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Insomnia may increase anesthetic requirement
Journal of Clinical Anesthesia (2016) 34, 367–372
Original contribution
Insomnia may increase anesthetic requirement☆,☆☆ Veysel Erden MD (Associate Professor), Süheyla Abitağaoğlu MD (Specialist), Cihan Güler MD (Assistant Doctor)⁎, Zuhal Doğan MD (Assistant Doctor), Şenay Kırgezen MD (Specialist), Yeşim Abut MD (Chief Assistant, Specialist) Anesthesiology and Reanimation Department, Istanbul Research and Education Hospital, 34098 Fatih, Istanbul, Turkey Received 17 December 2015; revised 4 May 2016; accepted 4 May 2016
Keywords: Insomnia; General anesthesia; Sevoflurane; Bispectral index; γ-Aminobutyric acid
Abstract Study Objective: Gamma aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. It is a common target for general anesthetics, and it is strongly related to the etiology of chronic insomnia. In this study, we aimed to investigate whether insomnia has any effect on anesthetic requirement, and we also assessed pain to reveal a relationship with insomnia. Design: This study designed as a prospective, observational study, registered ANZCTR (ACTRN12616000241437), with institutional review board approval and written informed consent. Setting: Preoperative and postoperative areas of the training and research hospital. Patients: Inpatients planning to undergo laparoscopic cholecystectomy as an elective surgery were enrolled in this study. Interventions: Patients were divided into 2 groups based on the results of the 4-item Jenkins Sleep Questionnaire which assesses the degree of sleep disturbance: those with or without insomnia. Anesthesia was standardized, and delivered sevoflurane concentration was adjusted according to bispectral index (BIS) value in both groups. Measurements: Parameters of the study were heart rate, noninvasive arterial blood pressure, arterial oxygen saturation, BIS, end-tidal carbon dioxide, and inspiratory and end-tidal concentrations of sevoflurane at 5minute intervals during the operation. Pain was assessed for all participants; preoperatively using 2-sided blank body manikin (front and back) and postoperatively with numeric rating scale between 0 and 10. Main Results: End-tidal concentration of sevoflurane found higher in insomnia group during the maintenance phase of anesthesia. Pain experience was higher in insomnia group. In addition, postoperative abdominal pain score was higher only at 18-hour interval in insomnia group. Although BIS values were similar in both groups during surgery, mean end-tidal sevoflurane concentrations were significantly higher in insomnia group (1.48 ± 0.20) than control group (1.23 ± 0.18) (P b .0001). Conclusion: Insomnia may result in increased anesthetic requirement and pain experience. Further study is required to identify the relationship between insomnia and anesthetics. © 2016 Elsevier Inc. All rights reserved.
☆
There is no conflict of interest for all authors. We did not receive any support from an organization for this study. ⁎ Correspondence: Cihan Güler, Anesthesiology and Reanimation Department, Istanbul Research and Education Hospital, Kasap Ilyas district Org. Abdurrahman Nafiz Gurman Street, 34098 Fatih, Istanbul, Turkey. Tel.: +90 2124596160. E-mail addresses: [email protected] (V. Erden), [email protected] (S. Abitağaoğlu), [email protected] (C. Güler), [email protected] (Z. Doğan), [email protected] (Ş. Kırgezen), [email protected] (Y. Abut). ☆☆
http://dx.doi.org/10.1016/j.jclinane.2016.05.020 0952-8180/© 2016 Elsevier Inc. All rights reserved.
368
1. Introduction Insomnia is a common sleep disorder that affects 10% to 30% of adult population [1–3]. Chronic insomnia is defined by insomnia symptoms persisting for more than 1 year [1]. Chronic insomnia has a comprehensive effect on health and quality of life [4]. Patients are usually influenced physically and emotionally by all aspects such as cognitive impairments, poor social functioning, and physical complaints including pain [5–9]. GABA, which is the primary inhibitory neurotransmitter in the central nervous system, is a common target for general anesthetics and strongly related with the etiology of chronic insomnia. Most of the studies showed that low GABA levels in some brain regions or whole brain are associated with chronic insomnia [10,11]. The GABA system is also suggested as a major substrate of anesthetic efficacy [12]. Therefore, anesthetic requirement may differ in patients with chronic insomnia depending on an abnormal GABA content. In literature, there is not any study about this subject. The aim of this study was to investigate whether insomnia has any effect on anesthetic requirement. In addition, we assessed pain to reveal a relationship with insomnia.
2. Materials and methods After institutional review board approval and informed consents, 50 patients, having planned to undergo laparoscopic cholecystectomy as an elective surgery, who had a history of cholelithiasis were enrolled in this study. Patients having renal failure, thyroid dysfunction, morbid obesity, obstructive sleep apnea, neurologic dysfunction, alcoholism, urgency about cholecystitis, and using anticonvulsant or opioid therapy were excluded. Heart rate, noninvasive arterial blood pressure, and arterial oxygen saturation were measured (CARESCAPE Monitor B650 GE Healthcare) and recorded during the surgery. All measurements were recorded at 5-minute intervals. The VISTA A bispectral index (BIS) monitor (Aspect Medical Systems, Norwood, MA) was used in the study. The BIS sensor was applied to patients' forehead and connected to digital signal converter before the induction of anesthesia. Inspiratory and end-tidal concentrations of sevoflurane and end-tidal CO2 were measured with Avance CS2 CARESCAPE Monitor (GE, Finland). The patients were divided into 2 groups by using the 4-item Jenkins Sleep Questionnaire (JSQ) according to degree of sleep disturbance [13]. Four items were asked to the patients: “how frequent they have trouble falling asleep, waking up several times per night, having trouble staying asleep, feeling tired and worn-out after the usual amount of sleep during the previous 4 weeks.” There were 6 alternative responses: not at all (1), 1 to 3 days (2), 4 to 7 days (3), 8 to 14 days (4), 15 to 21 days (5), and 22 to 28 days (6). All participants assessed in insomnia group had sleep problems for at least 1 year. Patients
V. Erden et al. reported sleep problems 4 to 7 days in the previous month at least for 1 item were classified as insomnia group. Patients reported any sleep problem 1 to 3 days in the previous month for 1 item or more were not included in insomnia group. Patients who responded “not at all” to all items were classified as control group. None of the patients was premedicated. In all groups, anesthesia was standardized and assessed by different anesthesiologists. Anesthesia was induced with propofol 2 mg/kg, rocuronium 0.5 mg/kg was given to establish muscle relaxation. Fentanyl was given to all patients intravenously as bolus 1 μg/kg before induction of anesthesia. No further fentanyl was given during operations. Anesthesia was maintained with sevoflurane in a mixture of nitrous oxide 2 L/min and oxygen 2 L/min, and all patients were mechanically ventilated to maintain an end-tidal CO2 concentration of 30 to 37 mm Hg. The BIS target range was maintained between 40 and 60 via adjustment of sevoflurane concentration. End-tidal concentration of sevoflurane was used as a parameter that showed anesthetic requirement in this study. All participants were asked about their pain experience lasting for 1 day or more in the previous month and to describe it on a 2-sided blank body manikin (front and back) before the operation. Then the outcomes were categorized as widespread pain, some pain, or no pain. Widespread pain was defined as pain located on the both sides of the body, above and below the waist and in the axial skeleton. Such cases in which all criteria of widespread pain could not be satisfied were defined as some pain. Postoperative abdominal pain was assessed by the patients themselves using numeric rating scale (0 = no pain; 10 = worst possible pain), from 0 to 10 at 2, 4, 8, 12, and 18 hours postoperatively at rest. All patients in both groups were informed about how to use patient-controlled intravenous analgesia (CADD-Legacy patient Control Analgesia device Model 6300; Ambulatory Infusion Pump Smith Medical ASD) self-control pump which was administered as soon as possible after the surgery ended. Each of the patientcontrolled intravenous analgesia pumps contained 300 mg tramadol dilution to 100 mL of 0.9% saline solution and adjusted as 10 mg/h background dose, bolus dose of 10 mg, and a locked out interval of 15 minutes. Table 1
Baseline demographic and clinical characteristics
Age (y) Sex (M:F) ASA BMI (kg/m2) Operation time (min) Tramadol consumption dose (mg) Duration of sleep problem (y)
Insomnia group
Control group
P
47.4 ± 7.5 6:19 1.28 ± 0.4 26.5 ± 4.4 57.6 ± 16.5 271.7 ± 42.4 4.0 (1-23)
48.04 ± 10.9 8:17 1.4 ± 0.5 27.5 ± 4.4 53.6 ± 13.5 262.1 ± 41.3 –
.82 .75 .38 .44 .35 .41 –
ASA = American Society of Anesthesiologists; BMI = body mass index; F = female; M = male. Data are presented as mean ± SD, median (minimum-maximum), and number.
Insomnia may increase anesthetic requirement
0
Fig. 1
10
369
20
30
40
Change in mean arterial pressure (MAP) and heart rate (HR) during operation; P N .05.
3. Statistics Sample size was calculated according to the results of the first 10 patients' mean end-tidal sevoflurane concentration for both groups. Then, we observed 0.2% of difference with SD of 0.2% among groups. Power analysis was conducted from these differences, assuming a 2-tailed α value of .05 and a β-risk of 0.10. With these assumptions, at least 22 patients per group were required. Therefore, we planned to recruit 50 patients (25 per group) to allow for dropouts. The Student t test, Mann-Whitney U test, or Fisher exact test was used to analyze the all outcomes. Data were presented as mean ± SD or number (%) unless otherwise stated. P b .05 was considered as statistically significant. Data analysis was performed using SPSS version 16.0 software.
maintenance phase of anesthesia (Table 3). Mean end-tidal sevoflurane concentrations were 1.48 ± 0.20 in insomnia group and 1.23 ± 0.18 in control group during operations, and there was a statistically significant difference between them (P b .0001). Preinduction BIS scores were 97.6 in insomnia group and 97.7 in control group (P = .7). BIS values were similar in both groups during surgery (Fig. 2). Considering preoperative pain experience, in insomnia group, 12 patients had some pain and 1 patient had widespread pain, and in control group, 4 patients had some pain. Pain experience was statistically higher in insomnia group (P = 0.032). Postoperative abdominal pain score at 18-hour interval was higher in insomnia group. (P = .044) (Fig. 3). There was no statistically significant difference in abdominal pain scores at 2, 4, 8, and 12 hours among groups (P = .071, P = .072, P = .43, and P = .52, respectively).
4. Result 5. Discussion The groups were similar for age, body mass index, sex, American Society of Anesthesiologists, operation time, total tramadol consumption, duration of sleep problems, mean arterial pressure, and heart rate (Table 1; Fig. 1). JSQ items in insomnia group were given in Table 2. End-tidal concentration of sevoflurane found higher in insomnia group during the Table 2
In this study, we found that anesthetic requirement was increased in insomnia group compared to control group. Pain experience was higher preoperatively in insomnia group patients whose postoperative abdominal pain score was higher at 18hour interval.
Jenkins Sleep Questionnaire items in insomnia group
Trouble falling asleep ⁎ Wake up several times per night ⁎ Trouble staying asleep ⁎ Wake up feeling tired and worn out ⁎
Not at all (1)
1-3 d (2)
4-7 d (3)
8-14 d (4)
15-21 d (5)
22-28 d (6)
6 (24) 1 (4) 5 (20) 3 (12)
– 2 (8) 5 (20) 2 (8)
5 (20) 6 (24) 5 (20) 5 (20)
3 (12) 2 (8) – 3 (12)
4 (16) – 5 (20) 4 (16)
7 (28) 14 (56) 5 (20) 8 (32)
All values are expressed as number (percentages). ⁎ Each item was asked to the patients how frequently during the previous 4 weeks.
370 Table 3
V. Erden et al. End-tidal concentrations of sevoflurane in groups
Insomnia group Control group P
5 min
10 min
15 min
20 min
25 min
30 min
35 min
40 min
1.4 ± 0.31 1.09 ± 0.27 .001
1.48 ± 0.31 1.29 ± 0.29 .03
1.58 ± 0.33 1.26 ± 0.2 b .0001
1.5 ± 0.29 1.28 ± 0.21 .005
1.48 ± 0.2 1.25 ± 0.24 .001
1.57 ± 0.3 1.31 ± 0.19 .002
1.62 ± 0.25 1.26 ± 0.21 b .0001
1.55 ± 0.28 1.18 ± 0.25 .001
Data are presented as mean ± SD.
Pathophysiology of insomnia has not been clearly understood yet; however, evidence points to a disorder of hyperarousal, increased brain metabolism, increased sympathetic activity, increased high-frequency electroencephalography (EEG) activation and hormonal changes concordant with hyperarousal [14–22]. During wakefulness, histaminergic, noradrenergic, serotonergic, and cholinergic neurotransmission are active, and this activation is reduced sharply with normal transition to sleep [23,24]. In addition, GABA system activation in central nervous system inhibits wakefulness-associated neurotransmitter activity, so GABA has a crucial role in the regulation of sleep [24–26]. There are several studies about insomnia that focused on GABA measurement in different brain regions via spectroscopy. In the first study, it was found that almost 30% lower global GABA levels in insomnia patients compared to healthy patients [10]. The second study also showed lower GABA levels, particularly in the cingulate and occipital cortex, in insomnia patients [11]. On the contrary to these results Morgan et al [27] reported a 12% increased occipital GABA level in insomnia patients compared with healthy controls. The incoherence between studies was owing to different sample characteristics and specific methods for spectroscopic data evaluation [28]. All presented results may indicate a potential relationship between brain GABA levels and insomnia. The decrement of GABA levels in brain may be result in insomnia; however, insufficient GABA signaling with an adaptive increase in GABA levels may contribute to insomnia. GABA is one of the targets for general anesthetics, especially GABAA receptor that also has an obvious relationship with the regulation of sleep. General anesthetics and sleep have similar effects on brain due to electroencephalography
records [29]. In some brain regions such as hippocampus, cortex, reticular-activating system, and hypothalamus, it is found that there is a relationship with both sleep and inhalation anesthetic agents sensitivity [30,31]. Therefore, sleep and general anesthesia may have a point of convergence. According to this point, effect of anesthetics may be different for sleep disorder patients due to abnormal GABA levels in their brain. Presumably, decrement of GABA or insufficient GABA signaling in central nervous system may cause an increase in requirement of sevoflurane in insomniacs. BIS is a derivative of electroencephalogram, and it is a dimensionless variable between 0 and 100. The BIS values shown on the monitor is proposed to reflect the depth of anesthesia and guide the practitioners to titrate anesthesia during the operation. BIS values between 40 and 60 are indicated a sufficient depth of anesthesia in general practice [32]. BIS monitor is affected from the external factors such as highfrequency signals [33,34]. There is no clinical and neurophysiological criterion standard beyond the loss of consciousness which can be measured by a monitor about anesthetic depth. The BIS monitor has no specific value of the index that predicts the transition between consciousness and unconsciousness, but there is a wide range to track anesthetic depth. On the other hand, several studies showed the advantages of BIS-guided anesthesia over clinical practice [35,36]. In our study, BIS values were similar in both groups during surgery. Clinical insomnia was found more frequent among chronic pain sufferers than healthy population [9,37]. Therefore, we assessed preoperative pain experience and postoperative pain; also, we found that preoperative pain experience was higher in insomnia group, whereas postoperative pain score at 18-hour interval was only higher in insomnia group compared with control group. Several studies showed that BIS value could
10 9
Intensity
8
Insomnia Group
7
Control Group
6 5 4
*
3 2 1 0
2
4
8
12
18
Time after operation (h)
Fig. 2
BIS values during surgery; P N .05.
Fig. 3 Intensity of postoperative abdominal pain on numeric rating scale. ⁎P b .05.
Insomnia may increase anesthetic requirement be affected by noxious stimuli during anesthesia [38–40]. Higher sensitivity to pain in insomnia group could have contributed the need of increasing sevoflurane concentrations to maintain the specific BIS target values. We did not blind the anesthesia providers to the results of the preoperative JSQ score, which was the limitation of this study. However, knowledge of the JSQ score would not greatly affect measurement of the primary objective outcome such as end-tidal sevoflurane concentrations to maintain the specific BIS target values. In this study, we selected laparoscopic cholecystectomy which is a common surgical model, to limit the potential impact of heterogeneity of surgical pathophysiology and surgical procedure upon the effects of insomnia on general anesthetic requirements. Patients who had a history of cholelithiasis undergoing elective scheduled procedures were selected. In addition, we standardized the anesthetic management including the selection of fentanyl dose because varying doses of fentanyl may influence the sevoflurane requirement among patients. In conclusion, anesthetic requirement measured by BIS might be increased in insomniacs. Pain experience may also found higher. Further research is necessary to understand the relationship between the pathophysiology of insomnia and anesthetic requirement.
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371 [12] Franks NP, Lieb WR. Molecular and cellular mechanisms of general anaesthesia. Nature 1994;367:607-14. [13] Jenkins CD, Stanton BA, Niemcryk SJ, Rose RM. A scale for the estimation of sleep problems in clinical research. J Clin Epidemiol 1988;41: 313-21. [14] Roth T, Roehrs T, Pies R. Insomnia: pathophysiology and implications for treatment. Sleep Med Rev 2007;11:71-9. [15] Bonnet MH, Arand DL. Hyperarousal and insomnia: state of the science. Sleep Med Rev 2010;14:9-15. [16] Bonnet MH, Arand DL. 24-hour metabolic rate in insomniacs and matched normal sleepers. Sleep 1995;18:581-8. [17] Bonnet MH, Arand DL. Heart rate variability in insomniacs and matched normal sleepers. Psychosom Med 1998;60:610-5. [18] Lushington K, Dawson D, Lack L. Core body temperature is elevated during constant wakefulness in elderly poor sleepers. Sleep 2000;23: 504-10. [19] Vgontzas AN, Tsigos C, Bixler EO, et al. Chronic insomnia and activity of the stress system: a preliminary study. J Psychosom Res 1998;45: 21-31. [20] Lichstein KL, Wilson NM, Noe SL, Aguillard RN, Bellur SN. Daytime sleepiness in insomnia: behavioral, biological and subjective indices. Sleep 1994;17:693-702. [21] Nofzinger EA, Buysse DJ, Germain A, Price JC, Miewald JM, Kupfer DJ. Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry 2004;161:2126-8. [22] Perlis ML, Smith MT, Andrews PJ, Orff H, Giles DE. Beta/gamma EEG activity in patients with primary and secondary insomnia and good sleeper controls. Sleep 2001;24:110-7. [23] John J, Wu MF, Boehmer LN, Siegel JM. Cataplexy-active neurons in the hypothalamus: implications for the role of histamine in sleep and waking behavior. Neuron 2004;42:619-34. [24] Saper CB, Chou TC, Scammell TE. The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci 2001;24:726-31. [25] Gottesman CV, Intraub H. Surface construal and the mental representation of scenes. J Exp Psychol Hum Percept Perform 2002;28:589-99. [26] Siegel JM. The neurotransmitters of sleep. J Clin Psychiatry 2004; 65(Suppl. 16):4-7. [27] Morgan PT, Pace-Schott EF, Mason GF, et al. Cortical GABA levels in primary insomnia. Sleep 2012;35:807-14. [28] Plante DT, Jensen JE, Winkelman JW. The role of GABA in primary insomnia. Sleep 2012;35:741-2. [29] Sloan TB. Anesthetic effects on electrophysiologic recordings. J Clin Neurophysiol 1998;15:217-26. [30] Alkire MT, Haier RJ, Fallon JH. Toward a unified theory of narcosis: brain imaging evidence for a thalamocortical switch as the neurophysiologic basis of anesthetic-induced unconsciousness. Conscious Cogn 2000;9:370-86. [31] Heinke W, Schwarzbauer C. In vivo imaging of anaesthetic action in humans: approaches with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Br J Anaesth 2002;89: 112-22. [32] Rampil IJ. A primer for EEG signal processing in anesthesia. Anesthesiology 1998;89:980-1002. [33] Hemmerling TM, Fortier JD. Falsely increased bispectral index values in a series of patients undergoing cardiac surgery using forced-air-warming therapy of the head. Anesth Analg 2002;95:322-3. [34] Bruhn J, Bouillon TW, Shafer SL. Electromyographic activity falsely elevates the bispectral index. Anesthesiology 2000;92:1485-7. [35] Wong J, Song D, Blansbard H, et al. Titration of isoflurane using BIS index improves early recovery of elderly patients undergoing orthopedic surgeries. Can J Anaesth 2002;49:13-8 [Full Text Bibliographic Links]. [36] Regan MJ, Eger EI II. Effect of hypothermia in dogs on anesthetizing and apneic doses of inhalation agents: determination of the anesthetic index (apnea/MAC). Anesthesiology 1967;28:689-700. [37] Purushothaman B, Singh A, Lingutla K, Bhatia C, Pollock R, Krishna M. Prevalence of insomnia in patients with chronic back pain. J Orthop Surg (Hong Kong) 2013;21(1):68-70.
372 [38] von Dincklage F, Send K, Hackbarth M, Rehberg B, Baars JH. Comparison of the nociceptive flexion reflex threshold and the bispectral index as monitors of movement responses to noxious stimuli under propofol mono-anaesthesia. Br J Anaesth 2009;102(2):244-50. [39] Sandin M, Thörn SE, Dahlqvist A, Wattwil L, Axelsson K, Wattwil M. Effects of pain stimulation on bispectral index, heart rate and blood
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Original contribution
Insomnia may increase anesthetic requirement☆,☆☆ Veysel Erden MD (Associate Professor), Süheyla Abitağaoğlu MD (Specialist), Cihan Güler MD (Assistant Doctor)⁎, Zuhal Doğan MD (Assistant Doctor), Şenay Kırgezen MD (Specialist), Yeşim Abut MD (Chief Assistant, Specialist) Anesthesiology and Reanimation Department, Istanbul Research and Education Hospital, 34098 Fatih, Istanbul, Turkey Received 17 December 2015; revised 4 May 2016; accepted 4 May 2016
Keywords: Insomnia; General anesthesia; Sevoflurane; Bispectral index; γ-Aminobutyric acid
Abstract Study Objective: Gamma aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. It is a common target for general anesthetics, and it is strongly related to the etiology of chronic insomnia. In this study, we aimed to investigate whether insomnia has any effect on anesthetic requirement, and we also assessed pain to reveal a relationship with insomnia. Design: This study designed as a prospective, observational study, registered ANZCTR (ACTRN12616000241437), with institutional review board approval and written informed consent. Setting: Preoperative and postoperative areas of the training and research hospital. Patients: Inpatients planning to undergo laparoscopic cholecystectomy as an elective surgery were enrolled in this study. Interventions: Patients were divided into 2 groups based on the results of the 4-item Jenkins Sleep Questionnaire which assesses the degree of sleep disturbance: those with or without insomnia. Anesthesia was standardized, and delivered sevoflurane concentration was adjusted according to bispectral index (BIS) value in both groups. Measurements: Parameters of the study were heart rate, noninvasive arterial blood pressure, arterial oxygen saturation, BIS, end-tidal carbon dioxide, and inspiratory and end-tidal concentrations of sevoflurane at 5minute intervals during the operation. Pain was assessed for all participants; preoperatively using 2-sided blank body manikin (front and back) and postoperatively with numeric rating scale between 0 and 10. Main Results: End-tidal concentration of sevoflurane found higher in insomnia group during the maintenance phase of anesthesia. Pain experience was higher in insomnia group. In addition, postoperative abdominal pain score was higher only at 18-hour interval in insomnia group. Although BIS values were similar in both groups during surgery, mean end-tidal sevoflurane concentrations were significantly higher in insomnia group (1.48 ± 0.20) than control group (1.23 ± 0.18) (P b .0001). Conclusion: Insomnia may result in increased anesthetic requirement and pain experience. Further study is required to identify the relationship between insomnia and anesthetics. © 2016 Elsevier Inc. All rights reserved.
☆
There is no conflict of interest for all authors. We did not receive any support from an organization for this study. ⁎ Correspondence: Cihan Güler, Anesthesiology and Reanimation Department, Istanbul Research and Education Hospital, Kasap Ilyas district Org. Abdurrahman Nafiz Gurman Street, 34098 Fatih, Istanbul, Turkey. Tel.: +90 2124596160. E-mail addresses: [email protected] (V. Erden), [email protected] (S. Abitağaoğlu), [email protected] (C. Güler), [email protected] (Z. Doğan), [email protected] (Ş. Kırgezen), [email protected] (Y. Abut). ☆☆
http://dx.doi.org/10.1016/j.jclinane.2016.05.020 0952-8180/© 2016 Elsevier Inc. All rights reserved.
368
1. Introduction Insomnia is a common sleep disorder that affects 10% to 30% of adult population [1–3]. Chronic insomnia is defined by insomnia symptoms persisting for more than 1 year [1]. Chronic insomnia has a comprehensive effect on health and quality of life [4]. Patients are usually influenced physically and emotionally by all aspects such as cognitive impairments, poor social functioning, and physical complaints including pain [5–9]. GABA, which is the primary inhibitory neurotransmitter in the central nervous system, is a common target for general anesthetics and strongly related with the etiology of chronic insomnia. Most of the studies showed that low GABA levels in some brain regions or whole brain are associated with chronic insomnia [10,11]. The GABA system is also suggested as a major substrate of anesthetic efficacy [12]. Therefore, anesthetic requirement may differ in patients with chronic insomnia depending on an abnormal GABA content. In literature, there is not any study about this subject. The aim of this study was to investigate whether insomnia has any effect on anesthetic requirement. In addition, we assessed pain to reveal a relationship with insomnia.
2. Materials and methods After institutional review board approval and informed consents, 50 patients, having planned to undergo laparoscopic cholecystectomy as an elective surgery, who had a history of cholelithiasis were enrolled in this study. Patients having renal failure, thyroid dysfunction, morbid obesity, obstructive sleep apnea, neurologic dysfunction, alcoholism, urgency about cholecystitis, and using anticonvulsant or opioid therapy were excluded. Heart rate, noninvasive arterial blood pressure, and arterial oxygen saturation were measured (CARESCAPE Monitor B650 GE Healthcare) and recorded during the surgery. All measurements were recorded at 5-minute intervals. The VISTA A bispectral index (BIS) monitor (Aspect Medical Systems, Norwood, MA) was used in the study. The BIS sensor was applied to patients' forehead and connected to digital signal converter before the induction of anesthesia. Inspiratory and end-tidal concentrations of sevoflurane and end-tidal CO2 were measured with Avance CS2 CARESCAPE Monitor (GE, Finland). The patients were divided into 2 groups by using the 4-item Jenkins Sleep Questionnaire (JSQ) according to degree of sleep disturbance [13]. Four items were asked to the patients: “how frequent they have trouble falling asleep, waking up several times per night, having trouble staying asleep, feeling tired and worn-out after the usual amount of sleep during the previous 4 weeks.” There were 6 alternative responses: not at all (1), 1 to 3 days (2), 4 to 7 days (3), 8 to 14 days (4), 15 to 21 days (5), and 22 to 28 days (6). All participants assessed in insomnia group had sleep problems for at least 1 year. Patients
V. Erden et al. reported sleep problems 4 to 7 days in the previous month at least for 1 item were classified as insomnia group. Patients reported any sleep problem 1 to 3 days in the previous month for 1 item or more were not included in insomnia group. Patients who responded “not at all” to all items were classified as control group. None of the patients was premedicated. In all groups, anesthesia was standardized and assessed by different anesthesiologists. Anesthesia was induced with propofol 2 mg/kg, rocuronium 0.5 mg/kg was given to establish muscle relaxation. Fentanyl was given to all patients intravenously as bolus 1 μg/kg before induction of anesthesia. No further fentanyl was given during operations. Anesthesia was maintained with sevoflurane in a mixture of nitrous oxide 2 L/min and oxygen 2 L/min, and all patients were mechanically ventilated to maintain an end-tidal CO2 concentration of 30 to 37 mm Hg. The BIS target range was maintained between 40 and 60 via adjustment of sevoflurane concentration. End-tidal concentration of sevoflurane was used as a parameter that showed anesthetic requirement in this study. All participants were asked about their pain experience lasting for 1 day or more in the previous month and to describe it on a 2-sided blank body manikin (front and back) before the operation. Then the outcomes were categorized as widespread pain, some pain, or no pain. Widespread pain was defined as pain located on the both sides of the body, above and below the waist and in the axial skeleton. Such cases in which all criteria of widespread pain could not be satisfied were defined as some pain. Postoperative abdominal pain was assessed by the patients themselves using numeric rating scale (0 = no pain; 10 = worst possible pain), from 0 to 10 at 2, 4, 8, 12, and 18 hours postoperatively at rest. All patients in both groups were informed about how to use patient-controlled intravenous analgesia (CADD-Legacy patient Control Analgesia device Model 6300; Ambulatory Infusion Pump Smith Medical ASD) self-control pump which was administered as soon as possible after the surgery ended. Each of the patientcontrolled intravenous analgesia pumps contained 300 mg tramadol dilution to 100 mL of 0.9% saline solution and adjusted as 10 mg/h background dose, bolus dose of 10 mg, and a locked out interval of 15 minutes. Table 1
Baseline demographic and clinical characteristics
Age (y) Sex (M:F) ASA BMI (kg/m2) Operation time (min) Tramadol consumption dose (mg) Duration of sleep problem (y)
Insomnia group
Control group
P
47.4 ± 7.5 6:19 1.28 ± 0.4 26.5 ± 4.4 57.6 ± 16.5 271.7 ± 42.4 4.0 (1-23)
48.04 ± 10.9 8:17 1.4 ± 0.5 27.5 ± 4.4 53.6 ± 13.5 262.1 ± 41.3 –
.82 .75 .38 .44 .35 .41 –
ASA = American Society of Anesthesiologists; BMI = body mass index; F = female; M = male. Data are presented as mean ± SD, median (minimum-maximum), and number.
Insomnia may increase anesthetic requirement
0
Fig. 1
10
369
20
30
40
Change in mean arterial pressure (MAP) and heart rate (HR) during operation; P N .05.
3. Statistics Sample size was calculated according to the results of the first 10 patients' mean end-tidal sevoflurane concentration for both groups. Then, we observed 0.2% of difference with SD of 0.2% among groups. Power analysis was conducted from these differences, assuming a 2-tailed α value of .05 and a β-risk of 0.10. With these assumptions, at least 22 patients per group were required. Therefore, we planned to recruit 50 patients (25 per group) to allow for dropouts. The Student t test, Mann-Whitney U test, or Fisher exact test was used to analyze the all outcomes. Data were presented as mean ± SD or number (%) unless otherwise stated. P b .05 was considered as statistically significant. Data analysis was performed using SPSS version 16.0 software.
maintenance phase of anesthesia (Table 3). Mean end-tidal sevoflurane concentrations were 1.48 ± 0.20 in insomnia group and 1.23 ± 0.18 in control group during operations, and there was a statistically significant difference between them (P b .0001). Preinduction BIS scores were 97.6 in insomnia group and 97.7 in control group (P = .7). BIS values were similar in both groups during surgery (Fig. 2). Considering preoperative pain experience, in insomnia group, 12 patients had some pain and 1 patient had widespread pain, and in control group, 4 patients had some pain. Pain experience was statistically higher in insomnia group (P = 0.032). Postoperative abdominal pain score at 18-hour interval was higher in insomnia group. (P = .044) (Fig. 3). There was no statistically significant difference in abdominal pain scores at 2, 4, 8, and 12 hours among groups (P = .071, P = .072, P = .43, and P = .52, respectively).
4. Result 5. Discussion The groups were similar for age, body mass index, sex, American Society of Anesthesiologists, operation time, total tramadol consumption, duration of sleep problems, mean arterial pressure, and heart rate (Table 1; Fig. 1). JSQ items in insomnia group were given in Table 2. End-tidal concentration of sevoflurane found higher in insomnia group during the Table 2
In this study, we found that anesthetic requirement was increased in insomnia group compared to control group. Pain experience was higher preoperatively in insomnia group patients whose postoperative abdominal pain score was higher at 18hour interval.
Jenkins Sleep Questionnaire items in insomnia group
Trouble falling asleep ⁎ Wake up several times per night ⁎ Trouble staying asleep ⁎ Wake up feeling tired and worn out ⁎
Not at all (1)
1-3 d (2)
4-7 d (3)
8-14 d (4)
15-21 d (5)
22-28 d (6)
6 (24) 1 (4) 5 (20) 3 (12)
– 2 (8) 5 (20) 2 (8)
5 (20) 6 (24) 5 (20) 5 (20)
3 (12) 2 (8) – 3 (12)
4 (16) – 5 (20) 4 (16)
7 (28) 14 (56) 5 (20) 8 (32)
All values are expressed as number (percentages). ⁎ Each item was asked to the patients how frequently during the previous 4 weeks.
370 Table 3
V. Erden et al. End-tidal concentrations of sevoflurane in groups
Insomnia group Control group P
5 min
10 min
15 min
20 min
25 min
30 min
35 min
40 min
1.4 ± 0.31 1.09 ± 0.27 .001
1.48 ± 0.31 1.29 ± 0.29 .03
1.58 ± 0.33 1.26 ± 0.2 b .0001
1.5 ± 0.29 1.28 ± 0.21 .005
1.48 ± 0.2 1.25 ± 0.24 .001
1.57 ± 0.3 1.31 ± 0.19 .002
1.62 ± 0.25 1.26 ± 0.21 b .0001
1.55 ± 0.28 1.18 ± 0.25 .001
Data are presented as mean ± SD.
Pathophysiology of insomnia has not been clearly understood yet; however, evidence points to a disorder of hyperarousal, increased brain metabolism, increased sympathetic activity, increased high-frequency electroencephalography (EEG) activation and hormonal changes concordant with hyperarousal [14–22]. During wakefulness, histaminergic, noradrenergic, serotonergic, and cholinergic neurotransmission are active, and this activation is reduced sharply with normal transition to sleep [23,24]. In addition, GABA system activation in central nervous system inhibits wakefulness-associated neurotransmitter activity, so GABA has a crucial role in the regulation of sleep [24–26]. There are several studies about insomnia that focused on GABA measurement in different brain regions via spectroscopy. In the first study, it was found that almost 30% lower global GABA levels in insomnia patients compared to healthy patients [10]. The second study also showed lower GABA levels, particularly in the cingulate and occipital cortex, in insomnia patients [11]. On the contrary to these results Morgan et al [27] reported a 12% increased occipital GABA level in insomnia patients compared with healthy controls. The incoherence between studies was owing to different sample characteristics and specific methods for spectroscopic data evaluation [28]. All presented results may indicate a potential relationship between brain GABA levels and insomnia. The decrement of GABA levels in brain may be result in insomnia; however, insufficient GABA signaling with an adaptive increase in GABA levels may contribute to insomnia. GABA is one of the targets for general anesthetics, especially GABAA receptor that also has an obvious relationship with the regulation of sleep. General anesthetics and sleep have similar effects on brain due to electroencephalography
records [29]. In some brain regions such as hippocampus, cortex, reticular-activating system, and hypothalamus, it is found that there is a relationship with both sleep and inhalation anesthetic agents sensitivity [30,31]. Therefore, sleep and general anesthesia may have a point of convergence. According to this point, effect of anesthetics may be different for sleep disorder patients due to abnormal GABA levels in their brain. Presumably, decrement of GABA or insufficient GABA signaling in central nervous system may cause an increase in requirement of sevoflurane in insomniacs. BIS is a derivative of electroencephalogram, and it is a dimensionless variable between 0 and 100. The BIS values shown on the monitor is proposed to reflect the depth of anesthesia and guide the practitioners to titrate anesthesia during the operation. BIS values between 40 and 60 are indicated a sufficient depth of anesthesia in general practice [32]. BIS monitor is affected from the external factors such as highfrequency signals [33,34]. There is no clinical and neurophysiological criterion standard beyond the loss of consciousness which can be measured by a monitor about anesthetic depth. The BIS monitor has no specific value of the index that predicts the transition between consciousness and unconsciousness, but there is a wide range to track anesthetic depth. On the other hand, several studies showed the advantages of BIS-guided anesthesia over clinical practice [35,36]. In our study, BIS values were similar in both groups during surgery. Clinical insomnia was found more frequent among chronic pain sufferers than healthy population [9,37]. Therefore, we assessed preoperative pain experience and postoperative pain; also, we found that preoperative pain experience was higher in insomnia group, whereas postoperative pain score at 18-hour interval was only higher in insomnia group compared with control group. Several studies showed that BIS value could
10 9
Intensity
8
Insomnia Group
7
Control Group
6 5 4
*
3 2 1 0
2
4
8
12
18
Time after operation (h)
Fig. 2
BIS values during surgery; P N .05.
Fig. 3 Intensity of postoperative abdominal pain on numeric rating scale. ⁎P b .05.
Insomnia may increase anesthetic requirement be affected by noxious stimuli during anesthesia [38–40]. Higher sensitivity to pain in insomnia group could have contributed the need of increasing sevoflurane concentrations to maintain the specific BIS target values. We did not blind the anesthesia providers to the results of the preoperative JSQ score, which was the limitation of this study. However, knowledge of the JSQ score would not greatly affect measurement of the primary objective outcome such as end-tidal sevoflurane concentrations to maintain the specific BIS target values. In this study, we selected laparoscopic cholecystectomy which is a common surgical model, to limit the potential impact of heterogeneity of surgical pathophysiology and surgical procedure upon the effects of insomnia on general anesthetic requirements. Patients who had a history of cholelithiasis undergoing elective scheduled procedures were selected. In addition, we standardized the anesthetic management including the selection of fentanyl dose because varying doses of fentanyl may influence the sevoflurane requirement among patients. In conclusion, anesthetic requirement measured by BIS might be increased in insomniacs. Pain experience may also found higher. Further research is necessary to understand the relationship between the pathophysiology of insomnia and anesthetic requirement.
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