Article, Critical Care

Middle latency auditory-evoked potential index for predicting the degree of consciousness of comatose patients in EDs

a b s t r a c t

Introduction: Digitized assessment of the degree of consciousness is a universal challenge in emergency departments (EDs) and Intensive care units . The middle latency auditory-evoked potential index (MLAEPi) monitor aepEX plus (Audiomex, Glasgow, Scotland, UK) is the first mobile middle latency auditory- evoked potential monitor. We speculated that the initial MLAEPi determined on arrival at EDs could indicate cerebral function and predict the degree of consciousness of comatose patients.

Methods: We used MLAEPi-related data from 50 comatose patients with disturbance of consciousness (DOC), 50 patients with cardiopulmonary arrest (CPA), and 50 healthy volunteers (control). Comatose patients were defined as those with an initial Glasgow Coma Scale score of 8 or less. The CPA group consisted of patients who arrived at EDs without restoration of spontaneous circulation. Among the patients with DOC who underwent sedation at EDs, the change in the MLAEPi was evaluated between arrival at the ED and ICU admission.

Results: The initial MLAEPi was significantly lower in the DOC group than in the control group but significantly higher in the DOC group than in the CPA group. Among the comatose patients, the receiver operating characteristic curve for the initial MLAEPi showed an area under the curve of 0.93 (P b .01) for the DOC group. Thirty patients with DOC underwent sedation at EDs, and the initial MLAEPi was significantly higher than those at other periods during emergency care.

Conclusion: The MLAEPi (simple numerical value) may be used to evaluate the degree of consciousness in comatose patients while performing emergency care in EDs.

Introduction

Digitized assessment of the degree of consciousness is a universal challenge in emergency departments (EDs) and intensive care units (ICUs). Several studies have examined the clinical application of the bispectral (BIS) index at different degrees of consciousness in unsedated critically ill patients in ICUs [1-3].

Auditory-evoked potentials (AEPs) as well as BIS monitoring provide a good indication of the degree of consciousness under anesthesia in an operative setting [4]. In particular, cerebral function can be noninvasively monitored by measuring middle latency AEPs (MLAEPs) [5]. Middle latency AEPs are derived from AEPs, which reflect the morphology of MLAEP curves. Middle latency AEPs are also less affected by age than other components of AEPs. However, analyzing AEPs or MLAEPs using large dedicated instruments during resuscitation in an ED is difficult. Moreover, data are usually

? Competing interests: All authors declare that they have no competing interests. The manuscript, including related data, figures, and tables, has not been published previously and is not under consideration for publication elsewhere.

?? Authors’ contributions: Junya Tsurukiri conceptualized and designed the study;

Katsuhiro Nagata, Taihei Okita, and Taishi Oomura provided technical support.

* Corresponding author. 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.

Tel.: +81 3 3342 6111; fax: +81 3 3342 5687.

E-mail address: [email protected] (J. Tsurukiri).

intermittently generated, and analyzing waveforms while delivering emergency resuscitation can be demanding.

The MLAEP monitor aepEX plus (Audiomex, Glasgow, Scotland, UK) is the first mobile MLAEP monitor that can evaluate the level of anesthesia [6]. This monitor is available in several European and Asian countries. It continuously generates an MLAEP index (MLAEPi), which is a dimensionless number scaled between 99 (wide awake) and 0 (no brain activity), with differences between successive segments of the curve constructed from its amplitude. The aepEX plus monitor is being increasingly used to measure both the level of anesthesia and cerebral function instead of BIS values in ICUs [4,7-9]. The effectiveness of MLAEPi monitoring at EDs in patients with cardiac arrest was previously reported, but apparently, no study has attempted to correlate the degree of disturbance of consciousness (DOC) changes with the MLAEPi [10]. We speculated that the initial MLAEPi determined on arrival at the ED could indicate cerebral function and predict the degree of consciousness of comatose patients.

Materials and methods

Patients and study design

This study was conducted at the Emergency Center of Tokyo Medical University Hachioji Medical Center between September 2010

J. Tsurukiri et al. / American Journal of Emergency Medicine 31 (2013) 1556–1559 1557

and March 2011 and at Tokyo Medical university hospital between April 2011 and March 2012. The ethics committees of both institutions approved the study design, and written informed consent was obtained from the next of kin of the patients or a posteriori from the patients themselves when possible.

Although the recommended range of the MLAEPi in general anesthesia settings is 30 to 45, there are no published data concerning the use of the MLAEPi in unsedated patients with DOC at EDs [6]. At first, we enrolled the comatose patients with DOC and the patients with cardiopulmonary arrest (CPA) on arrival at the ED, and the healthy volunteers separately in this study and compared the MLAEPi among these 3 groups. Comatose patients were defined as those with an initial Glasgow Coma Scale score of 8 or less without dilatation of the pupils of more than 6 mm at the ED. Cardiopulmonary arrest was defined as having no cerebral activity and the absence of both spontaneous breathing and a palpable carotid pulse within 1 hour after collapse, without sequential restoration of spontaneous circulation after resuscitation at the ED. Healthy volunteers without cerebrovascular diseases or brain tumors and not taking anticonvulsive agents or antipsychotic, hypnotic, or psychotropic drugs were included.

We excluded from the study comatose patients younger than 15 years; those who had experienced DOC before collapse; and those who had drug intoxication, alcoholism, tympanic injury, or terminal diseases. None of the comatose patients received any medications, such as dextrose, Antiepileptic drugs, or sedatives in the prehospital setting or the ED before the initial MLAEPi was measured.

Intervention

Using the aepEX plus monitor, the MLAEPi was continuously calculated from information provided by disposable sensor electro- encephalogram (EEG) electrodes affixed to the patients’ middle (ground electrode) and right (active electrode) forehead as well as the right mastoid (active electrode), after cleaning the skin with 70% isopropanol. In addition, an emergency medical physician used earphones to determine auditory stimuli. Auditory-evoked potentials were elicited with bilateral click stimuli through earphones at an intensity of less than 60 dB for a nominal frequency of 6.9 Hz. The detected AEPs were extracted consecutively from the raw EEG signal reflecting the brainstem AEP and MLAEP provided by an internal processor. The aepEX plus MLAEPi values were closely related to the AEP waveforms and were calculated as the sum of the square root of the absolute difference between every 2 successive 0.56-millisecond segments of the AEP waveforms (Fig. 1).

On arrival at the ED, all comatose or CPA patients were evaluated by 2 or more experienced emergency physicians, and then, they were administered emergency resuscitation, including tracheal intubation,

Fig. 1. The aepEX plus monitor.

peripheral venous catheters, adrenaline (1 mg), external chest compressions, or defibrillation. The initial MLAEPi was measured within 2 minutes of arrival at the hospital, and a 3-second average of MLAEPi was entered as the initial MLAEPi. The initial MLAEPi was measured in the healthy volunteers after a 5-minute rest.

Among comatose patients who required tracheal intubation after receiving sedatives in the ED, we continuously measured the MLAEPi between arrival at the ED and admission to the ICU or operating room. All procedural sedations were performed by experienced emergency physi- cians, and the choice of sedatives was at the discretion of the emergency physician. In our EDs, we often choose midazolam (5-10 mg) given intravenously as a sedative. Propofol was administered intravenously as an initial bolus of 0.5 mg/kg (up to a maximum total dose of 1 mg/kg).

Data collection

The following characteristics were noted from the charts of the comatose patients: age, sex, initial GCS, vital signs, clinical history, initial MLAEPi, and blood values (pH, lactate, glucose concentration, and base excess). Continuous MLAEPi monitoring did not affect standard resuscitation practices in the ED.

Statistical analyses

Data from all eligible patients were analyzed. Continuous variables were shown as median values with interquartile ranges (IQRs). Intergroup differences were statistically assessed using the Kruskal- Wallis test and 1-way analysis of variance with repeated measures, depending on the distribution of measured variables using Prism version 5.0d statistical software (GraphPad Software, San Diego, CA). Categorical variables were calculated as ratios (%) of the frequency of occurrence. Sensitivity, specificity, and positive likelihood ratios at various MLAEPi cutoff points were calculated based on analyses of receiver operating characteristic curves using the Youden index. P b .01 was considered to indicate a statistically significant difference.

Results

MLAEPi of study subjects

Fifty comatose patients with DOC (DOC group) and 50 patients with CPA (CPA group) upon arrival at the ED and 50 healthy volunteers (control group) were included in this study. A comparison of their characteristics is shown in Table 1. The initial MLAEPi was significantly higher in the DOC group than in the CPA group and was significantly lower in the DOC group than in the control group. The initial MLAEPi was also significantly lower in the CPA group than in the control and DOC groups.

Prediction of the degree of DOC

The demographics and clinical characteristics of the DOC group are shown in Table 2. A positive correlation was found between the initial MLAEPi and GCS score (Spearman’s rank correlation coefficient [r] =

Table 1

Comparison of the control, CPA, and DOC groups

Variable	Control group	DOC group	CPA group
	(n = 50)	(n = 50)	(n = 50)
Age (y), median (IQR)	53 (37-66)	61 (53-72)	62 (50-72)
Male, n (%)	31 (62)	31 (62)	30 (60)
MLAEPi, median (IQR)	86 (77-96)^a^,^b	52 (35-61)^b	28 (24-34)
^a P b .01 vs DOC group. ^b P b .01 vs CPA group.

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Table 2

Clinical characteristics of patients with DOC

Age (y), median (IQR)	61 (53-72)
Male, n (%)	31 (62)
GCS score, n (%) 3	17 (34)
4	13 (26)
5	2 (4)
6	8 (16)
7	6 (12)
8	4 (8)
Systolic blood pressure (mm Hg), median (IQR)	168 (129-194)
Diastolic blood pressure (mm Hg), median (IQR)	88 (76-114)
Heart rate (beats/min), median (IQR)	95 (80-112)
Respiratory rate (beats/min), median (IQR)	17 (12-23)
Body temperature (?C)	35.9 (35.3-36.6)
pH, median (IQR)	7.31 (7.15-7.40)
Base excess, median (IQR)	-4.8 (-8.6 to -1.3)
Lactate concentration (mmol/L), median (IQR)	4.5 (2.5-9.7)
Glucose concentration (mg/dL), median (IQR) Etiologies of DOC 1. Internal, n (%)	195 (146-252)
Cerebrovascular disease
Stroke	22 (44)
Hypoxic-ischemic encephalopathy	12 (24)
Epilepsy	3 (6)
Cardiovascular disease	2 (4)
Hypoglycemia	2 (4)
Respiratory failure	1 (2)
Renal failure	1 (2)
Sepsis	1 (2)
2. External, n (%) Trauma	3 (6)
Heat stroke	3 (6)

Variable n = 50

Fig. 3. Optimal ROC curve for the initial MLAEPi and the degree of DOC. The AUC is 0.93 (95% CI, 0.88-0.98; P b .01).

(10 mg) was used in 1 case, and both 10 mg of midazolam and 35 mg of propofol were used in 1 case. Emergency care, including tracheal intubation, transportation to the CT suite, and CT evaluation, was completely successful, and none of the patients required additional sedation during these periods. The median initial MLAEPi was 51 (IQR, 40-61). The median MLAEPi values were 32 (IQR, 25-35), 30

(IQR, 28-34), 30 (IQR, 28-34), 32 (IQR, 28-36), and 32 (IQR, 28-38)

after undergoing sedation, preintubation, postintubation, CT scan completion, and ICU admission, respectively (Fig. 4).

Discussion

0.76; 95% confidence interval [CI], 0.61-0.86; P b .01) and between the initial MLAEPi and motor response of the GCS score (r = 0.75; 95% CI, 0.59-0.85; P b .01) (Fig. 2). A relatively positive correlation was also found between the initial MLAEPi and the eye response of the GCS score (r = 0.44; 95% CI, 0.18-0.65; P b .01).

Figure 3 shows the ROC curve for the initial MLAEPi to predict the degree of DOC. The area under the curve (AUC) was 0.93 (95% CI, 0.88- 0.98; P b .01). We, therefore, used this value to generate sensitivity and specificity values for the various initial MLAEPi cutoff points shown in Table 3. Receiver operating characteristic analysis suggested that a cutoff point comprising an initial MLAEPi of 68 or less was most predictive of DOC.

3.3. Changes in the MLAEPi at the ED

Thirty patients with DOC undergoing tracheal intubation at the ED received sedatives, and all of them required computed tomography (CT) after undergoing tracheal intubation. Midazolam was used in 28 cases, and the median dosage was 10 mg (IQR, 5-10). Diazepam

Fig. 2. Correlation between the MLAEPi and GCS score.

This study is apparently the first to evaluate the MLAEPi for patients with DOC at EDs. Middle latency AEPs are derived from AEPs, which reflect the morphology of MLAEP curves. The aepEX plus monitor identifies the brainstem and cortical components, particu- larly positive Pa and negative Nb waves, of MLAEPs after auditory stimuli. The MLAEPi is calculated from consistent decreases in amplitude and increases in latency, resulting in individual waves within 144 milliseconds [11]. It is difficult to analyze waves in real time during clinical emergency situations using MLAEPs, which are usually obtained intermittently. However, the mobile, battery- operated aepEX plus monitor can provide consistent assessment of the MLAEP during life-saving procedures, while transporting patients within the hospital, and for hospitalized patients.

Several studies found that the GCS score and BIS value were significantly correlated in critically ill patients [1-3]. Processed EEG, which computes the BIS index, a combination of time and frequency domains, and second-order spectral subparameters, is a noninvasive method for monitoring consciousness during anesthesia or critical care sedation [11]. Alternatively, the effectiveness of the MLAEPi in anesthesia or intensive care settings has been described. The MLAEPi is a more effective indicator of the level of anesthesia than BIS or any other EEG-based monitoring method and is profoundly affected by the decreasing amplitudes and increasing latencies induced by hypnotic drugs [7,8,12,13]. Most studies have evaluated the MLAEPi as an indicator of the state of anesthesia with 100% specificity using an MLAEPi cutoff value of 37 for

Table 3

Sensitivity and specificity values at initial MLAEPi cutoff points to predict the degree of DOC

Initial MLAEPi	Sensitivity	95% CI	Specificity	95% CI	Likelihood ratio
b97	100.0	89.4-100	22.0	11.5-36.0	1.28
b88	96.0	86.3-99.5	44.0	30.0-58.8	1.71
b78	90.0	78.2-96.7	66.0	51.2-78.8	2.65
b71	88.0	75.7-95.5	90.0	78.2-96.7	8.80
b68	86.0	73.3-94.2	96.0	86.3-99.5	21.50
b67	86.0	73.3-94.2	98.0	89.4-100	43.00
b54	56.0	41.3-70.0	100.0	92.9-100

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Fig. 4. The initial MLAEPi was significantly higher than those at other periods during emergency care, such as tracheal intubation and CT evaluation. *P b .01.

unconsciousness during anesthesia [12]. In this study, we demon- strated that the MLAEPi might be a reasonable indicator of cerebral function in patients with DOC.

Our results show a significantly different initial MLAEPi in patients with DOC compared with those in patients with CPA or in healthy patients. In addition, a strong positive correlation was found between the initial MLAEPi and the GCS score (r = 0.76) on arrival at the ED. Several studies have shown a positive correlation between the BIS value and GCS score with a relationship between 0.67 and 0.88 in patients with head injuries [2,3]. We also identified a correlation between the initial MLAEPi and the motor response of the GCS score (r = 0.75). The ROC with AUC indicated the degree of DOC as follows: AUC of 0.93, with an initial MLAEPi cutoff of 68 or less, as determined by the Youden index. The specificity was 100% for an initial MLAEPi cutoff value of 54 or less to predict DOC.

We demonstrated that the MLAEPi was decreased among patients with DOC compared with healthy volunteers and was significantly decreased after undergoing sedation. We suggest that these results are important in patients with DOC to evaluate the degree of consciousness, when Procedural sedation and analgesia are adminis- tered in EDs. Procedural sedation is commonly performed in EDs to facilitate Orthopedic reductions, cardioversions, incision and drainage, and wound care [14-16]. Thus, emergency physicians must have sufficient knowledge of monitoring sedation depth as well as changes in the science of procedural sedation. We also determined in 2 hypoglycemic patients that the MLAEPi increased after dextrose administration as well as after the improvement of consciousness (patient 1, 55-74; patient 2, 53-68, respectively). Thus, MLAEPi monitoring may be useful for the patients with metabolic coma, such as hypoglycemic patients.

This study has several limitations. First, the number of patients evaluated was small. Second, we did not use other monitors, such as BIS, to evaluate the degree of DOC during resuscitation in the ED. Third, the measurement of MLAEPi was performed by 1 emergency physician (JT) at the ED. Thus, the patients with DOC or patients with CPA were not enrolled sequentially in this study. Fourth, we only obtained MLAEPi data during primary resuscitation and had no records from the early phase of postresuscitation care in the ED. The

purpose of this study was to assess MLAEPi monitoring for evaluating the degree of DOC in the setting of an ED. Thus, we limited the study end point to initial evaluation at the ED and did not follow up.

Conclusion

The initial MLAEPi may satisfactorily denote cerebral function as represented by simple numerical values and evaluate the degree of consciousness in patients with DOC while performing emergency care in the ED.

Acknowledgments

The authors are indebted to the medical editors and Associate Professor Edward F. Barroga (DVM, PhD) of the Department of International Medical Communications of Tokyo Medical University for the editorial review of the English manuscript.

References

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