Patent Application: US-37266609-A

Abstract:
a method for monitoring the depth of anesthesia is provided for detecting the conscious state of one being anesthetized in the recovery phase or induction phase of anesthesia course in order to facilitate an anesthesiologist to predict exactly the dosage of an anesthetic required . at first , an original electroencephalogram is taken from one being tested . then , the original electroencephalogram is analyzed by approximate entropy to obtain its approximate entropy value . next , the approximate entropy value is multiplied by 1000 / 17 , and the corrected value is assumed as the predicted value of depth of anesthesia . the predicted value of depth of anesthesia represents degree of the conscious state or the depth of anesthesia for the one being tested . the higher the predicted depth of anesthesia value , the more conscious the one being tested is , i . e ., in a shallower depth of anesthesia . on the other hand , the lower the predicted depth of anesthesia value , the less conscious the one being tested is , i . e ., in a deeper depth of anesthesia .

Description:
the investigated subjects of this example were patients to be subjected to an operation of nasosinusitis in national taiwan university hospital . twenty - five patients were enrolled . thirteen of them are male , and the other twelve are female . they are in an average age of 42 ± 13 years , and the average operation time is 110 ± 45 minutes . the patient being tested was made first into anesthesia by intravenous injecting with thiopental . then , the anesthesia manner was changed into general gas anesthesia ( general anesthesia using inhalant anesthetics ), which the main inhalant anesthetics were isoflurane , sevoflurane , and desflurane . referring to fig2 a number 14 , a method for predicting the depth of anesthesia , comprising step 1 : attaching measuring patch on the center , ground , and right of the brow of the subject and using electroencephalography ( eeg ) monitor to measure obtaining original electroencephalogram ( eeg ) from one the subject being tested . in this example , the brain wave signal , bis index , sef95 , and mef of the anesthetized subject was collected with a bis monitor ( aspect a - 1050 ). as shown in fig1 , the brain wave measuring patch was attached on the center ( ctr ) 11 , ground ( gnd ) 12 , and right ( r ) 13 of the brow of the subject . the sampling time for bis index , sef95 , and mef data was 5 sec / time . the sampling time for eeg data was 1 / 128 sec / time . the brain wave monitor was connected to a computer through rs232 . all of the data measured were transmitted to the computer for analysis . bis index was used to indicate the degree of conscious state and the depth of anesthesia or tranquilization based on a scale of 0 - 100 . generally , it can be divided into four grades as follows : ( 1 ) 70 - 100 : the subject is in a conscious state or slightly sedation state and is freely movable . the bis index is usually in the range of 90 - 100 . ( 2 ) 60 - 70 : the subject is in a slight non - conscious state or gradually restoring the conscious state and the state occurred in a patient is just at the end of the operation but not regaining consciousness . ( 3 ) 40 - 60 : the subject is in a non - conscious state . in general , a patient undergoing an operation should be controlled within this range of depth of anesthesia , which indicates the optimal dosage range . ( 4 ) 0 - 40 : the subject is in an excessively non - conscious state . if the subject is a patient in an operation room , this indicates the over dosage of anesthetics that makes the depth of anesthesia of the patient being into excessively deep . in addition , values of sef95 and mef obtained from bis monitor were in the range of 0 . 5 - 30 hz . mef defines the energy distribution change below 50 % of total energy as the brain wave is in the frequency domain range of 0 . 5 - 30 hz . sef95 defines the energy distribution change below 95 % of total energy as the brain wave is in the frequency domain range of 0 . 5 - 30 hz . the more conscious the subject is , the frequency value is closer to 30 hz . on the contrary , as the subject in low consciousness , the frequency value is closer to 0 . 5 hz . for comparing conveniently with other method , in this example , values of sef95 and mef were set in the range of 0 to 100 , where 0 represented 0 . 5 hz , and 100 represented 30 hz . referring to fig2 a number 15 , a method for predicting the depth of anesthesia , comprising step 2 : a computer records the electroencephalography ( eeg ) data from electroencephalography ( eeg ) monitor in the induction phase or recovery phase of anesthesia course . in this example , the anesthesia course was divided into three phases , i . e . induction , maintenance , and recovery , so as to analyze the depth of anesthesia of the subject in terms of various phases . ( 1 ) the induction phase : from 1 minute after intravenous injecting thiopental to 1 minute after inhalating the inhalant anesthetics . ( 2 ) the maintenance phase : from 1 minute after inhalating the inhalant anesthetics to 1 minute after stopping the inhalation of the inhalant anesthetics . ( 3 ) the recovery phase : from 1 minute after stopping the inhalation of the inhalant anesthetics till the subject regains consciousness . referring to fig2 a number 16 , a method for predicting the depth of anesthesia , comprising step 3 : using a computer to calculate the approximate entropy value from the recorded electroencephalogram ( eeg ) signal using the formula in this example , the brain wave signal of the subject was analyzed with approximate entropy , and the result of which was used to predict further the depth of anesthesia of the subject . low approximate entropy value indicated the anesthesia state of the subject , where the brain wave signal had a regularity and predictability . on the contrary , high approximate entropy value represented the irregularity and non - predictability of the brain wave signal from the subject , which in turn indicated that the subject was readily to regain consciousness . φ m ( r ) is defined as in the following formula ( 2 ): φ m ⁡ ( r ) = ( n - m + 1 ) - 1 · ∑ i = 1 n - m + 1 ⁢ ln ⁢ ⁢ c i m ⁡ ( r ) ( 2 ) c i m ( r ) is defined as in the following formula ( 3 ): c i m ( r )=( number of x ( j ) such that d [ x ( i ), x ( j )]≦ r )/( n − m + 1 ) ( 3 ) x ( i ) and x ( j ) are defined as in the following formula ( 4 ): x ( i )=[ u ( i ), . . . , u ( i − m − 1 )] x ( j )=[ u ( j ), . . . , u ( j = m − 1 )] ( 4 ) referring to fig2 a number 17 , a method for predicting the depth of anesthesia , comprising step 4 : using a computer to compute corrected approximate entropy value by multiplying the approximate entropy value obtained in step 2 to 1000 / 17 . in order to compare conveniently with other method , in this example , the value ( 0 to 1 . 7 ) of approximate entropy calculated as described above was set linearly within a range of 0 to 100 . that is , the value of approximate entropy calculated originally was multiplied by 1000 / 17 . thus , the corrected approximate entropy value was used to represent the degree of conscious state , the depth of anesthesia or the degree of tranquilization of a subject . the approximate entropy value can also be divided into following 4 grades : ( 1 ) 70 - 100 : the subject is in a conscious state or slightly tranquilized state and is freely movable . ( 2 ) 60 - 70 : the subject is in a slight non - conscious state or gradually restoring the conscious state and the state occurred in a patient is just at the end of the operation but not regaining consciousness . ( 3 ) 40 - 60 : the subject is in a non - conscious state . in general , a patient undergoing an operation should be controlled within this range of depth of anesthesia , which indicates the optimal dosage range . ( 4 ) 0 - 40 : the subject is in an excessively non - conscious state . if the subject is a patient in an operation room , this indicates the over dosage of anesthetics that makes the depth of anesthesia of the patient being into excessively deep . finally , referring to fig2 a number 18 , a method for predicting the depth of anesthesia , comprising step 5 : displaying calculated corrected approximate entropy value on a monitor as the subject &# 39 ; s the depth of anesthesia state . irregularity calculated from approximate entropy value was deduced on the base of three parameters , i . e ., the length of data cycle ( n ), the number of data comparison ( m ), and the noise filtering coefficient ( r ). these three parameters can be correlated as illustrated in fig2 b , and they are defined as follows : ( 1 ) the length of data cycle ( n ) 21 : it is derived from the segmentation of the original data 2 . in the approximate entropy theory , the length of data cycle ( n ) 21 is defined as the sliding block of data analysis , and it is also one of the most important parameters that can affect the result . since the approximate entropy theory calculates the regularity based on the difference between points within the time domain data , in case of too little set of the sliding block , data groups will be so deficient that the regularity cannot be predicted precisely . on the other hand , if the setting of the sliding block is too much , the precision of the analysis will be affected adversely due to the abundant duplicate data and lengthy analysis time . ( 2 ) the number of data comparison ( m ) 22 : it relates to the smaller data groups obtained by segmenting the above - mentioned length of data cycle ( n ) 21 with sliding blocks . in the approximate entropy theory , the number of data comparison ( m ) 22 is defined as the sliding block in the length of data cycle ( n ). ( 3 ) the noise filtering coefficient ( r ) 23 : the quantity of the admissible error ( r ) 24 , which is among data points within each of various groups obtained from the segmentation of the data group , is defined by multiplying the noise filtering coefficient ( r ) by the standard deviation of the data . in this example , set n = 1024 , m = 2 , r = 0 . 2 for analyzing clinical data . in order to explain the step by step of how to calculate the approximate entropy , the following one group of x 1 to x 10 using approximate entropy for illustrating steps of approximate entropy analysis : x 1 x 2 x 3 x 4 x 5 x 6 x 7 x 8 x 9 x 10 2 3 1 2 3 4 3 2 4 1 the noise filtering coefficient ( r ) was assumed a value of 0 , meaning that data points having a difference of 0 among them were data in coincidence with one another . the number of those coincidental data is referred as a match number . next , the number of data comparison ( m ) was set as 1 and 2 , and compared with all of the data sequence in m groups to obtain the match number . the process in step 1 was repeated , while the number of data comparison ( m ) was set as m + 1 , and compared with all of the data sequence in m + 1 group to obtain the match number . the result obtained in step 1 was divided by the result obtained in step 2 , and took logarithm , thereby the following result was yielded : the processes as described in step 1 , step 2 and step 3 were repeated , but using x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 , x 8 , x 9 and x 10 as initial points , logarithms obtained in step 3 were summed up , the sum thus yielded was divided by ( n − m ), and finally , the quotient was multiplied by − 1 . values of approximate entropy ( m , r , n ) were thus obtained as follows : fig3 - 1 to 3 - 25 shows analytical value of bis index , sef95 , mef , and approximate entropy obtained during the anesthesia period of the subject tested . next , the anesthesia course was divided into three phases , i . e ., induction , maintenance and recovery , and thereafter , the depth of anesthesia of the subject in each phase was analyzed using bis index , sef95 , mef , and approximate entropy . results were shown in table 1 , 2 and 3 . thereafter , variations of bis index , sef95 , mef and approximate entropy in the induction and maintenance phases of anesthesia were compared in a quantitative manner . as results shown in table 4 , median values of difference between the induction and the maintenance phases of anesthesia obtained by each analytical method of bis index , sef95 , mef , and approximate entropy were , 34 . 3 , 4 . 5 , − 2 . 6 and 22 . 3 , respectively . since values from these 4 types of analytical methods did not show normal distribution , a non - parametric statistical method of kruskal wallis test was used to cross compare bis index , sef95 , mef , and approximate entropy with one another in order to reveal whether there were significant differences in the anesthesia course among them . the obtained p value was less than 0 . 05 , indicating that there were differences among these 4 analytical methods . furthermore , a difference analysis of mann - whitney rank sum test was conducted over results from these 4 analytical methods . as the result , p value for the difference between sef95 and bis index , and between mef and bis index , were less than 0 . 05 , indicating both sef95 and mef had significant difference with bis index , and in addition , values of difference from these two methods were less than that of bis index . consequently , both sef95 and mef failed to recognize effectively the course of consciousness change from conscious state to anesthetized state of the subject . fig3 - 1 to 3 - 25 illustrated same results . conversely , p values for approximate entropy and bis index were more than 0 . 05 , which indicated not only the analytical method based on approximate entropy was capable of predicting the course from conscious to anesthesia state of the subject as effectively as the analytical method based on bis index , but also its performance on the induction phase , like the analytical method based on bis index , exhibited no dramatic change just . during the recovery phase of anesthesia , the conscious state of the subject would regain consciousness gradually from coma . therefore , a quantitative method was used further to compare changes of bis index , sef95 , mef , and approximate entropy during the recovery and the maintenance phases of anesthesia . results in table 5 indicated that median values of the difference between the recovery and the maintenance phases of anesthesia obtained by various analytical methods were 13 . 8 , 11 . 6 , 16 . 8 and 20 . 5 , respectively . these medium values in top - down order were successively as approximate entropy , mef , bis index , and sef95 . since values from these 4 types of analytical methods did not show normal distribution , a non - parametric statistical method of kruskal wallis test was used to cross compare bis index , sef95 , mef , and approximate entropy with one another in order to reveal whether there were significant differences in the anesthesia course among them . the obtained p value was less than 0 . 05 , indicating that there were differences among these 4 analytical methods . furthermore , a difference analysis of mann - whitney rank sum test was conducted over results from these 4 analytical methods . as the result , p value for the difference between sef95 and bis index , and between mef and bis index , were more than 0 . 05 , indicating both sef95 and mef were , like bis index , capable of predicting the course from anesthesia to conscious state of the subject . in addition , p values for approximate entropy and bis were less than 0 . 05 , and the median value of approximate entropy is higher than the median value of bis index . this indicated approximate entropy was more effective than bis index in predicting the course from maintenance to anesthesia phases of the subject . next , after intravenous injecting the subject with thiopental , the sensitivities to the drug of these 4 analytical methods , i . e . those based on bis index , sef95 , mef , and approximate entropy , respectively , were compared with one another . as the subject entered the induction phase of anesthesia , the slope of the line from the minimum value to the maximum value of the depth of anesthesia obtained from each analytical method was used to determine the sensitivity of the respective analytical theory to the drug . for this , the maximum value of depth of anesthesia from bis index was assumed to be b 1 , while its minimum value was assumed to be b 2 . the maximum value of depth of anesthesia from sef95 was assumed to be s 1 , while its minimum value was assumed to be s 2 . the maximum value of depth of anesthesia from mef was assumed to be m 1 , while its minimum value was assumed to be m 2 . the maximum value of depth of anesthesia from approximate entropy was assumed to be a 1 , while its minimum value was assumed to be a 2 . values of b 1 , b 2 , s 1 , s 2 , m 1 , m 2 , a 1 and a 2 were shown in fig3 - 1 to 3 - 25 . thereafter , the difference between the time at each point of the above - described b 1 , b 2 , s 1 , s 2 , m 1 , m 2 , a 1 and a 2 and the time the induction phase of anesthesia started was defined as the relative time . the relative time of each analytical method was expressed as bis ( b 1 ′, b 2 ′), sef95 ( s 1 ′, s 2 ), mef ( m 1 ′, m 2 ′), and approximate entropy ( a 1 ′, a 2 ′). then , the sensitivity of each of these 4 analytical methods to the brain wave change was compared using the slope between two points . the result was shown in table 6 . table 6 shows variation of sensitivities of these four analytical methods , i . e ., bis index , sef95 , mef and approximate entropy . their median values of slopes were − 15 , 0 , 0 , and − 20 . 4 , respectively . thus , after intravenous injecting the subject with thiopental , these medium values in top - down order were successively as approximate entropy , bis index , sef95 and mef . since values from these 4 types of analytical methods did not show normal distribution , a non - parametric statistical method of kruskal wallis test was used to cross compare bis index , sef95 , mef and approximate entropy with one another in order to reveal whether there were significant differences in the anesthesia course among them . the obtained p value was less than 0 . 05 , indicating that there were differences among these 4 analytical methods . furthermore , a difference analysis of mann - whitney rank sum test was conducted over results from these 4 analytical methods . as the result , p value for the difference between sef95 and bis index , and between mef and bis index , were less than 0 . 05 , indicating both sef95 and mef differed significantly from bis index . further , slopes of sef95 and mef were less than that of bis index , indicating both of sef95 and mef exhibited sensitivities to the drug inferior to that of bis index . in addition , no difference existed between approximate entropy and bis ( p & gt ; 0 . 05 ), which represented , after intravenous injecting the subject with thiopental , both approximate entropy and bis index could display rapidly a sensitivity in response to the metabolism of the drug . moreover , the slope value (− 20 . 4 ) obtained from approximate entropy analysis was the greatest one among those obtained from four methods , which indicated that approximate entropy not only could differentiate the course from conscious to anesthesia , but also could respond rapidly to the change from conscious to anesthesia of the subject immediately after intravenous injection with thiopental . next , in the recovery phase of anesthesia , these 4 analytical methods , i . e ., bis index , sef95 , mef and approximate entropy , were compared with one another in terms of the sensitivity to the metabolism of the drug from anesthesia to conscious state of the subject . as the subject entered the recovery phase of anesthesia , the slope of the line from the minimum value to the maximum value of the depth of anesthesia obtained from each analytical method was used to determine the sensitivity of the respective analytical theory to the metabolism of the drug . for this , the minimum value of depth of anesthesia from bis index was assumed to be b 3 , while its maximum value was assumed to be b 4 . the minimum value of depth of anesthesia from sef95 was assumed to be s 3 , while its maximum value was assumed to be s 4 . the minimum value of depth of anesthesia from mef was assumed to be m 3 , while its maximum value was assumed to be m 4 . the minimum value of depth of anesthesia from approximate entropy was assumed to be a 3 , while its maximum value was assumed to be a 4 . values of b 3 , b 4 , s 3 , s 4 , m 3 , m 4 , a 3 and a 4 from each of the subject were shown in fig3 - 1 to 3 - 25 . thereafter , the difference between the time at each point of the above - described b 3 , b 4 , s 3 , s 4 , m 3 , m 4 , a 3 and a 4 and the time the recovery phase of anesthesia started was defined as the relative time . the relative time of each analytical method was expressed as bis ( b 3 ′, b 4 ′), sef95 ( s 3 ′, s 4 ), mef ( m 3 ′, m 4 ′), and approximate entropy ( a 3 ′, a 4 ′). then , the sensitivity of each of these 4 analytical methods to the brain wave change was compared using the slope between two points . the result was shown in table 7 . table 7 shows variation of sensitivities of these four analytical methods , i . e ., bis index , sef95 , mef and approximate entropy . their median values of slopes were 4 , 3 . 2 , 5 . 3 , and 3 . 5 , respectively . these medium values in top - down order were successively as mef , bis index , approximate entropy and sef95 . since values from these 4 types of analytical methods did not show normal distribution , a non - parametric statistical method of kruskal wallis test was used to cross compare bis index , sef95 , mef and approximate entropy with one another in order to reveal whether there were significant differences in the anesthesia course among them . the obtained p value was higher than 0 . 05 , indicating that there were no differences among these 4 analytical methods . furthermore , a difference analysis of mann - whitney rank sum test was conducted over results from these 4 analytical methods . as the result , all of the p values for the difference between sef95 and bis index , between mef and bis index , and between approximate entropy and bis index were higher than 0 . 05 , indicating all of these four methods exhibited quite good sensitivity with respect to the metabolism of the anesthesia gas . finally , the anesthesia was divided into phases of induction , maintenance and recovery , and investigated the change of depth of anesthesia in 25 subjects using statistical method , as shown in table 8 . as shown in table 8 , a kruskal wallis test was conducted to analyze results from bis index , sef95 , mef and approximate entropy to reveal whether there was any difference . as a result , p values from these four methods were all less than 0 . 05 , indicating that there were significant differences among these four analytical methods in the three phases of anesthesia . furthermore , a mann - whitney rank sum test was conducted to analyze various methods in order to reveal whither there were any difference among analytical results in the induction , maintenance and recovery phases obtained from various methods . where , p & gt ; 0 . 05 indicated no difference with one another . on the contrary , p & lt ; 0 . 05 indicated a significant difference with one another . as shown in table 8 , no difference ( p & gt ; 0 . 05 ) existed between sef95 and mef with respect the result obtained in the induction and maintenance phases , which indicated that both of sef95 and mef failed to differentiate the conscious states of the subject in the induction and maintenance phases . on the other hand , there were significant difference ( p & lt ; 0 . 05 ) between analytical results in the induction and maintenance phases , as well as between analytical results in the recovery and maintenance phases obtained from bis index and approximate entropy , which represented that both of bis index and approximate entropy were able to differentiate effectively the conscious state and anesthesia state of a subject . it is worthy to note that there was no difference ( p = 0 . 05 ) between approximate entropy analytical results in the induction phase and in the recovery phase , which indicated that approximate entropy could present the course of regaining a conscious state before anesthesia from the end of anesthesia for a subject . it can be seen from the above - 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