A patient undergoing anesthesia for a surgical procedure generally receives one or more pharmacological anesthetic agents. Different anesthetic agents produce different effects, the most important of which are sedation or hypnosis (the lack of consciousness or awareness of the surrounding world), analgesia (the blunting or absence of pain) and paralysis (lack of movement). Anesthetic agents may provide one or more of these effects and to varying extents. For example, neuromuscular blocking agents provide potent paralysis, but no sedation or analgesia. Opioids provide analgesia and relatively light levels of sedation. Volatile anesthetic agents provide significant levels of sedation and much smaller levels of analgesia, while the intravenous sedative agent propofol provides sedation but essentially no analgesia. For this reason, anesthesia providers generally administer several of these agents simultaneously to provide the desired set of effects. For example, an anesthesia provider may administer a volatile anesthetic agent for its sedative effect, a neuromuscular blocking agent for paralysis and an opioid agent to provide analgesia. In general, the magnitude of the effects provided by these agents are dose-dependent; the higher the dose, the more profound the effect.
The anesthetic administration is complicated by the multiple effects of the administered anesthetic agents. For example, since volatile agents have analgesic as well as sedative effects, an increase in the administered concentration of a volatile agent will result in a concomitant, and possibly undesired, increase in analgesic effect. All anesthetic agents have deleterious effects associated with excessive doses. While the effect on the patient may be estimated from the administered dose, patients vary widely in their response to a specific dose and such estimates are therefore based upon group norms (average effects). While the group norm may be representative of the effect of a specific dose on a population of patients, the actual effect in any one patient may vary widely.
It would therefore be beneficial to the patient to monitor the effect of the administered anesthetic agents to ensure that the patient receives the appropriate dose of anesthetic agents. It is common in anesthesia practice to monitor the sedative effects of anesthetic agents by the use of devices which analyze the patient's electroencephalograph (EEG). One such device is the line of monitors made by Aspect Medical Systems, Inc. (Norwood, Mass.) which calculate the Bispectral Index®. By way of example, U.S. Pat. No. 5,458,117, entitled CEREBRAL BIOPOTENTIAL ANALYSIS SYSTEM AND METHOD, issued to Chamoun et al. on Oct. 17, 1996, which is assigned to the assignee of the present invention, describes a system and method for generating a bispectral index from EEG signals. The Bispectral Index® (BIS®) discussed in that patent is an electroencephalograph (EEG)-based measure which quantifies a patient's level of consciousness during anesthesia and sedation from EEG signals acquired from scalp, forehead or temple electrodes. BIS is a single time varying number that is generally indicative of a patient's sedative state and is scaled from 0 to 100, where 100 is fully awake and alert and zero represents isoelectric EEG activity. BIS may be used by anesthesia providers to effectively monitor the sedative state of a patient during a surgical procedure and to maintain a patient's sedative or hypnotic state in an optimal range, generally 50-60.
Similarly, a patient's level of paralysis may be measured by a tetanic nerve simulator, a device which delivers a train of four electrical stimuli to the nerve in the forearm innervating the muscles of the thumb. Each electrical stimulus results in a twitch of the patient's thumb, which may be quantified using a strain gauge attached to the patient's thumb. Successively higher levels of paralysis result in the abolition of the twitch responses, beginning with the fourth and final response and finally abolishing the first twitch response. The degree of paralysis may be gauged by the degree to which the twitches are abolished. It is common practice to administer neuromuscular blocking agents until three of the four twitches are abolished.
While BIS may be used to monitor a patient's level of sedation and a tetanic nerve simulator used to monitor the degree of paralysis, there is no similar measure of analgesia. Typically, the adequacy of analgesia is gauged by the presence or absence of various indirect autonomic signs, such as hemodynamic responses (hypertension or tachycardia), sweating, eye tearing or movement. These measures are nonspecific, however, and a patient may experience significant pain without exhibiting any of them. In addition, agents administered to maintain blood pressure and heart rate within desired ranges may abolish hemodynamic responses.
Pain is a subjective, self-reported phenomenon. It is often associated with somatic responses, such as sweating, movement, etc. The measurement of pain is difficult, since patient descriptions vary. Standardized measurement techniques such as Visual-Analog Scales (VAS), which ask a patient to rank their pain on a numeric scale (e.g., 0-10), provide some degree of comparability. However, since different patients have different pain thresholds and expectations, VAS assessments are inherently limited. In addition, VAS assessments are not useful when a patient cannot respond, such as during surgery. Postoperative pain and lower doses of opioids have been determined to be risk factors for increased risk of postoperative delirium, with the conclusion that more effective control of postoperative pain improves outcomes by reducing the incidence of postoperative delirium [Lynch EPMD, Lazor MAMD, Gellis JEMD, et al. The Impact of Postoperative Pain on the Development of Postoperative Delirium. Anesthesia & Analgesia 1998; 86(4):781-5; Morrison R S, Magaziner J, Gilbert M et al. Relationship between Pain and Opioid Analgesics on the Development of Delirium Following Hip Fracture. J Gerontol A Biol Sci Med Sci 2003; 58: 76-81]. Perioperative pain is also linked to postoperative cognitive dysfunction (POCD). Duggleby determined that postoperative pain, not analgesic intake, predicted postoperative mental status decline, and recommended improved pain management [Duggleby W, Lander J. Cognitive Status and Postoperative Pain: Older Adults. J Pain Symptom Manage 1994; 9:19-27]. Minimization of intraoperative and postoperative pain should therefore result in improved patient outcomes.
As discussed earlier, volatile anesthetics have both sedative (hypnotic) and analgesic properties, and are often administered at quite large concentrations in order to assure adequate analgesia and hemodynamic stability, especially if relatively small doses of opioids and other analgesics are in use. Volatile anesthetics have recently been associated with processes leading to cell death and amyloid β-protein aggregation; excessive aggregation of amyloid β-protein is the hallmark of Alzheimer's disease [Xie Z, Dong Y, Maeda U, et al. The Inhalation Anesthetic Isoflurane Induces a Vicious Cycle of Apoptosis and Amyloid β-Protein Accumulation. J. Neurosci. 2007; 27:12-1254]. In addition, deeper anesthetic intraoperative hypnotic levels have been linked with increased rates of postoperative mortality [Monk T G, Saini V, Weldon B C, Sigl J C: Anesthetic Management and One-Year Mortality after Noncardiac Surgery. Anesth Analg 2005; 100:4-10].
While excessive doses of the various anesthetic agents may have deleterious effects, inadequate doses may result in different but also undesirable effects. It is therefore important that all the pharmacological components of an anesthetic (sedative/hypnotic, analgesic, paralytic, etc.) be properly administered and titrated to the patient's requirement. While monitoring means exist to determine the adequacy of the sedative/hypnotic and paralytic states, no similar monitoring technology allows the objective assessment of analgesic state and analgesic adequacy. A patient's analgesic state is the degree of analgesia provided by the administered pharmacological agents, while the analgesic adequacy is the degree to which the current level of analgesia is sufficient to block the current and expected level of noxious stimuli. The ability to assess analgesic state and determine analgesic adequacy during surgery and anesthesia would be extremely useful to establish the analgesic dose required and would improve outcome over existing practice.
U.S. Pat. No. 5,601,090 issued to Musha discloses an apparatus and method for determining the somatic state of a human subject. The method acquires characteristic values of the subject, which may be brain waves, muscle potentials, heart-rate, eye-movement and frequency of eye blinks, or any combination thereof. A neural network model is applied to these characteristic values to determine the subject's somatic state, which Musha defines as mental state due to such things as the subject's emotions (e.g., joy, anger, happiness, sadness, elation, surprise, disgust or fear), level of mental activity (e.g., as a result of doing mental arithmetic or writing a poem) or motor activity (e.g., moving a hand or foot). The Musha patent does not quantify the subject's analgesic state or adequacy, or any state related to the effect of medications.
U.S. Pat. Nos. 6,654,632; 6,751,499; 6,757,558 and 6,826,426 issued to Lange et al. disclose an objective pain measurement system and method based on bilateral biopotentials recorded from electrodes placed symmetrically about the midline on the forehead of a subject. The Lange et al. patents teach that in general, biopotentials on the subject's skin surface are generated by several sources, including background electroencephalographic (EEG) activity, electrodermal activity, electromyographic (EMG) activity, motion artifacts (such as caused by eyeball, eyelid and head movements), and other electrophysiological phenomena. Background EEG measurements from each side of the vertical midline and artifacts, such as those caused by eyeball movement, are negatively-correlated while pain signals from each side of the vertical midline are generally positively correlated and may override the negatively correlated EEG activity. Consequently, the system and method of pain detection of the Lange et al. patents preferably use positive bilateral correlation as a discriminant for pain signals when the measurements are taken from electrodes located on opposite sides of the subject's vertical midline. The Lange et al. patents further state that pain detection may also use signal linearity to distinguish pain, because pain signals detected from each side of the vertical midline are generally linearly related. In contrast, various artifacts in the detected signal, even those that are positively correlated (e.g., eyelid or head movements), are often not linearly related. The Lange et al. patents teach the use of coherence to determine whether the bilateral signals are linearly related. The Lange et al. patents further teach that signals between about 0.5 Hertz and about 2 Hertz appear to carry the bulk of pain intensity information. The system and method described in the Lange et al. patent computes a quantified pain level signal using band pass filtering to 0.1 to 2 Hz, linear prediction, frequency transformation, non-linear weighted averaging of the frequency-transformed signal components and scaling of the weighted average. The Lange et al. patents do not discuss the source of the pain signals, nor why these signals are positively correlated while the non pain-related signals are not or why pain signals detected from each side of the vertical midline are generally linearly related while non-pain signals from each side of the vertical midline are not linearly related. The Lange et al. patents teach a system and method for measuring pain and for differentiating pain signals from artifact. However, they do not teach a method of determining analgesic state or analgesic adequacy, nor do they teach how to resolve the separate influences of the level of consciousness and pain on the EEG signal.
Shander evaluated a measure called FACE based on the ratio of EMG activity in four facial muscles and determined that the time in minutes of the FACE RATIO>20 during surgery was associated with total amount of administered postoperative analgesics [Shander A, Qin F, Bennett H. Prediction of Postoperative Analgesic Requirements by Facial Electromyography during Simultaneous BIS Monitoring. European Journal of Anaesth 2001; 18 (Suppl. 21):A464].
U.S. Pat. No. 6,731,975 issued to Viertiö-Oja, et al, teach a method and apparatus for ascertaining the cerebral state of a patient, specifically for ascertaining the depth of anesthesia of the patient. The entropy of the patient's EEG signal data is determined as an indication of the cerebral state. A frequency domain power spectrum quantity is obtained from the patient's EMG signal data. The EEG entropy indication and the EMG power spectrum indication are combined into a composite indicator that provides an immediate indication of changes in the cerebral state of the patient. In an alternate embodiment, the frequency range over which the entropy of the biopotential signal from the patient is determined is broadened to encompass both EEG signal data and EMG signal data and the entropy so determined used as an indication of the patient's cerebral state. In a continuation patent U.S. Pat. No. 6,801,803, Viertiö-Oja et al. teach the use of time windows of differing lengths. For lower frequency component, longer time windows are used. For higher frequency components, shorter time windows are used. Such techniques are common in the art of wavelet analysis. Both of these patents teach the combination of a power spectral measure from the EMG with an entropy measure derived from the EEG in order to ascertain the depth of anesthesia of the patient with a faster response time over the EEG metric alone. Neither of the Viertiö-Oja et al. patents teach the determination of the analgesic state or analgesic adequacy of a patient.
Bloom et al. [Bloom M, Greenwald S D, Day R, Analgesics Decrease Arousal Response to Stimulation as Measured by Changes in Bispectral Index (BIS). Anesthesiology 1996; 85(3A):A481] investigated the intrinsic variability of BIS in volunteers who received various concentrations of sedative and analgesic agents. Bloom determined that the variability in the absence of stimulation was decreased by the addition of analgesic agents compared to sedative agents alone. Bloom and Jopling (Jopling M W, Cork R, Greenwald S D. Changes in the Bispectral Index (BIS) in the Presence of Surgical Stimulation Reflect the Level of Analgesia. Anesthesiology 1996; 85 (3A): A478) reported that analgesics blunt the increase in BIS that follows surgical stimulation. In a study evaluating the response to painful stimulus, Iselin-Chaves demonstrated that the absolute change in BIS after a painful stimulus was significantly decreased by both an increase in the concentration of the sedative agent and the presence of the analgesic agent, [Iselin-Chaves I A, Flaishon R, Sebel P S, et al. The Effect of the Interaction of Propofol and Alfentanil on Recall, Loss of Consciousness, and the Bispectral Index. Anesth Analg 1998; 87(4):949-55]. Guignard also investigated the effect of the addition of an analgesic agent of the sedative in terms of response of BIS to the stimulus of intubation. His group concluded that “the addition of an analgesic (remifentanil) to propofol (a sedative) affects BIS only when a painful stimulus is applied. Moreover, remifentanil attenuated or abolished increases in BIS and MAP (mean arterial pressure) in a comparable dose-dependent fashion” [Guignard B, Menigaux C, Dupont X, et al. The Effect of Remifentanil on the Bispectral Index Change and Hemodynamic Responses after Orotracheal Intubation. Anesth Analg 2000; 90(1):161-7]. In a later publication Bloom suggested that using a variability measure based on BIS (the maximum minus the minimum BIS value over a three minute time window), wide short-term BIS variability may be an indicator of insufficient analgesia [Bloom M, Jurmann A, Cuff G, Bekker A. BIS Variability Reflects Analgesia. J Neurosurg Anesthesiol 2005; 17(4):254-5].
U.S. patent application Ser. No. 11/211,137 filed by Viertiö-Oja, et al. teaches a method and apparatus for measuring the responsiveness of a subject with a lowered level of consciousness. In the system of the Viertiö-Oja et al. application, the EEG signal measured from a patient is digitized, filtered to exclude high- and low-frequency artifacts and processed as sets of 5 second time windows or “epochs”. The processing method calculates the high-frequency power of the EEG signal, which the Viertiö-Oja et al. application defines as the power in a band extending from 20 Hz to 35 Hz within a single epoch, and stores the calculated value. This calculation is repeated for each epoch producing a time series (known as the first measure), which is the high-frequency EEG power in each epoch.
The processing method of the Viertiö-Oja et al, application next calculates a change variable indicative of the changes in the high-frequency EEG power. The process first finds the minimum value within the preceding 1 minute of the first measure. The change variable is then determined by subtracting the minimum value of the first measure from the current value of the first measure. Finally, a responsiveness index is calculated by averaging successive values of the logarithm of the change variable over 30 minutes. The responsiveness index is indicative of the mean/cumulative high-frequency EEG power changes with respect to time. The Viertiö-Oja et al. application teaches that other measures may be used instead of high-frequency EEG power as the first measure, such as EEG entropy or measures based on fractal spectrum analysis, Lempel-Ziv complexity, or bispectral or multispectral analyses or the Bispectral Index.
The responsiveness index of the Viertiö-Oja et al. application is designed to differentiate between natural sleep and unconsciousness induced by sedatives is based on the theory that deepening sedation tends to suppress naturally occurring arousals, while test persons in natural sleep remain relative responsive. The responsiveness index is therefore intended to provide a selective mechanism for differentiating between sedation and natural sleep. Due to the long time window (i.e., 30 minutes) used to calculate the responsiveness index, the index is sensitive only to stimuli which result in sustained changes in high-frequency EEG power and is insensitive to isolated transient stimuli, such as those occurring during care procedures.
Knowledge of a patient's analgesic state and adequacy would enable an anesthesia provider to more effectively administer the needed pharmacological agents in the precise dosage required to ensure an optimal intraoperative patient state. This optimal state will result in improved patient outcomes. None of the systems proposed to date has disclosed a system or method of which would allow such a determination.
It is therefore an objective of this invention to provide a system and method of assessing and quantifying a patient's level of analgesic state and adequacy.
USPTO Backgrounds
USPTO Backgrounds