fast in response time
(less than 1 minute), low cost, and should be rugged and
reliable.
Electrochemical Sensors
[0199] Electrochemical sensors measure a change in output voltage
of a sensing element caused by chemical interaction of a target
marker on the sensing element. Certain electrochemical sensors are
based on a transducer principle. For example, certain
electrochemical sensors use ion-selective electrodes that include
ion-selective membranes, which generate a charge separation between
the sample and the sensor surface. Other electrochemical sensors
use an electrode by itself as the surface as the complexation
agent, where a change in the electrode potential relates to the
concentration of the target marker. Further examples of
electrochemical sensors are based on semiconductor technology for
monitoring charges at the surface of an electrode that has been
built up on a metal gate between the so-called source and drain
electrodes. The surface potential varies with the target marker
concentration.
[0200] Additional electrochemical sensor devices include
amperometric, conductometric, and capacitive immunosensors.
Amperometric immunosensors are designed to measure a current flow
generated by an electrochemical reaction at a constant voltage.
Generally, electrochemically active labels directly, or as products
of an enzymatic reaction, are needed for an electrochemical
reaction of a target marker at a sensing electrode. Any number of
commonly available electrodes can be used in amperometric
immunosensors, including oxygen and H.sub.2O.sub.2 electrodes.
[0201] Capacitive immunosensors are sensor-based transducers that
measure the alteration of the electrical conductivity in a solution
at a constant voltage, where alterations in conductivity are caused
by biochemical enzymatic reactions, which specifically generate or
consume ions. Capacitance changes are measured using an
electrochemical system, in which a bioactive element is immobilized
onto a pair of metal electrodes, such as gold or platinum
electrodes.
[0202] Conductometric immunosensors are also sensor-based
transducers that measure alteration of surface conductivity. As
with capacitive immunosensors, bioactive elements are immobilized
on the surface of electrodes. When the bioactive element interacts
with a target marker, it causes a decrease in the conductivity
between the electrodes.
[0203] Electrochemical sensors are excellent for detecting low
parts-per-million concentrations. They are also rugged, draw little
power, linear and do not require significant support electronics or
vapor handling (pumps, valves, etc.) They are moderate in cost ($50
to $200 in low volumes) and small in size.
Gas Chromatography/Mass Spectrometry (GC/MS)
[0204] Gas Chromatography/Mass Spectrometry (GC/MS) is actually a
combination of two technologies. One technology separates the
chemical components (GC) while the other one detects them (MS).
Technically, gas chromatography is the physical separation of two
or more compounds based on their differential distribution between
two phases, the mobile phase and stationary phase. The mobile phase
is a carrier gas that moves a vaporized sample through a column
coated with a stationary phase where separation takes place. When a
separated sample component elutes from the column, a detector
converts the column eluent to an electrical signal that is measured
and recorded. The signal is recorded as a peak in the chromatogram
plot. Chromatograph peaks can be identified from their
corresponding retention times. The retention time is measured from
the time of sample injection to the time of the peak maximum, and
is unaffected by the presence of other sample components. Retention
times can range from seconds to hours, depending on the column
selected and the component. The height of the peak relates to the
concentration of a component in the sample mixture.
[0205] After separation, the chemical components need to be
detected. Mass spectrometry is one such detection method, which
bombards the separated sample component molecules with an electron
beam as they elute from the column. This causes the molecules to
lose an electron and form ions with a positive charge. Some of the
bonds holding the molecule together are broken in the process, and
the resulting fragments may rearrange or break up further to form
more stable fragments. A given compound will ionize, fragment, and
rearrange reproducibly under a given set of conditions. This makes
identification of the molecules possible. A mass spectrum is a plot
showing the mass/charge ratio versus abundance data for ions from
the sample molecule and its fragments. This ratio is normally equal
to the mass for that fragment. The largest peak in the spectrum is
the base peak. The GC/MS is accurate, selective and sensitive.
Infrared Spectroscopy (FTIR, NDIR)
[0206] Infrared (IR) spectroscopy is one of the most common
spectroscopic techniques used by organic and inorganic chemists.
Simply, it is the absorption measurement of different IR
frequencies by a sample positioned in the path of an IR beam. IR
radiation spans a wide section of the electromagnetic spectrum
having wavelengths from 0.78 to 1000 micrometers (microns).
Generally, IR absorption is represented by its wave number, which
is the inverse of its wavelength times 10,000. For a given sample
to be detected using IR spectroscopy, the sample molecule must be
active in the IR region, meaning that the molecule must vibrate
when exposed to IR radiation. Several reference books are available
which contain this data, including the Handbook of Chemistry and
Physics from the CRC Press.
[0207] There are two general classes of IR
spectrometers--dispersive and non-dispersive. In a typical
dispersive IR spectrometer, radiation from a broadband source
passes through the sample and is dispersed by a monochromator into
component frequencies. The beams then fall on a detector, typically
a thermal or photon detector, which generates an electrical signal
for analysis. Fourier Transform IR spectrometers (FTIR) have
replaced the dispersive IR spectrometer due to their superior speed
and sensitivity. FTIR eliminates the physical separation of optical
component frequencies by using a moving minor Michelson
interferometer and taking the Fourier transform of the signal.
[0208] Conversely, in the non-dispersive IR (NDIR) spectrometer,
instead of sourcing a broad IR spectrum for analyzing a range of
sample gases, the NDIR sources a specific wavelength which
corresponds to the absorption wavelength of the target sample. This
is accomplished by utilizing a relatively broad IR source and using
spectral filters to restrict the emission to the wavelength of
interest. For example, NDIR is frequently used to measure carbon
monoxide (CO), which absorbs IR energy at a wavelength of 4.67
microns. By carefully tuning the IR source and detector during
design, a high volume production CO sensor is manufactured. This is
particularly impressive, as carbon dioxide is a common interferent
and has an IR absorption wavelength of 4.26 microns, which is very
close to that of CO.
[0209] NDIR sensors promise low cost (less than $200), no recurring
costs, good sensitivity and selectivity, no calibration and high
reliability. They are small, draw little power and respond quickly
(less than 1 minute). Warm up time is nominal (less than 5
minutes). Unfortunately, they only detect one target gas. To detect
more gases additional spectral filters and detectors are required,
as well as additional optics to direct the broadband IR source.
Ion Mobility Spectrometry (IMS)
[0210] Ion Mobility Spectrometry (IMS) separates ionized molecular
samples on the basis of their transition times when subjected to an
electric field in a tube. As the sample is drawn into the
instrument, it is ionized by a weak radioactive source. The ionized
molecules drift through the cell under the influence of an electric
field. An electronic shutter grid allows periodic introduction of
the ions into the drift tube where they separate based on charge,
mass, and shape. Smaller ions move faster than larger ions through
the drift tube and arrive at the detector sooner. The amplified
current from the detector is measured as a function of time and a
spectrum is generated. A microprocessor evaluates the spectrum for
the target compound, and determines the concentration based on the
peak height.
[0211] IMS is an extremely fast method and allows near real time
analysis. It is also very sensitive, and should be able to measure
all the analytes of interest. IMS is moderate in cost (several
thousand dollars) and larger in size and power consumption.
Metal Oxide Semiconductor (MOS) Sensors
[0212] Metal Oxide Semiconductor (MOS) sensors utilize a
semiconducting metal-oxide crystal, typically tin-oxide, as the
sensing material. The metal-oxide crystal is heated to
approximately 400.degree. C., at which point the surface adsorbs
oxygen. Donor electrons in the crystal transfer to the adsorbed
oxygen, leaving a positive charge in the space charge region. Thus,
a surface potential is formed, which increases the sensor's
resistance. Exposing the sensor to deoxidizing, or reducing, gases
removes the surface potential, which lowers the resistance. The end
result is a sensor which changes its electrical resistance with
exposure to deoxidizing gases. The change in resistance is
approximately logarithmic.
[0213] MOS sensors have the advantage of being extremely low cost
(less than $8 in low volume) with a fast analysis time
(milliseconds to seconds). They have long operating lifetimes
(greater than five years) with no reported shelf life issues.
Thickness-Shear Mode Sensors (TSM)
[0214] TSM sensors consist of an AT-cut piezoelectric crystal disc,
most commonly of quartz because of its chemical stability in
biological fluids and resistance to extreme temperatures, and two
electrodes (preferably metal) attached to opposite sides of the
disc. The electrodes apply the oscillating electric field.
Generally, TSM sensor devices are run in a range of 5-20 MHz.
Advantages are, besides the chemical inertness, the low cost of the
devices and the reliable quality of the mass-produced quartz
discs.
Photo-Ionization Detectors (PID)
[0215] Photo-Ionization Detectors rely on the fact that all
elements and chemicals can be ionized. The energy required to
displace an electron and `ionize` a gas is called its Ionization
Potential (IP), measured in electron volts (eV). A PID uses an
ultraviolet (UV) light source to ionize the gas. The energy of the
UV light source must be at least as great as the IP of the sample
gas. For example, benzene has an IP of 9.24 eV, while carbon
monoxide has an IP of 14.01 eV. For the PID to detect the benzene,
the UV lamp must have at least 9.24 eV of energy. If the lamp has
an energy of 15 eV, both the benzene and the carbon monoxide would
be ionized. Once ionized, the detector measures the charge and
converts the signal information into a displayed concentration.
Unfortunately, the display does not differentiate between the two
gases, and simply reads the total concentration of both summed
together.
[0216] Three UV lamp energies are commonly available: 9.8, 10.6 and
11.7 eV. Some selectivity can be achieved by selecting the lowest
energy lamp while still having enough energy to ionize the gases of
interest. The largest group of compounds measured by a PID are the
organics (compounds containing carbon), and they can typically be
measured to parts per million (ppm) concentrations. PIDs do not
measure any gases with an IP greater than 11.7 eV, such as
nitrogen, oxygen, carbon dioxide and water vapor. The CRC Press
Handbook of Chemistry and Physics includes a table listing the IPs
for various gases.
[0217] PIDs are sensitive (low ppm), low cost, fast responding,
portable detectors. They also consume little power.
Surface Acoustic Wave Sensors (SAW)
[0218] Surface Acoustic Wave (SAW) sensors are constructed with
interdigitated metal electrodes fabricated on piezoelectric
substrates both to generate and to detect surface acoustic waves.
Surface acoustic waves are waves that have their maximum amplitude
at the surface and whose energy is nearly all contained within 15
to 20 wavelengths of the surface. Because the amplitude is a
maximum at the surface such devices are very surface sensitive.
Normally, SAW devices are used as electronic bandpass filters in
cell phones. They are hermetically packaged to insure that their
performance will not change due to a substance contacting the
surface of the SAW.
[0219] SAW chemical sensors take advantage of this surface
sensitivity to function as sensors. To increase specificity for
specific compounds, SAW devices are frequently coated with a thin
polymer film that will affect the frequency and insertion loss of
the device in a predictable and reproducible manner. Each sensor in
a sensor array is coated with a different polymer and the number
and type of polymer coating are selected based on the chemical to
be detected. If the device with the polymer coating is then
subjected to chemical vapors that absorb into the polymer material,
then the frequency and insertion loss of the device will further
change. It is this final change that allows the device to function
as a chemical sensor.
[0220] If several SAW devices are each coated with a different
polymer material, the response to a given chemical vapor will vary
from device to device. The polymer films are normally chosen so
that each will have a different chemical affinity for a variety of
organic chemical classes, that is, hydrocarbon, alcohol, ketone,
oxygenated, chlorinated, and nitrogenated. If the polymer films are
properly chosen, each chemical vapor of interest will have a unique
overall effect on the set of devices. SAW chemical sensors are
useful in the range of organic compounds from hexane on the light,
volatility extreme to semi-volatile compounds on the heavy, low
volatility extreme.
[0221] Motors, pumps and valves are used to bring the sample into
and through the array. The sensitivity of the system can be
enhanced for low vapor concentrations by having the option of using
a chemical preconcentrator before the array. In operation, the
preconcentrator absorbs the test vapors for a period of time and is
then heated to release the vapors over a much shorter time span
thereby increasing the effective concentration of the vapor at the
array. The system uses some type of drive and detection electronics
for the array. An on board microprocessor is used to control the
sequences of the system and provide the computational power to
interpret and analyze data from the array.
[0222] SAW sensors are reasonably priced (less than $200) and have
good sensitivity (tens of ppm) with very good selectivity. They are
portable, robust and consume nominal power. They warm up in less
than two minutes and require less than one minute for most
analysis. They are typically not used in high accuracy quantitative
applications, and thus require no calibration. SAW sensors do not
drift over time, have a long operating life (greater than five
years) and have no known shelf life issues. They are sensitive to
moisture, but this is addressed with the use of a thermally
desorbed concentrator and processing algorithms.
Amplifying Fluorescent Polymer Technology
[0223] Sensors can use fluorescent polymers that react with
volatile chemicals as sensitive target marker detectors.
Conventional fluorescence detection normally measures an increase
or decrease in fluorescence intensity or an emission wavelength
shift that occurs when a single molecule of the target marker
interacts with an isolated chromophore, where the chromophore that
interacts with the target marker is quenched; the remaining
chromophores continue to fluoresce.
[0224] A variation of this approach is the "molecular wire"
configuration, as described by Yang and Swager, J. Am. Chem. Soc.,
120:5321-5322 (1998) and Cumming et al., IEEE Trans Geoscience and
Remote Sensing, 39:1119-1128 (2001), both of which are incorporated
herein by reference in their entirety. In the molecular wire
configuration, the absorption of a single photon of light by any
chromophore will result in a chain reaction, quenching the
fluorescence of many chromophores and amplifying the sensory
response by several orders of magnitude. Sensors based on the
molecular wire configuration have been assembled for detecting
explosives (see Swager and Wosnick, MRS Bull, 27:446-450 (2002),
which is incorporated herein by reference in its entirety.
Fiber Optic Micro sphere Technology
[0225] Fiber optic microsphere technology is based upon an array of
a plurality of microsphere sensors (beads), wherein each
microsphere belongs to a discrete class that is associated with a
target marker, that is placed on an optical substrate containing a
plurality of micrometer-scale wells (see, for example, Michael et
al., Anal Chem, 71:2192-2198 (1998); Dickinson et al., Anal Chem.,
71:2192-2198 (1999); Albert and Walt, Anal Chem, 72:1947-1955
(2000); and Stitzel et al., Anal Chem, 73:5266-5271 (1001), all of
which are incorporated herein by reference in their entirety). Each
type of bead is encoded with a unique signature to identify the
bead as well as its location. Upon exposure to a target marker, the
beads respond to the target marker and their intensity and
wavelength shifts are used to generate fluorescence response
patterns, which are, in turn, compared to known patterns to
identify the target marker.
Interdigitated Microelectrode Arrays (IME)
[0226] Interdigitated microelectrode arrays are based on the used
of a transducer film that incorporates an ensemble of
nanometer-sized metal particles, each coated by an organic
monomolecular layer shell (see, for example, Wohltjen and Snow,
Anal Chem, 70:2856-2859 (1998); and Jarvis et al., Proceedings of
the 3.sup.rd Intl Aviation Security Tech Symposium, Atlantic City,
N.J., 639-647 (2001), both of which are incorporated herein by
reference in their entirety). Such sensor devices are also known as
metal-insulator-metal ensembles (MIME) because of the combination
of a large group of colloidal-sized, conducting metal cores
separated by thin insulating layers.
Microelectromechanical Systems (MEMS)
[0227] Sensor technology based on MEMS integrate mechanical
elements, sensors, actuators, and electronics on a common silicon
substrate for use in detecting target markers (see, for example,
Pinnaduwage et al., Proceedings of 3.sup.rd Intl Aviation Security
Tech Symposium, Atlantic City, N.J., 602-615 (2001); and Lareau et
al., Proceedings of 3.sup.rd Intl Aviation Security Tech Symposium,
Atlantic City, N.J., 332-339 (2001), both of which are incorporated
herein by reference in their entirety).
[0228] One example of sensor technology based on MEMS is
microcantilever sensors. Microcantilever sensors are hairlike,
silicon-based devices that are at least 1,000 times more sensitive
and smaller than currently used sensors. The working principle for
most microcantilever sensors is based on a measurement of
displacement. Specifically, in biosensor applications, the
displacement of a cantilever-probe is related to the binding of
molecules on the (activated) surface of the cantilever beam, and is
used to compute the strength of these bonds, as well as the
presence of specific reagents in the solution under consideration
(Fritz, J. et al., "Translating biomolecular recognition into
nanomechanics," Science, 288:316-318 (2000); Raiteri, R. et al.,
"Sensing of biological substances based on the bending of
microfabricated cantilevers," Sensors and Actuators B, 61:213-217
(1999), both of which are incorporated herein by reference in their
entirety). It is clear that the sensitivity of these devices
strongly depends on the smallest detectable motion, which poses a
constraint on the practically vs. theoretically achievable
performance.
[0229] One example of microcantilever technology uses silicon
cantilever beams (preferably a few hundred micrometers long and 1
.mu.m thick) that are coated with a different sensor/detector layer
(such as antibodies or aptamers). When exposed to a target marker,
the cantilever surface absorbs the target marker, which leads to
interfacial stress between the sensor and the absorbing layer that
bends the cantilever. Each cantilever bends in a characteristic way
typical for each target marker. From the magnitude of the
cantilever's bending response as a function of time, a fingerprint
pattern for each target marker can be obtained.
[0230] Microcantilever sensors are highly advantageous in that they
can detect and measure relative humidity, temperature, pressure,
flow, viscosity, sound, ultraviolet and infrared radiation,
chemicals, and biomolecules such as DNA, proteins, and enzymes.
Microcantilever sensors are rugged, reusable, and extremely
sensitive, yet they cost little and consume little power. Another
advantage in using the sensors is that they work in air, vacuum, or
under liquid environments.
Molecularly Imprinted Polymeric Film
[0231] Molecular imprinting is a process of template-induced
formation of specific molecular recognition sites (binding or
catalytic) in a polymeric material where the template directs the
positioning and orientation of the polymeric material's structural
components by a self-assembling mechanism (see, for example,
Olivier et al., Anal Bioanal Chem, 382:947-956 (2005); and Ersoz et
al., Biosensors & Bioelectronics, 20:2197-2202 (2005), both of
which are incorporated herein by reference in their entirety). The
polymeric material can include organic polymers as well as
inorganic silica gels. Molecularly imprinted polymers (MIPs) can be
used in a variety of sensor platforms including, but not limited
to, fluorescence spectroscopy; UV/Vis spectroscopy; infrared
spectroscopy; surface plasmon resonance; chemiluminescent adsorbent
assay; and reflectometric interference spectroscopy. Such
approaches allow for the realization of highly efficient and
sensitive target marker recognition.
Example 4
Detection of Glucose in Exhaled Breath
[0232] Persons with diabetes presently check their blood glucose
levels between 1 and 6-8 times each day. Knowledge of blood glucose
levels is an absolute necessity for guiding proper administration
and dosing of insulin and other medications used to control
hyperglycemia. Presently the person must draw blood samples,
usually from a finger using a lancet device, and place the sample
on a "test strip" which is inserted into a glucose monitor that
gives the blood glucose concentration. This process requires
considerable skill, time and subjects the person with diabetes to
immediate recognition as a diabetic and thus results in the
potential for embarrassment and even prejudice and/or
discrimination when applying for employment.
[0233] An attractive alternative is to use a sensor system that
collects a sample of exhaled breath which for compounds such as
glucose, which are extremely hydrophilic, condenses the sample into
a "condensate" which is then placed in contact with the sensor by a
pump or microfluidic system. Thus, persons with diabetes are far
more likely to inconspicuously blow into a small hand-held device
that provides a blood glucose concentration from an exhaled breath
sample then to perform the multiple steps required for a blood
sample, particularly in public places. This technology is likely to
increase the acceptance of frequent blood glucose monitoring and
reduce the embarrassment that many persons with diabetes feel when
having to draw blood samples from their fingers.
Example 5
Measurement of Blood Glucose and Lactic Acid Concentrations in the
Operating Room During Surgical Procedures Using Exhaled Breath
[0234] An elderly patient with a history of insulin dependent
diabetes (Type I) requires a serious operation in which significant
blood loss is anticipated. As part of the routine monitoring of the
patient, the anesthesiologist continuously monitors exhaled breath
glucose and lactic acid. Several recent medical research studies
have shown that tight control of glucose in the normal range
improves outcome, wound healing and rate of post-operative
infection in persons with diabetes. Presently, the anesthesiologist
can only monitor blood glucose intermittently by drawing blood
samples. These results guide the administration of insulin.
Excessive doses can lead to hypoglycemia, with disastrous
consequences and inadequate doses can lead to hyperglycemia, which
can result in intra- and post-operative complications. Exhaled
breath affords the potential of continuous tight glucose control
without the potential for either hyperglycemia or hypoglycemia. In
fact, a "closed loop" system is possible where the exhaled breath
glucose concentration is used to control and insulin infusion, thus
freeing the anesthesiologist of having to give boluses of
insulin.
[0235] In addition to monitoring glucose continuously, the
anesthesiologist monitors exhaled breath lactic acid to determine
whether there is excessive blood loss or other reasons for decrease
perfusion of vital organs. Presently, blood pressure, heart rate
and on occasions, central venous pressure are used to monitor
patients for blood loss with resulting hypovolemia and diminished
perfusion. This in turn leads to lactic acidosis, an ominous
complication, but presently lactic acid can only be measured
intermittently from blood samples. By continuously monitoring
lactic acid levels in exhaled breath condensate, the
anesthesiologist will have a much better means of determining if
there is hypoperfusion of vital organs. Thus, measurement of
compounds continuously in exhaled breath in either the gaseous or
condensed state can lead to marked improvement in monitoring, and
therefore, treatment of patients in the operating room and the
intensive care unit.
[0236] It should be understood that the examples and embodiments
described herein are for illustrative purposes only and that
various modifications or changes in light thereof will be suggested
to persons skilled in the art and are to be included within the
spirit and purview of this application and the scope of the
appended claims. Specifically, the marker detection method of the
present invention is intended to cover detection not only through
the exhalation by a patient with a device utilizing electronic nose
technology, but also other suitable technologies, such as gas
chromatography, transcutaneous/transdermal detection,
semiconductive gas sensors, mass spectrometers, IR or UV or visible
or fluorescence spectrophotometers.
[0237] All patents, patent applications, provisional applications,
and publications referred to or cited herein, or from which a claim
for benefit of priority has been made, are incorporated by
reference in their entirety to the extent they are not inconsistent
with the explicit teachings of this specification.
* * * * *
References