Pupillary measurements and uses thereof

Abstract

The disclosure provides that certain pupillary Light Off (LO) responses can be used to determine physiological statuses, for example, covert consciousness during general anesthesia, opioid intoxication, or respiratory depression. Thus, certain aspects of the disclosure provide methods of determining certain LO responses and their uses. In some embodiments, certain thresholds of LO response can be used to determine in a subject certain physiological statuses, such as covert consciousness during general anesthesia, opioid intoxication, and / or respiratory depression. In further embodiments, methods disclosed herein include monitoring a subject's LO responses and avoiding or limiting adverse events in the subject. Even further embodiments of the disclosure provide devices and kits for determining and / or monitoring LO responses and / or avoiding or limiting adverse events.

Description

PUPILLARY MEASUREMENTS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATION[OOOIJT is application claims benefit under 35 U.S.C. § 119(e) of provisional application 63 / 719,331 , filed November 12, 2024, which application is hereby incorporated by reference in its entirety.INTRODUCTION

[0002] The “Light Off” (LO) response of the pupil occurs when a subject experiences a sudden shift from an illuminated to dark environment. Such responses can be measured using a pupillometer. Within less than a second of light going out, the pupil size begins to increase, and within 7 seconds, reaches diameters 50-60% above baseline. The magnitude of LO response can be determined using any suitable pupilometer, for example, an infrared pupillometer that continuously records pupil size.SUMMARY

[0003] The disclosure describes that certain pupillary characteristics can be used as indicators of certain physiological statuses, such as covert consciousness during general anesthesia, opioid intoxication, or respiratory depression. In certain aspects, such pupillary characteristics relate to dilation of the pupil during the LO response, i.e. , the behavior of the pupil of a subject after a sudden shift from an illuminated environment to dark environment.

[0004] In certain aspects, the LO response is used to determine certain physiological statuses in the subject, such as covert consciousness during general anesthesia, opioid intoxication, or respiratory depression. To that end, the LO response value calculated in the subject is compared with specific thresholds that are indicative of certain physiological statuses, such as the presence or absence of covert consciousness during general anesthesia, opioid intoxication, and / or respiratory depression. Based on the comparison, the subject is determined to exhibit certain physiological statuses.

[0005] In certain embodiments, the disclosure provides computer implemented methods of determining certain LO responses in subjects and based on the determined LO responses, determining certain physiological statuses in the subjects.

[0006] In further embodiments, the disclosure provide computer readable media and / or devices that determine LO responses and indicate whether the subjects exhibit certain physiological statuses, such as the presence or absence of covert consciousness during general anesthesia, opioid intoxication, or respiratory depression.BRIEF DESCRIPTION OF THE FIGURES

[0007] FIG. 1: LO response (LO_MAX dilation) in ten subjects undergoing sixteen experimental remifentanil infusion protocol sequences.

[0008] FIG. 2: The LO response in ten subjects undergoing standardized remifentanil infusion.

[0009] FIG. 3: Changes in the LO response (LO_MAX dilation) showing excellent discrimination between low-risk (zero to moderate) opioid effect (estimated remifentanil effect site concentration < 2 ng / mL, corresponding to measurements taken at baseline and 2.5 minutes after start of the infusion) versus high-risk opioid effect (at estimated remifentanil effect site concentration > 2.2 ng / mL, corresponding to measurements taken at 5 - 12.5 minutes after start of the infusion).

[0010] FIG. 4: Graph of pupil diameter versus duration of pupillary measurement after and before anesthesia medication in a 58-year old patient.DETAILED DESCRIPTION

[0011] As noted above, the disclosure relates to methods of determining certain LO responses in subjects and utilizing the LO responses to determine in the subject certain physiological statuses. In certain embodiments, the methods can be implemented using a computer, optionally, in combination with electronic devices that measure pupillary parameters.

[0012] LO response can be calculated in different ways. In certain embodiments, an LO response is a difference between the maximum pupil diameter at any point after light goes off and stays off (maximum diameter) and the pupil diameter immediately after light goes off (initial diameter). This difference is referenced herein as the “LO_MAX dilation.”

[0013] In additional embodiments, an LO response is a difference between the pupil diameter observed at the end of a predetermined period of between 6 and 10-seconds after light goes off and stays off (end diameter) and the pupil diameter immediately afterlight goes off (initial diameter). This difference is referenced herein as the “LO_END dilation.”

[0014] In further embodiments, an LO response is a ratio of the initial pupil diameter to the maximum pupil diameter, which is referenced herein as the “LO_MAX PERCENT dilation.”

[0015] In even further embodiments, an LO response is a ratio of the initial diameter to the end diameter, which is referenced herein as “LO_END PERCENT dilation.”

[0016] In further embodiments, the disclosure provides devices that determine LO responses, such as LO_MAX dilation, LO_END dilation, LO_MAX PERCENT dilation, or LO_END PERCENT dilation. The devices can further indicate whether the subjects exhibit certain physiological statuses, such as the presence or absence of covert consciousness during general anesthesia, opioid intoxication, or respiratory depression.

[0017] Before the methods, devices, and computer-readable media of the present disclosure are described in greater detail, it is to be understood that the methods, computer-readable media, and devices are not limited to the embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing the embodiments only, and is not intended to be limiting, since the scope of the methods, computer-readable media, and devices will be limited only by the appended claims.

[0018] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only,” and the like in connection with the recitation of claim elements or use of a “negative” limitation.

[0019] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed, subject to any specifically excluded limit in the stated range. Where thestated range includes one or both the limits, ranges excluding either or both of those included limits are also included.

[0020] Certain ranges are presented herein with numerical values being preceded by the term “about.” The term “about” is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recited number, the near or approximating unrecited number may be a number which, in the context in which it is presented, provides the substantial equivalent of the specifically recited number.

[0021] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the methods, computer-readable media and devices belong. Although any methods, computer-readable media and devices similar or equivalent to those described herein can also be used in the practice or testing of the methods, computer-readable media and devices, representative illustrative methods, computer-readable media and devices are now described.

[0022] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the materials and / or methods in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present methods, computer-readable media and devices are not entitled to antedate such publication, as the date of publication provided may be different from the actual publication date which may need to be independently confirmed.

[0023] It is appreciated that certain features of the methods, devices, and computer-readable media, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the methods, computer-readable media and devices, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments are specifically embraced by the present disclosure and are disclosedherein just as if each combination was individually and explicitly disclosed, to the extent that such combinations embrace operable processes and / or compositions. In addition, all sub-combinations listed in the embodiments describing such variables are also specifically embraced by the present methods, computer-readable media and devices and are disclosed herein just as if each such sub-combination was individually and explicitly disclosed herein.

[0024] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present methods, computer-readable media, and devices. Any recited method can be carried out in the order of events recited or in any other order that is logically possible.METHODS

[0025] Certain aspects of the disclosure provide a method for determining in a subject an LO response. In some cases, the method comprises determining a subject’s pupil diameter immediately after the light goes off (initial dilation), determining the subject’s maximum pupil diameter after light goes off (maximum dilation), for example, the pupil diameter after between 6 and 10 seconds after light goes off, and determining the difference between the maximum dilation and the initial dilation. This difference is described herein as LO MAX dilation.

[0026] In certain embodiments, the method comprises determining a subject’s initial dilation, determining the subject’s pupil diameter at the end of between 6 and 10 seconds after light goes off (end dilation), and determining the difference between the end dilation and initial dilation. This difference is described herein as LO_END dilation.

[0027] In further embodiments, the method comprises determining a subject’s initial dilation, determining the subject’s maximum dilation or end dilation, and determining the ratio of the initial dilation to maximum dilation or the ration of initial dilation to maximum dilation. The ratio of a subject’s initial dilation to maximum dilation is referenced herein as LO_MAX PERCENT dilation. The ration of a subject’s initial dilation to end dilation is referenced herein as LO_END PERCENT dilation.

[0028] As used herein, the term “initial dilation” refers to a subject’s pupil diameter immediately after light goes off. The term “immediately after the light goes off” in this context refers to between 0.01 and 0.1 seconds after light goes off, for example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.1 seconds after light goes off.

[0029] Also, as used herein, the term maximum dilation refers to a subject’s maximum pupil diameter after light goes off and stays off. Typically, a subject’s pupil reaches its maximum diameter after between 6 and 15 seconds after light goes off. Thus, the term “maximum dilation” in this context refers a subject’s pupil diameter after between 6 and 15 seconds, for example, 6, 7, 8, 9, 10. 11 , 12, 13, 14, or 15 seconds after light goes off and stays off.

[0030] As used herein, the term “end dilation” refers to a subject’s pupil diameter after a predetermined time after light goes off and stays off, the predetermined time being between 6 and 15 seconds after light goes off. Thus, the term “end dilation” in this context refers a subject’s pupil diameter after between 6 and 15 seconds, for example, 6, 7, 8, 9, 10. 11 , 12, 13, 14, or 15 seconds after light goes off and stays off.

[0031] As a skilled artisan would recognize, in some instances, the maximum dilation and the end dilation have the same value, for example, if the pupil dilation is measured about at least 8 seconds after light goes off and the pupil does not dilate further. Also, as a skilled artisan would recognize, in some instances, the maximum dilation would be bigger than the end dilation if the dilation is measured about 6 or 7 seconds after light goes off and maximum pupil dilation is reached thereafter, for example, 10 seconds after light goes off. Further, a skilled artisan would recognize that, in some instances, the end dilation is smaller than the maximum dilation because the pupil reaches the maximum dilation and then constricts until the end diameter measurement.

[0032] In certain embodiments, the methods described herein for determining LO_MAX dilation, LO_END dilation, LO_MAX PERCENT dilation, or LO_END PERCENT dilation are performed using a computer, optionally, in combination with one or more additional electronic devices. In some cases, such electronic device comprises

[0033] The hypothesized mechanism for producing the LO response is twofold. It involves the inhibition of the Edinger Westphal (EW) nucleus, which causes the initial dilation. It also involves secondary activation of the sympathetically innervated dilater muscle of the iris. The LO response becomes significantly blunted and eventuallyobliterated after two events: 1) induction of general anesthesia, when anesthetic agent produces unconsciousness, and 2) in the setting of opioid administration in conscious subjects, preceding and coinciding with opioid induced respiratory arrest events.

[0034] The inventors describe certain relationship between the LO responses and physiological statuses. Accordingly, in certain embodiments, the disclosure provides that specific threshold values for different LO responses indicate that a subject exhibits certain physiological statuses. Certain such physiological statuses include unconsciousness, consciousness, or intoxication, e.g., opioid intoxication.

[0035] In subjects that are awake and / or non-intoxicated, the LO response values are typically higher, referenced herein as “robust LO response.” For example, the LO_MAX dilation or LO_END dilation in awake humans is at least 0.75 mm. The disclosure provides that LO MAX dilation or LO END dilation threshold most associated with increased likelihood of consciousness in critically ill patients is > 0.75 mm, i.e., a critically ill patient who exhibits the LO_MAX dilation or LO_END dilation of above 0.75 mm indicates increased likelihood that the subject is conscious. The disclosure also provides that the LO_MAX dilation or LO_END dilation associated with awareness after induction of general anesthesia is > 0.75 mm, i.e., a patient who even after induction of general anesthesia exhibits the LO_MAX dilation or LO_END dilation of above 0.75 mm indicates increased likelihood that the subject has covert consciousness after general anesthesia.

[0036] On the other hand, in unconscious or intoxicated subjects, the LO response values are lower, referenced herein as “diminished LO response.” For example, the LO_MAX dilation or LO_END dilation is below about 0.25 mm in subjects that are unconscious or intoxicated. Thus, in some cases, the LO_MAX dilation or LO_END dilation associated with opioid induced respiratory depression is 0.25 mm indicating that a value below 0.25 mm indicates opioid induced respiratory depression.

[0037] Moreover, in humans that are not entirely awake but not entirely intoxicated or unconscious, the LO_MAX dilation or LO_END dilation is between 0.25 - 0.50 mm, referenced herein as “indeterminant LO response.”

[0038] The disclosure provides several benefits over the conventional methods of monitoring certain physiological conditions.

[0039] For example, the presence of a robust LO response in a critically ill patients who cannot verbally communicate indicates greater likelihood that the patient may be conscious with full perception of painful interventions and disturbing events. Presence of this covert consciousness may offer actionable prognostic data at the bedside, data that would otherwise require transport of the patient to the MRI scanner, which may incur unreasonable cost and risk. Also, the LO response > 0.75 mm in a surgical patient after induction of anesthesia may indicate that the patient is still conscious. Persistence of robust range LO raises the possibility that the patient may be at risk for intraoperative awareness with possible postoperative recall of events in the operating room, and possibly respond to the incision in a way that could either jeopardize the safety of the operation, or induce hemodynamic instability. If a patient received high concentration of opioid medication before or during induction of anesthesia, absence of robust LO response would have less sensitivity for identifying covert consciousness during surgery.

[0040] Presence of diminished LO response in awake subjects receiving opioid medication would alert a clinician of a greater likelihood of intensive opioid exposure that may produce side effects (ileus, nausea, dysphoria) and most importantly, risk of respiratory depression.

[0041] Thus the LO response thresholds provide important data to clinicians regarding patients’ physiological statuses. For example, the categorical ranges of LO response values would allow clinicians to promptly recognize important clinical conditions, which would allow timely intervention.

[0042] Presence of diminished LO response in awake subjects receiving opioid medication should alert the clinician to greater likelihood of intensive opioid exposure that may produce side effects (ileus, nausea, dysphoria) and most importantly, risk of respiratory depression.

[0043] Thus, in some cases, the disclosure provides a method for determining a pupillary light-off (LO) maximum dilation response (LO_MAX dilation) in a subject, the method comprising: determining the LO_MAX dilation in the subject as a difference between the maximum pupillary diameter after light goes off and stays off and the pupillary diameter within 0.01 to 0.1 seconds after the light goes off. In some cases,the maximum pupillary dilation after light goes off and stays off is determined at least 8 seconds after light goes off.

[0044] In additional cases, the disclosure provides a method for determining a pupillary light-off (LO) end dilation response (LO_END dilation) in a subject, the method comprising: determining the LO_END dilation in the subject as a difference between the pupillary diameter after a predetermined time after light goes off and stays off and the pupillary diameter within 0.01 to 0.1 seconds after the light goes off. In certain embodiments, the predetermined time is 6 seconds or 7 seconds after the light goes off.

[0045] In further embodiments, the disclosure provides a method for determining a pupillary light-off (LO) maximum percent dilation response (LO_MAX PERCENT dilation) in a subject, the method comprising: determining the LO MAX PERCENT dilation in the subject as a ratio of the maximum pupillary diameter after light goes off and stays off to the pupillary diameter within 0.01 to 0.1 seconds after light goes off. In certain such methods, the maximum pupillary dilation after light goes off and stays off is determined at least 8 seconds after light goes off.

[0046] In even further embodiments, the disclosure provides a method for determining a pupillary light-off (LO) end percent dilation response (LO_END PERCENT dilation) in a subject, the method comprising: determining the LO_END PERCENT dilation in the subject as a ratio of the pupillary diameter after a predetermined time after light goes off and stays off to the pupillary diameter within 0.01 to 0.1 seconds after light goes off. In certain such embodiments, the predetermined time is 6 seconds or 7 seconds after light goes off.

[0047] In some cases, determining the LO_MAX dilation, LO_END dilation, LO_MAX PERCENT dilation, or LO_END PERCENT dilation comprises using an electronic device. Such electronic device can be equipped with a software programmed to measure pupillary diameter and fitted with an adapter that engages at one end with an infrared camera on the electronic device and engages at the other end with an eye of the subject. Based on the readings obtained by the electronic device, the software on the electronic device can determine the LO_MAX dilation, LO_END dilation, LO_MAX PERCENT dilation, or LO_END PERCENT dilation.

[0048] In certain embodiments of the electronic devices, the adapter is substantially cylindrical or cone shaped with one end designed to be connected or placed on to the camera of the portable electronic device and the other end designed to be placed on the eye of a subject. In some cases, the adapter is black or dark colored.

[0049] As noted above, in certain embodiments of the disclosure, the methods of determining LO_MAX dilation, LO_END dilation, LO_MAX PERCENT dilation, or LO_END PERCENT, further comprises determining a physiological status of the subject. In certain such embodiments, the physiological status is consciousness, unconsciousness, intoxication, or opioid induced adverse events.

[0050] In specific embodiments, the consciousness in the subject is covert consciousness under general anesthesia. In certain such cases, the method further comprises administering an anesthetic to the subject until the covert consciousness under general anesthesia is not observed in the subject. Alternatively, the method comprises avoiding performing any procedures on the subject that requires general anesthesia at least until additional anesthetic is administered and / or the subject does not exhibit covert consciousness under general anesthesia.

[0051] As noted above, LO response values below specific thresholds indicate that a subject may exhibit an opioid related adverse event. Non-limiting examples of such opioid related adverse event include respiratory depression, mild pruritus / dermatitis, gastrointestinal complications, central nervous system complications, and acute respiratory failure requiring mechanical ventilation. Additional opioid related adverse events are known in the art and identifying their presence in a subject is within the purview of the disclosure.

[0052] In some cases, the method of determining that a subject exhibits an opioid related adverse event further comprises administering an appropriate therapy to the subject based on the determined opioid related adverse event.

[0053] In additional embodiments, the method of determining a physiological status in a subject based on an LO response further comprises administering appropriate therapy to the subject based on the determined physiological status.COMPUTER I PLEMENTED METHODS

[0054] In certain aspects, the methods described herein of determining certain LO responses and, optionally, further determining certain physiological statuses, are performed using computers, optionally, in combination with additional electronic devices. Thus, in some cases, the disclosure provides a computer-implemented method for determining a physiological status of a subject, the method comprising:

[0055] determining a pupillary light-off (LO) maximum dilation response (LO_MAX dilation) in a subject, the method comprising: determining the LO_MAX dilation in the subject as a difference between the maximum pupillary diameter after light goes off and stays off and the pupillary diameter within 0.01 to 0.1 seconds after light goes off;

[0056] obtaining one or more of threshold values for: robust LO_MAX dilation, diminished LO_MAX dilation, and indeterminant LO_MAX dilation; and

[0057] depending on the LO MAX dilation in the subject and the threshold value for robust LO_MAX dilation, diminished LO_MAX dilation, and indeterminant LO_MAX dilation, determining the physiological status of the subject.

[0058] In certain such computer-implemented methods, the maximum pupillary dilation after light goes off and stays off is determined at least 8 seconds after light goes off.

[0059] In some cases, the computer-implemented methods comprise obtaining, via one or more processors, the threshold value for robust LO_MAX dilation and, depending on the LO_MAX dilation in the subject and the threshold value for robust LO_MAX dilation, determining, via one or more processors, the physiological status in the subject as conscious or unconscious. The consciousness can be covert consciousness under general anesthesia. In certain such cases, the methods further comprise administering an anesthetic to the subject until the covert consciousness under general anesthesia is not observed in the subject. In further such cases, the methods further comprise avoiding performing any procedures on the subject that require general anesthesia. In even further cases, the consciousness is in the subject in a critically ill condition.

[0060] In some cases, the computer-implemented methods described herein comprise obtaining, via one or more processors, the threshold value for diminished LO_MAX dilation and, depending on the LO_MAX dilation in the subject and the threshold value for diminished LO_MAX dilation, determining, via one or more processors, the physiological status of the subject as unconscious or intoxicated. The physiological status of the subject can be an opioid induced adverse event, such as respiratorydepression, mild pruritus / dermatitis, gastrointestinal complications, central nervous system complications, and acute respiratory failure requiring mechanical ventilation. Certain such methods further comprise administering an appropriate therapy to the subject based on the determined opioid-related adverse event.

[0061] In specific embodiments, the computer-implemented methods of determining a physiological status in a subject further comprises administering an appropriate therapy to the subject based on the determined physiological status.

[0062] A computer-implemented method for determining a physiological status of a subject, the method comprising:

[0063] determining, via one or more processors, a pupillary light-off (LO) end dilation response (LO_END dilation) in the subject, the method comprising: determining LO END dilation in the subject as a difference between the pupillary diameter after a predetermined time after light goes off and stays off and the pupillary diameter within 0.01 to 0.1 seconds after the light goes off;

[0064] obtaining, via one or more processors, one or more of threshold values for: robust LO_END dilation, diminished LO_END dilation, and indeterminant LO_END dilation; and

[0065] depending on the LO_END dilation in the subject and the threshold value for robust LO_END dilation, diminished LO_END dilation, and indeterminant LO_END dilation, determining, via one or more processors, the physiological status of the subject.

[0066] In some cases, the predetermined time after light goes off and stays off is 6 or 7 seconds.

[0067] In some cases, the computer-implemented methods comprise obtaining, via one or more processors, the threshold value for robust LO_END dilation and, depending on the LO_END dilation in the subject and the threshold value for robust LO_END dilation, determining, via one or more processors, the physiological status in the subject as conscious or unconscious. The consciousness can be covert consciousness under general anesthesia. In certain such cases, the methods further comprise administering an anesthetic to the subject until the covert consciousness under general anesthesia is not observed in the subject. In further such cases, the methods further comprise avoiding performing any procedures on the subject that require general anesthesia. In even further cases, the consciousness is in the subject in a critically ill condition.

[0068] In some cases, the computer-implemented methods described herein comprise obtaining, via one or more processors, the threshold value for diminished LO_END dilation and, depending on the LO_END dilation in the subject and the threshold value for diminished LO_END dilation, determining, via one or more processors, the physiological status of the subject as unconscious or intoxicated. The physiological status of the subject can be an opioid induced adverse event, such as respiratory depression, mild pruritus / dermatitis, gastrointestinal complications, central nervous system complications, and acute respiratory failure requiring mechanical ventilation. Certain such methods further comprise administering an appropriate therapy to the subject based on the determined opioid-related adverse event.

[0069] In specific embodiments, the computer-implemented methods of determining a physiological status in a subject further comprises administering an appropriate therapy to the subject based on the determined physiological status.COMPUTER-READABLE MEDIA AND DEVICES

[0070] Also provided are computer readable media for implementing a computer-implemented method for determining in a subject a physiological status depending on LO response in the subject and devices including such computer readable media.

[0071] In certain aspects, provided is a non-transitory computer readable medium including instructions for carrying out the methods for determining a physiological status depending on LO response in the subject, where the instructions, when executed by one or more processors, cause the one or more processors to implement the methods disclosed above for determining in a subject a physiological status depending on LO response in the subject.

[0072] Various steps of determining LO responses in the subject, determining various physiological statuses, and optionally administering an appropriate therapy to the subject may be as described in the Methods section above. For purposes of brevity, details regarding these steps and other features / elements described in the Methods section of the present disclosure are incorporated but not reiterated herein. In some embodiments, the instructions, when executed by one or more processors, cause the one or more processors to perform any of the methods described in the Methods section herein.

[0073] Instructions can be coded onto a non-transitory computer-readable medium in the form of “programming,” where the term “computer-readable medium” as used herein refers to any non-transitory storage or transmission medium that participates in providing instructions and / or data to a computer for execution and / or processing. Examples of storage media include a hard disk, optical disk, magneto-optical disk, CD-ROM, CD-R, magnetic tape, non-volatile memory card, ROM, DVD-ROM, Blue-ray disk, solid state disk, network attached storage (NAS), etc., whether such devices are internal or external to the computer. A file containing information can be “stored” on computer readable medium, where “storing” means recording information such that it is later accessible and retrievable by a computer.

[0074] The instructions may be in the form of programming that is written in one or more of any number of computer programming languages. Such languages include, for example, Java (Sun Microsystems, Inc., Santa Clara, CA), Visual Basic (Microsoft Corp., Redmond, WA), and C++ (AT&T Corp., Bedminster, NJ), as well as many others.

[0075] The present disclosure also provides computer devices. The computer devices include one or more processors and any of the non-transitory computer readable media of the present disclosure. Accordingly, in some embodiments, the computer devices can perform any of the methods described in the Methods section herein.

[0076] In certain aspects, a computer device of the present disclosure is a local computer device. In some embodiments, the computer device is a remote computer device (e.g., a remote server), meaning that the instructions are executed on a computer device different from a local computer device and / or the instructions are downloadable from the remote computer device to a local computer device, e.g., for execution on the local computer device. In some embodiments, the instructions constitute a web-based application stored on a remote server.

[0077] Notwithstanding the appended claims, the present disclosure is further defined by the following embodiments:

[0078] Embodiment 1 . A method for determining a pupillary light-off (LO) maximum dilation response (LO_MAX dilation) in a subject, the method comprising: determining the LO_MAX dilation in the subject as a difference between the maximum pupillarydiameter after light goes off and stays off and the pupillary diameter within 0.01 to 0.1 seconds after the light goes off.

[0079] Embodiment 2. The method of Embodiment 1, wherein the maximum pupillary dilation after light goes off and stays off is determined at least 8 seconds after light goes off.

[0080] Embodiment 3. A method for determining a pupillary light-off (LO) end dilation response (LO_END dilation) in a subject, the method comprising: determining the LO_END dilation in the subject as a difference between the pupillary diameter after a predetermined time after light goes off and stays off and the pupillary diameter within 0.01 to 0.1 seconds after light goes off.

[0081] Embodiment 4. The method of Embodiment 3, wherein the predetermined time is 6 seconds or 7 seconds after light goes off.

[0082] Embodiment 5. A method for determining a pupillary light-off (LO) maximum percent dilation response (LO_MAX PERCENT dilation) in a subject, the method comprising: determining the LO_MAX PERCENT dilation in the subject as a ratio of the maximum pupillary diameter after light goes off and stays off to the pupillary diameter within 0.01 to 0.1 seconds after light goes off.

[0083] Embodiment 6. The method of Embodiment 5, wherein the maximum pupillary dilation after light goes off and stays off is determined at least 8 seconds after light goes off.

[0084] Embodiment 7. A method for determining a pupillary light-off (LO) end percent dilation response (LO_END PERCENT dilation) in a subject, the method comprising: determining the LO_END PERCENT dilation in the subject as a ratio of the pupillary diameter after a predetermined time after light goes off and stays off to the pupillary diameter within 0.01 to 0.1 seconds after light goes off.

[0085] Embodiment 8. The method of Embodiment 7, wherein the predetermined time is 6 seconds or 7 seconds after light goes off.

[0086] Embodiment 9. The method of any one of Embodiments 1 to 8, wherein determining the LO_MAX dilation, LO_END dilation, LO_MAX PERCENT dilation, or LO_END PERCENT dilation comprises using an electronic device equipped with a software programmed to measure pupillary diameter and fitted with an adapter that engages at one end with an infrared camera on the electronic device and engages atthe other end with an eye of the subject to facilitate the software on the electronic device to determine the LO_MAX dilation, LO_END dilation, LO_MAX PERCENT dilation, or LO_END PERCENT dilation.

[0087] Embodiment 10. The method of Embodiment 9, wherein the adapter is substantially cylindrical or cone shaped with one end designed to be connected or placed on to the camera of the portable electronic device and the other end designed to be placed on the eye of a subject.

[0088] Embodiment 11. The method of Embodiment 10, wherein the adapter is black or dark colored.

[0089] Embodiment 12. The method of any one of the preceding Embodiments, further comprising determining a physiological status of the subject.

[0090] Embodiment 13. The method of Embodiment 12, wherein the physiological status is consciousness.

[0091] Embodiment 14. The method of Embodiment 13, wherein the consciousness is covert consciousness under general anesthesia.

[0092] Embodiment 15. The method of Embodiment 14, further comprising administering an anesthetic to the subject until the covert consciousness under general anesthesia is not observed in the subject.

[0093] Embodiment 16. The method of Embodiment 12, wherein the physiological status is an opioid related adverse event.

[0094] Embodiment 17. The method of Embodiment 15, wherein the opioid related adverse event is respiratory depression, mild pruritus / dermatitis, gastrointestinal complications, central nervous system complications, and acute respiratory failure requiring mechanical ventilation.

[0095] Embodiment 18. The method of Embodiment 16 or 17, further comprising administering appropriate therapy to the subject based on the determined opioid-related adverse event.

[0096] Embodiment 19. The method of any one of Embodiments 12 to 18, further comprising administering an appropriate therapy to the subject based on the determined physiological status.

[0097] Embodiment 20. A method for determining a physiological status of a subject, the method comprising:

[0098] determining a pupillary light-off (LO) maximum dilation response (LO_MAX dilation) in a subject, the method comprising: determining the LO_MAX dilation in the subject as a difference between the maximum pupillary diameter after light goes off and stays off and the pupillary diameter within 0.01 to 0.1 seconds after light goes off;

[0099] obtaining one or more of threshold values for: robust LO_MAX dilation, diminished LO_MAX dilation, and indeterminant LO_MAX dilation; and

[0100] depending on the LO_MAX dilation in the subject and the threshold value for robust LO_MAX dilation, diminished LO_MAX dilation, and indeterminant LO_MAX dilation, determining the physiological status of the subject.

[0101] Embodiment 21. The method of Embodiment 20, wherein the maximum pupillary dilation after light goes off and stays off is determined at least 8 seconds after light goes off.

[0102] Embodiment 22. The method of Embodiment 20 or 21 , comprising obtaining the threshold value for robust LO_MAX dilation and, depending on the LO_MAX dilation in the subject and the threshold value for robust LO_MAX dilation, determining the physiological status of the subject as conscious or unconscious.

[0103] Embodiment 23. The method of Embodiment 22, wherein the consciousness in the subject is covert consciousness under general anesthesia.

[0104] Embodiment 24. The method of Embodiment 23, further comprising administering an anesthetic to the subject until the covert consciousness under general anesthesia is not observed in the subject.

[0105] Embodiment 25. The method of Embodiment 22, wherein the consciousness is in the subject in a critically ill condition.

[0106] Embodiment 26. The method of Embodiment 20 or 21 , comprising obtaining the threshold value for diminished LO_MAX dilation and, depending on the LO_MAX dilation in the subject and the threshold value for diminished LO_MAX dilation, identifying in the subject the physiological status as unconscious or intoxicated.

[0107] Embodiment 27. The method of Embodiment 26, comprising obtaining the threshold value for diminished LO_MAX dilation and, depending on the LO_MAX dilation in the subject and the threshold value for diminished LO_MAX dilation, determining the physiological status of the subject as having an opioid induced adverse event.

[0108] Embodiment 28. The method of Embodiment 27, wherein the opioid related adverse event is respiratory depression, mild pruritus / dermatitis, gastrointestinal complications, central nervous system complications, and acute respiratory failure requiring mechanical ventilation.

[0109] Embodiment 29. The method of Embodiment 27 or 28, further comprising administering an appropriate therapy to the subject based on the determined opioid-related adverse event.

[0110] Embodiment 30. The method of any one of Embodiments 20 to 29, further comprising administering an appropriate therapy to the subject based on the determined physiological status.

[0111] Embodiment 31. A method for determining a physiological status of a subject, the method comprising:

[0112] determining a pupillary light-off (LO) end dilation response (LO_END dilation) in a subject, the method comprising: determining the LO_END dilation in the subject as a difference between the pupillary diameter after a predetermined time after light goes off and stays off and the pupillary diameter within 0.01 to 0.1 seconds after light goes off;

[0113] obtaining one or more of threshold values for: robust LO_END dilation, diminished LO_END dilation, and indeterminant LO_END dilation; and

[0114] depending on the LO_END dilation in the subject and the threshold value for robust LO_END dilation, diminished LO_END dilation, and indeterminant LO_END dilation, determining the physiological status of the subject.

[0115] Embodiment 32. The method of Embodiment 31 , wherein the predetermined time after light goes off and stays off is 6 or 7 seconds.

[0116] Embodiment 33. The method of Embodiment 31 or 32, comprising obtaining the threshold value for robust LO_END dilation and, depending on the LO_END dilation in the subject and the threshold value for robust LO_END dilation, determining the physiological status in the subject as conscious or unconscious.

[0117] Embodiment 34. The method of Embodiment 33, wherein the consciousness in the subject is covert consciousness under general anesthesia.

[0118] Embodiment 35. The method of Embodiment 34, further comprising administering an anesthetic to the subject until the covert consciousness under general anesthesia is not observed in the subject.

[0119] Embodiment 36. The method of Embodiment 34, wherein the consciousness is in the subject in a critically ill condition.

[0120] Embodiment 37. The method of Embodiment 31 or 32, comprising obtaining the threshold value for diminished LO_END dilation and, depending on the LO_END dilation in the subject and the threshold value for diminished LO_END dilation, determining the physiological status in the subject as unconscious or intoxicated.

[0121] Embodiment 38. The method of Embodiment 31 or 32, comprising obtaining the threshold value for diminished LO_END dilation and, depending on the LO_END dilation in the subject and the threshold value for diminished LO_END dilation, determining the physiological status in the subject as having an opioid induced adverse event.

[0122] Embodiment 39. The method of Embodiment 38, wherein the opioid related adverse event is respiratory depression, mild pruritus / dermatitis, gastrointestinal complications, central nervous system complications, and acute respiratory failure requiring mechanical ventilation.

[0123] Embodiment 40. The method of Embodiment 38 or 39, further comprising administering appropriate therapy to the subject based on the determined opioid-related adverse event.

[0124] Embodiment 41. The method of any one of Embodiments 31 to 40, further comprising administering an appropriate therapy to the subject based on the determined physiological status.

[0125] Embodiment 42. A computer-implemented method for determining a physiological status of a subject, the method comprising:

[0126] determining, via one or more processors, a pupillary light-off (LO) maximum dilation response (LO_MAX dilation) in a subject, the method comprising: determining the LO_MAX dilation in the subject as a difference between the maximum pupillary diameter after light goes off and stays off and the pupillary diameter within 0.01 to 0.1 seconds after light goes off;

[0127] obtaining, via one or more processors, one or more of threshold values for: robust LO_MAX dilation, diminished LO_MAX dilation, and indeterminant LO_MAX dilation; and

[0128] depending on the LO_MAX dilation in the subject and the threshold value for robust LO_MAX dilation, diminished LO_MAX dilation, and indeterminant LO_MAX dilation, determining, via one or more processors, the physiological status of the subject.

[0129] Embodiment 43. The computer-implemented method of Embodiment 42, wherein the maximum pupillary dilation after light goes off and stays off is determined at least 8 seconds after light goes off.

[0130] Embodiment 44. The computer-implemented method of Embodiment 42 or 43, comprising obtaining, via one or more processors, the threshold value for robust LO_MAX dilation and, depending on the LO_MAX dilation in the subject and the threshold value for robust LO_MAX dilation, determining, via one or more processors, the physiological status in the subject as conscious or unconscious.

[0131] Embodiment 45. The computer-implemented method of Embodiment 44, wherein the consciousness in the subject is covert consciousness under general anesthesia.

[0132] Embodiment 46. The computer-implemented method of Embodiment 45, further comprising administering an anesthetic to the subject until the covert consciousness under general anesthesia is not observed in the subject.

[0133] Embodiment 47. The computer-implemented method of Embodiment 44, wherein the consciousness is in the subject in a critically ill condition.

[0134] Embodiment 48. The method of Embodiment 42 or 43, comprising obtaining, via one or more processors, the threshold value for diminished LO MAX dilation and, depending on the LO_MAX dilation in the subject and the threshold value for diminished LO_MAX dilation, determining, via one or more processors, the physiological status of the subject as unconscious or intoxicated.

[0135] Embodiment 49. The computer-implemented method of Embodiment 42 or 43, comprising obtaining, via one or more processors, the threshold value for diminished LO_MAX dilation and, depending on the LO_MAX dilation in the subject and the threshold value for diminished LO_MAX dilation, determining, via one or more processors, the physiological status of the subject as having an opioid induced adverse event.

[0136] Embodiment 50. The computer-implemented method of Embodiment 49, wherein the opioid related adverse event is respiratory depression, mildpruritus / dermatitis, gastrointestinal complications, central nervous system complications, and acute respiratory failure requiring mechanical ventilation.

[0137] Embodiment 51. The method of Embodiment 49 or 50, further comprising administering appropriate therapy to the subject based on the determined opioid-related adverse event.

[0138] Embodiment 52. The computer-implemented method of any one of Embodiments 42 to 51 , further comprising administering appropriate therapy to the subject based on the determined physiological status.

[0139] Embodiment 53. A computer-implemented method for determining a physiological status of a subject, the method comprising:

[0140] determining, via one or more processors, a pupillary light-off (LO) end dilation response (LO END dilation) in the subject, the method comprising: determining LO_END dilation in the subject as a difference between the pupillary diameter after a predetermined time after light goes off and stays off and the pupillary diameter within 0.01 to 0.1 seconds after the light goes off;[0141 Jobtaining, via one or more processors, one or more of threshold values for: robust LO_END dilation, diminished LO_END dilation, and indeterminant LO_END dilation; and

[0142] depending on the LO_END dilation in the subject and the threshold value for robust LO_END dilation, diminished LO_END dilation, and indeterminant LO_END dilation, determining, via one or more processors, the physiological status of the subject.

[0143] Embodiment 54. The computer-implemented method of Embodiment 53, wherein the predetermined time after light goes off and stays off is 6 or 7 seconds.

[0144] Embodiment 55. The computer-implemented method of Embodiment 53 or 54, comprising obtaining the threshold value for robust LO_END dilation and, depending on the LO_END dilation in the subject and the threshold value for robust LO_END dilation, determining, via one or more processors, the physiological status of the subject as conscious or unconscious.

[0145] Embodiment 56. The computer-implemented method of Embodiment 55, wherein the consciousness in the subject is covert consciousness under general anesthesia.

[0146] Embodiment 57. The computer-implemented method of Embodiment 56, further comprising administering an anesthetic to the subject until the covert consciousness under general anesthesia is not observed in the subject.

[0147] Embodiment 58. The computer-implemented method of Embodiment 56, wherein the consciousness is in the subject in a critically ill condition.

[0148] Embodiment 59. The computer-implemented method of Embodiment 53 or 54, comprising obtaining, via one or more processors, the threshold value for diminished LO_END dilation and, depending on the LO_END dilation in the subject and the threshold value for depressed LO_END dilation, determining, via one or more processors, the physiological status in the subject as unconscious or intoxicated.

[0149] Embodiment 60. The computer-implemented method of Embodiment 53 or 54, comprising obtaining, via one or more processors, the threshold value for diminished LO_END dilation and, depending on the LO_END dilation in the subject and the threshold value for diminished LO_END dilation, identifying in the subject the physiological status as having an opioid induced adverse event.

[0150] Embodiment 61. The computer-implemented method of Embodiment 60, wherein the opioid related adverse event is respiratory depression, mild pruritus / dermatitis, gastrointestinal complications, central nervous system complications, and acute respiratory failure requiring mechanical ventilation.

[0151] Embodiment 62. The computer-implemented method of Embodiment 60 or 61 , further comprising administering an appropriate therapy to the subject based on the determined opioid-related adverse event.

[0152] Embodiment 63. The computer-implemented method of any one of Embodiments 53 to 62, further comprising administering an appropriate therapy to the subject based on the determined physiological status.

[0153] Embodiment 64. A non-transitory computer readable medium comprising instructions, when executed by one or more processors, cause the one or more processors to perform the method according to any one of Embodiments 1 to 63.

[0154] Embodiment 65. A computer device, comprising: one or more processors; and the non-transitory computer readable medium of Embodiment 64.

[0155] Embodiment 66. An electronic device comprising one or more processors, an infrared camera, and an adapter fitted with the infrared camera to obtain an infraredvideo of an eye of a subject, the portable electronic device further comprising a non-transitory computer readable medium comprising instructions, when executed by the one or more processors, cause the electronic device to perform the method according to any one of Embodiments 1 to 63.

[0156] Embodiment 67. The electronic device of Embodiment 66, wherein the adapter is substantially cylindrical or cone shaped with one end designed to engage with the infrared camera of the portable electronic device and the other end designed to be placed on an eye of the subject.

[0157] Embodiment 68. The electronic device of Embodiment 67, wherein the adapter is black or dark colored.EXPERIMENTAL EXAMPLE 1 - DETERMINING LO RESPONSES IN HEALTHY INDIVIDUALS

[0158] The LO response was studied in healthy volunteers undergoing a standardized remifentanil infusion protocol. The measurements were made by a pupillometer in one eye while the contralateral eye was covered by the operator’s hand. The measurement instrument was the Neuroptics model PLR 3000. A 180-mW light stimulus (approximately 1500 Lux) was directed into the measured eye for 3 seconds before the recording was initiated by button release. The 180-mW light stimulus was continued for 1 second and then the light was turned off while the measurement continued in darkness for an additional 7 seconds. Although dilation of the pupil was calculated with four methods, as the difference between maximum size observed at any point after light goes off minus the size at the time of light off (LO_MAX dilation) is reported in this Example.

[0159] Following baseline measurements, the remifentanil infusion was started and maintained at 0.2 micrograms / kg / min for 5 minutes, then increased to 0.3 micrograms / kg / min for an additional 5 minutes, and then discontinued. This infusion scheme was based on estimates from a previously published pharmacokinetic model and was employed with the intention of reaching a remifentanil effect site concentrationbetween 4 and 6 ng / mL within 10 minutes. At ten minutes, the infusion was stopped, and data collection continued every 2.5 minutes for an additional 25-minute period.

[0160] Results:

[0161] Ten healthy participants completed 16 separate experiments. In cases where the same subject participated more than once, the two experiments were separated by a wash-out period to ensure that the remifentanil effect site concentration had returned to zero before the start of the second run. Severe respiratory depression leading to apnea was observed in 15 / 16 trials, at an average of 5.9 ± 1 .7 minutes after start of the infusion, corresponding to average estimated remifentanil concentration = 3.96 ± 0.97 ng / mL.

[0162] From baseline to the conclusion of the 10-minute remifentanil infusion, LO_MAX dilation declined by 86.4 ± 12.4%, and from baseline and time of desaturation, LO_MAX dilation declined by 85.7 ± 11 .5%. The measurement periods associated with high-risk opioid effect were considered to be those from 5 to 12.5 minutes after start of the infusion, when modeled remifentanil effect site concentration was consistently > 2.2 ng / mL and apneic events occurred.

[0163] FIG. 1 shows the results from ten subjects undergoing sixteen experimental remifentanil infusion protocol sequences. LO_MAX dilation declined significantly from baseline to maximum drug concentration (corresponding to 10 minutes after start of the infusion), by an average of 0.13 (-0.159, -0.105) mm per minute (P < 0.001 , R2 = 0.47). LO MAX dilation increased significantly between 10 minutes and recovery, by an average of 0.034 (0.029, 0.039) mm per minute (P < 0.001 , R2 = 0.47).

[0164] The ability of LO_MAX dilation to discriminate between low-risk versus high-risk opioid concentration was significantly greater than that of LO_END dilation. Therefore, LO MAX was reported for the remainder of the analysis of participants receiving remifentanil.

[0165] FIG. 2 shows the graph of pupil size versus time in ten subjects undergoing standardized remifentanil infusion. The LO responses in light gray are those prior to drug administration. The average of the pre-drug scans is shown in black. The LO responses in darker gray are those taken 10 minutes after the start of the infusion, at maximum drug concentration. The average of these scans is shown in white.EXAMPLE 2 - LO RESPONSE AND OPIOID EFFECTS

[0166] As shown in FIG. 3, changes in the LO_MAX dilation showed excellent discrimination between low-risk opioid effect (estimated remifentanil effect site concentration < 2.2 ng / mL, corresponding to measurements taken at baseline and 2.5 minutes after start of the infusion) versus high-risk opioid effect (corresponding to measurements taken at 5 - 12.5 minutes after start of the infusion).

[0167] For LO_MAX dilation of < 0.25 mm (diminished threshold), the interval likelihood ratio (iLR) was 8.85 for high-toxic opioid effect site concentration.

[0168] For LO_MAX dilation of 0.25 - 0.75 mm (indeterminant range), iLR = 2.52 for high toxic opioid effect site concentration.

[0169] For LO_MAX dilation > 0.75 mm (robust threshold), iLR = 0.02 for high-toxic opioid effect site concentration.EXAMPLE 3 - LO RESPONSE UNDER GENERAL ANESTHESIA

[0170] FIG. 4 shows a graph of pupil diameter over time of pupillary measurements. In a healthy 58-year-old patient undergoing urologic surgery under general anesthesia, both LO_MAX and LO_END at baseline were 1.359 mm before any anesthetic medication was given. After the anesthetic induction was complete, LO_MAX dilation and LO_END dilation declined significantly to 0.268 mm and 0.132 mm respectively.References:1. Loewenfeld IE, The pupil: anatomy, physiology and clinical applications. Detroit: Wayne State University Press, 1999.2. R. Omary, C. J. Bockisch, K. Landau, R. H. Kardon, and K. P. Weber, "Buzzing Sympathetic Nerves: A New Test to Enhance Anisocoria in Horner's Syndrome," Front Neurol, vol. 10, p. 107, 2019, doi: 10.3389 / fneur.2019.00107.3. I. Loewenfeld, The Pupil: Anatomy, Physiology and Clinical Applications. Woburn, MA 01801 : Butterworth-Heinemann, 1999, p. 1590.4. C. F. Minto, T. W. Schnider, and S. L. Shafer, "Pharmacokinetics and pharmacodynamics of remifentanil. IL Model application," Anesthesiology, vol. 86, no.1, pp. 24-33, Jan 1997. [Online].5. E. Lang, A. Kaplia, D. Shlugman, J. Hoke, and P. Sebel, "Reduction of isoflurane minimal alveolar concentration by remifentanil," Anesthesiology, vol. 85, pp. 721-8, 1996.6. E. Olofsen et al., "modeling the non-steady state respiratory effects of remifentanil in awake and propofol-sedated healthy volunteers," Anesthesiology, vol.112, pp. 1382-95, 2010.7. P. Zarifkar, M.H.Othman, K.L Tanderups Hansen, et al, “The Pupillary Light Off in Acute Disorders of Consciousness”, Neurocrit Care 2024: In Press.

[0171] Accordingly, the preceding merely illustrates the principles of the present disclosure. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein.

Claims

CLAIMSWE CLAIM:

1. A method for determining a pupillary light-off (LO) maximum dilation response (LO MAX dilation) in a subject, the method comprising: determining the LO MAX dilation in the subject as a difference between the maximum pupillary diameter after light goes off and stays off and the pupillary diameter within 0.01 to 0.1 seconds after the light goes off.

2. The method of claim 1, wherein the maximum pupillary dilation after light goes off and stays off is determined at least 8 seconds after light goes off.

3. A method for determining a pupillary light-off (LO) end dilation response (LO_END dilation) in a subject, the method comprising: determining the LO_END dilation in the subject as a difference between the pupillary diameter after a predetermined time after light goes off and stays off and the pupillary diameter within 0.01 to 0.1 seconds after light goes off.

4. The method of claim 3, wherein the predetermined time is 6 seconds or 7 seconds after light goes off.

5. A method for determining a pupillary light-off (LO) maximum percent dilation response (LO_MAX PERCENT dilation) in a subject, the method comprising: determining the LO_MAX PERCENT dilation in the subject as a ratio of the maximum pupillary diameter after light goes off and stays off to the pupillary diameter within 0.01 to 0.1 seconds after light goes off.

6. The method of claim 5, wherein the maximum pupillary dilation after light goes off and stays off is determined at least 8 seconds after light goes off.

7. A method for determining a pupillary light-off (LO) end percent dilation response (LO_END PERCENT dilation) in a subject, the method comprising: determining the LO_END PERCENT dilation in the subject as a ratio of the pupillary diameter after a predetermined time after light goes off and stays off to the pupillary diameter within 0.01 to 0.1 seconds after light goes off.

8. The method of claim 7, wherein the predetermined time is 6 seconds or 7 seconds after light goes off.

9. The method of any one of claims 1 to 8, wherein determining the LO_MAX dilation, LO_END dilation, LO_MAX PERCENT dilation, or LO_END PERCENT dilation comprises using an electronic device equipped with a software programmed to measure pupillary diameter and fitted with an adapter that engages at one end with an infrared camera on the electronic device and engages at the other end with an eye of the subject to facilitate the software on the electronic device to determine the LO_MAX dilation, LO_END dilation, LO_MAX PERCENT dilation, or LO_END PERCENT dilation.

10. The method of Claim 9, wherein the adapter is substantially cylindrical or cone shaped with one end designed to be connected or placed on to the camera of the portable electronic device and the other end designed to be placed on the eye of a subject.11 . The method of claim 10, wherein the adapter is black or dark colored.

12. The method of any one of the preceding claims, further comprising determining a physiological status of the subject.

13. The method of claim 12, wherein the physiological status is consciousness.

14. The method of claim 13, wherein the consciousness is covert consciousness under general anesthesia.

15. The method of claim 14, further comprising administering an anesthetic to the subject until the covert consciousness under general anesthesia is not observed in the subject.

16. The method of claim 12, wherein the physiological status is an opioid related adverse event.

17. The method of claim 15, wherein the opioid related adverse event is respiratory depression, mild pruritus / dermatitis, gastrointestinal complications, central nervous system complications, and acute respiratory failure requiring mechanical ventilation.

18. The method of claim 16 or 17, further comprising administering appropriate therapy to the subject based on the determined opioid-related adverse event.

19. The method of any one of claims 12 to 18, further comprising administering an appropriate therapy to the subject based on the determined physiological status.

20. A method for determining a physiological status of a subject, the method comprising:determining a pupillary light-off (LO) maximum dilation response (LO_MAX dilation) in a subject, the method comprising: determining the LO_MAX dilation in the subject as a difference between the maximum pupillary diameter after light goes off and stays off and the pupillary diameter within 0.01 to 0.1 seconds after light goes off; obtaining one or more of threshold values for: robust LO_MAX dilation, diminished LO_MAX dilation, and indeterminant LO_MAX dilation; anddepending on the LO_MAX dilation in the subject and the threshold value for robust LO_MAX dilation, diminished LO_MAX dilation, and indeterminant LO_MAX dilation, determining the physiological status of the subject.21 . The method of claim 20, wherein the maximum pupillary dilation after light goes off and stays off is determined at least 8 seconds after light goes off.

22. The method of claim 20 or 21 , comprising obtaining the threshold value for robust LO_MAX dilation and, depending on the LO_MAX dilation in the subject and the threshold value for robust LO_MAX dilation, determining the physiological status of the subject as conscious or unconscious.

23. The method of claim 22, wherein the consciousness in the subject is covert consciousness under general anesthesia.

24. The method of claim 23, further comprising administering an anesthetic to the subject until the covert consciousness under general anesthesia is not observed in the subject.

25. The method of claim 22, wherein the consciousness is in the subject in a critically ill condition.

26. The method of claim 20 or 21 , comprising obtaining the threshold value for diminished LO_MAX dilation and, depending on the LO_MAX dilation in the subject and the threshold value for diminished LO_MAX dilation, identifying in the subject the physiological status as unconscious or intoxicated.

27. The method of claim 26, comprising obtaining the threshold value for diminished LO_MAX dilation and, depending on the LO_MAX dilation in the subject and the threshold value for diminished LO_MAX dilation, determining the physiological status of the subject as having an opioid induced adverse event.

28. The method of claim 27, wherein the opioid related adverse event is respiratory depression, mild pruritus / dermatitis, gastrointestinal complications, central nervous system complications, and acute respiratory failure requiring mechanical ventilation.

29. The method of claim 27 or 28, further comprising administering an appropriate therapy to the subject based on the determined opioid-related adverse event.

30. The method of any one of claims 20 to 29, further comprising administering an appropriate therapy to the subject based on the determined physiological status.

31. A method for determining a physiological status of a subject, the method comprising:determining a pupillary light-off (LO) end dilation response (LO_END dilation) in a subject, the method comprising: determining the LO_END dilation in the subject as a difference between the pupillary diameter after a predetermined time after light goes off and stays off and the pupillary diameter within 0.01 to 0.1 seconds after light goes off;obtaining one or more of threshold values for: robust LO_END dilation, diminished LO_END dilation, and indeterminant LO_END dilation; anddepending on the LO_END dilation in the subject and the threshold value for robust LO_END dilation, diminished LO_END dilation, and indeterminant LO_END dilation, determining the physiological status of the subject.

32. The method of claim 31 , wherein the predetermined time after light goes off and stays off is 6 or 7 seconds.

33. The method of claim 31 or 32, comprising obtaining the threshold value for robust LO_END dilation and, depending on the LO_END dilation in the subject and the threshold value for robust LO_END dilation, determining the physiological status in the subject as conscious or unconscious.

34. The method of claim 33, wherein the consciousness in the subject is covert consciousness under general anesthesia.

35. The method of claim 34, further comprising administering an anesthetic to the subject until the covert consciousness under general anesthesia is not observed in the subject.

36. The method of claim 34, wherein the consciousness is in the subject in a critically ill condition.

37. The method of claim 31 or 32, comprising obtaining the threshold value for diminished LO_END dilation and, depending on the LO_END dilation in the subject and the threshold value for diminished LO_END dilation, determining the physiological status in the subject as unconscious or intoxicated.

38. The method of claim 31 or 32, comprising obtaining the threshold value for diminished LO_END dilation and, depending on the LO_END dilation in the subject and the threshold value for diminished LO_END dilation, determining the physiological status in the subject as having an opioid induced adverse event.

39. The method of claim 38, wherein the opioid related adverse event is respiratory depression, mild pruritus / dermatitis, gastrointestinal complications, central nervous system complications, and acute respiratory failure requiring mechanical ventilation.

40. The method of claim 38 or 39, further comprising administering appropriate therapy to the subject based on the determined opioid-related adverse event.41 . The method of any one of claims 31 to 40, further comprising administering an appropriate therapy to the subject based on the determined physiological status.

42. A computer-implemented method for determining a physiological status of a subject, the method comprising:determining, via one or more processors, a pupillary light-off (LO) maximum dilation response (LO_MAX dilation) in a subject, the method comprising: determining the LO_MAX dilation in the subject as a difference between the maximum pupillary diameter after light goes off and stays off and the pupillary diameter within 0.01 to 0.1 seconds after light goes off;obtaining, via one or more processors, one or more of threshold values for: robust LO_MAX dilation, diminished LO_MAX dilation, and indeterminant LO_MAX dilation; anddepending on the LO_MAX dilation in the subject and the threshold value for robust LO_MAX dilation, diminished LO_MAX dilation, and indeterminant LO_MAX dilation, determining, via one or more processors, the physiological status of the subject.

43. The computer-implemented method of claim 42, wherein the maximum pupillary dilation after light goes off and stays off is determined at least 8 seconds after light goes off.

44. The computer-implemented method of claim 42 or 43, comprising obtaining, via one or more processors, the threshold value for robust LO_MAX dilation and, depending on the LO_MAX dilation in the subject and the threshold value for robust LO_MAX dilation, determining, via one or more processors, the physiological status in the subject as conscious or unconscious.

45. The computer-implemented method of claim 44, wherein the consciousness in the subject is covert consciousness under general anesthesia.

46. The computer-implemented method of claim 45, further comprising administering an anesthetic to the subject until the covert consciousness under general anesthesia is not observed in the subject.

47. The computer-implemented method of claim 44, wherein the consciousness is in the subject in a critically ill condition.

48. The method of claim 42 or 43, comprising obtaining, via one or more processors, the threshold value for diminished LO_MAX dilation and, depending on the LO_MAX dilation in the subject and the threshold value for diminished LO_MAX dilation, determining, via one or more processors, the physiological status of the subject as unconscious or intoxicated.

49. The computer-implemented method of claim 42 or 43, comprising obtaining, via one or more processors, the threshold value for diminished LO_MAX dilation and,depending on the LO_MAX dilation in the subject and the threshold value for diminished LO_MAX dilation, determining, via one or more processors, the physiological status of the subject as having an opioid induced adverse event.

50. The computer-implemented method of claim 49, wherein the opioid related adverse event is respiratory depression, mild pruritus / dermatitis, gastrointestinal complications, central nervous system complications, and acute respiratory failure requiring mechanical ventilation.

51. The method of claim 49 or 50, further comprising administering appropriate therapy to the subject based on the determined opioid-related adverse event.

52. The computer-implemented method of any one of claims 42 to 51 , further comprising administering appropriate therapy to the subject based on the determined physiological status.

53. A computer-implemented method for determining a physiological status of a subject, the method comprising:determining, via one or more processors, a pupillary light-off (LO) end dilation response (LO_END dilation) in the subject, the method comprising: determining LO_END dilation in the subject as a difference between the pupillary diameter after a predetermined time after light goes off and stays off and the pupillary diameter within 0.01 to 0.1 seconds after the light goes off;obtaining, via one or more processors, one or more of threshold values for: robust LO_END dilation, diminished LO_END dilation, and indeterminant LO_END dilation; anddepending on the LO_END dilation in the subject and the threshold value for robust LO_END dilation, diminished LO_END dilation, and indeterminant LO_END dilation, determining, via one or more processors, the physiological status of the subject.

54. The computer-implemented method of claim 53, wherein the predetermined time after light goes off and stays off is 6 or 7 seconds.

55. The computer-implemented method of claim 53 or 54, comprising obtaining the threshold value for robust LO_END dilation and, depending on the LO_END dilation in the subject and the threshold value for robust LO_END dilation, determining, via one or more processors, the physiological status of the subject as conscious or unconscious.

56. The computer-implemented method of claim 55, wherein the consciousness in the subject is covert consciousness under general anesthesia.

57. The computer-implemented method of claim 56, further comprising administering an anesthetic to the subject until the covert consciousness under general anesthesia is not observed in the subject.

58. The computer-implemented method of claim 56, wherein the consciousness is in the subject in a critically ill condition.

59. The computer-implemented method of claim 53 or 54, comprising obtaining, via one or more processors, the threshold value for diminished LO_END dilation and, depending on the LO_END dilation in the subject and the threshold value for depressed LO_END dilation, determining, via one or more processors, the physiological status in the subject as unconscious or intoxicated.

60. The computer-implemented method of claim 53 or 54, comprising obtaining, via one or more processors, the threshold value for diminished LO_END dilation and, depending on the LO_END dilation in the subject and the threshold value for diminished LO_END dilation, identifying in the subject the physiological status as having an opioid induced adverse event.

61. The computer-implemented method of claim 60, wherein the opioid related adverse event is respiratory depression, mild pruritus / dermatitis, gastrointestinal complications, central nervous system complications, and acute respiratory failure requiring mechanical ventilation.

62. The computer-implemented method of claim 60 or 61, further comprising administering an appropriate therapy to the subject based on the determined opioid-related adverse event.

63. The computer-implemented method of any one of claims 53 to 62, further comprising administering an appropriate therapy to the subject based on the determined physiological status.

64. A non-transitory computer readable medium comprising instructions, when executed by one or more processors, cause the one or more processors to perform the method according to any one of claims 1 to 63.

65. A computer device, comprising: one or more processors; and the non-transitory computer readable medium of claim 64.

66. An electronic device comprising one or more processors, an infrared camera, and an adapter fitted with the infrared camera to obtain an infrared video of an eye of a subject, the portable electronic device further comprising a non-transitory computer readable medium comprising instructions, when executed by the one or more processors, cause the electronic device to perform the method according to any one of claims 1 to 63.

67. The electronic device of claim 66, wherein the adapter is substantially cylindrical or cone shaped with one end designed to engage with the infrared camera of the portable electronic device and the other end designed to be placed on an eye of the subject.

68. The electronic device of claim 67, wherein the adapter is black or dark colored.

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