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Year : 2009  |  Volume : 53  |  Issue : 2  |  Page : 187-192 Table of Contents     

Effects of Phenytoin Therapy on Bispectral Index and Haemodynamic Changes Following Induction and Tracheal Intubation

1 Professor, Department of Neuroanesthesia, All India Institute of Medical Sciences, New Delhi, India
2 Assistant Professor, Department of Neuroanesthesia, All India Institute of Medical Sciences, New Delhi, India
3 Associate Professor, Department of Neuroanesthesia, All India Institute of Medical Sciences, New Delhi, India
4 Senior Resident, Department of Neuroanesthesia, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication3-Mar-2010

Correspondence Address:
Parmod P Bithal
Department of Neuroanaesthesiology, Neurosciences Centre, All India Institute of Medical Sciences, New Delhi 110 029
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Source of Support: None, Conflict of Interest: None

PMID: 20640121

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Laryngoscopy and tracheal intubation (LTI) increase blood pressure and heart rate (HR). Intensity of these changes is influenced by the anaesthetic depth assessed by the bispectral index (BIS). We determined the effect of phenytoin on anaesthetic depth and its influence on haemodynamics following LTI. Fifty patients of ASA grades I and II on oral phenytoin 200 to 300mg per day for more than one week were compared with 48 control patients. Standard anaesthesia technique was followed. BIS, non invasive mean blood pressure (MBP) and HR were recorded 30, 60, 90 and 120 sec after LTI. Phenytoin group needed lesser thiopentone for induction, 5 mg (1.1) vs. 4.3 mg (0.7) [p=0.036]. BIS was significantly lower in the phenytoin group vs. the control 30, 60, 90 and 120 sec after LTI [43.1 (16.0) vs. 48.9 (14.9), p=0.068, 56.3 (16.7) vs. 64.3 (14.4), p=0.013, 59.8 (15.8) vs. 67.5 (12.1), p=0.008, 62.6 (14) vs. 68.9 (11.2), p=0.017, and 64.2 (11.3) vs. 69 (11.7), p=0.033], respectively. MBP was also lower in the phenytoin group 30, 60, 90 and 120 sec after LTI [112.8 mmHg (13.8), vs. 117.9 mmHg (18) p=0.013, 108.6 (12.8) vs. 117.5 (16) p=0.003, 106.1 mmHg (14.1) vs. 113.2 mmHg (14.9), p=0.017, 101.8 mmHg (13.8) vs. 109.5 mmHg (14.1), p=0.007], respectively. HR was lower in phenytoin group at 30 sec. (p=0.027), 60 sec (p=0.219), and again at 120 sec (p=0.022). Oral phenytoin therapy for over a week results in greater anaesthetic depth as observed using BIS, which also attenuated haemodynamic response of LTI.

Keywords: Phenytoin sodium; Anaesthetic requirement; Bispectral index; Intubation response

How to cite this article:
Bithal PP, Pandia MP, Chouhan RS, Prabhakar H, Rath GP, Dash HH, Marda MK. Effects of Phenytoin Therapy on Bispectral Index and Haemodynamic Changes Following Induction and Tracheal Intubation. Indian J Anaesth 2009;53:187-92

How to cite this URL:
Bithal PP, Pandia MP, Chouhan RS, Prabhakar H, Rath GP, Dash HH, Marda MK. Effects of Phenytoin Therapy on Bispectral Index and Haemodynamic Changes Following Induction and Tracheal Intubation. Indian J Anaesth [serial online] 2009 [cited 2021 May 12];53:187-92. Available from: https://www.ijaweb.org/text.asp?2009/53/2/187/60276

   Introduction Top

Laryngoscopy and tracheal intubation (LTI) maneouvers induce undesirable hypertension and ta­chycardia. [1] A significant factor that determines the se­verity of these haemodynamic perturbations is anaes­thetic depth at this stage. [2] Introduction of bispectral index (BIS) monitor into anaesthesia practice has made monitoring of anaesthetic depth feasible. Previous stud­ies have demonstrated that noxious stimulation of laryn­goscopy and tracheal intubation is associated with in­creases in BIS besides increases in blood pressure and heart rate. [3] Therefore it is common practice to admin­ister a variety of pharmacological adjunct either with premedication or at the time of induction of anaesthe­sia, to obtund /attenuate increases in BIS value as well as haemodynamics following laryngoscopy and tracheal intubation. [4],[5] Patients of intracranial tumours usually receive oral phenytoin from the day they are examined by the neurosurgeon to prevent seizures with their at­tendant complications. The commonly followed regi­men in an adult patient is administration of phenytoin sodium 200 to 300 mg orally, at night. This dose is continued for varying duration in the postoperative pe­riod. At our centre, on the morning of surgery, these patients receive 100 mg phenytoin intravenous, approxi­mately 90 min before induction of anaesthesia. It has been stated that a steady state of plasma concentration is achieved after at least one week of continuous oral phenytoin treatment. We hypothesized that because of its effects on the central nervous system and cardio­vascular system, phenytoin therapy could influence the BIS value and haemodynamic responses during induc­tion of general anaesthesia and tracheal intubation. The objectives of the present study were to compare the BIS value and haemodynamic responses associated with induction and tracheal intubation in patients with or without phenytoin therapy.

   Methods Top

This preliminary observational study was ap­proved by local Ethics committee and informed con­sent for participation in the study was obtained from 120 adult patients of either gender and American Soci­ety of Anesthesiologists (ASA) physical status I and II, scheduled for elective intracranial and spine surgery. Patients of intracranial surgical procedures, who were taking oral phenytoin 200 to 300 mg daily for more than seven days, were included in the study. Exclusion criteria were patients with intracranial vascular lesions, patients on phenytoin for less than one week, altered sensorium, cardiovascular, metabolic or chronic ob­structive pulmonary disease, drug / alcohol abuse, and anticipated difficult laryngoscopy / intubation. They were divided into two groups: patients on phenytoin were taken as phenytoin group while patients of spine sur­gery not on phenytoin therapy served as control. All patients were premedicated with 5 mg oral diazepam 2 hours before anaesthesia induction. Patients in the phenytoin group received an IV bolus of 100 mg pheny­toin approximately 90 min before induction, as per our hospital protocol. In the operation theatre BIS sensors were attached as per instructions of the manufacturers and connected to Aspect-2000 BIS monitor (Aspect medical system, Natick, MA, USA). Routine monitor­ing consisted of ECG, heart rate (HR), mean blood pressure (MBP) and SpO2 (Datex Engstrom, Helsinki, Finland). Non-invasive blood pressure (NIBP) moni­tor was set on stat mode which displays and records blood pressure reading every 30 sec. BIS smoothing rate was set at 15 sec. After noting baseline values of BIS, mean blood pressure (MBP) and HR, patients were administered fentanyl 2mcg.kg -1 approximately, and five minutes later thiopentone was administered until abolition of eye-lash reflex. Rocuronium 1mg.kg -1 was administered and trachea intubated 90 sec later. BIS, MBP and HR were recorded after induction (immedi­ate prior to laryngoscopy) and subsequently, at 30 sec interval for 120 sec after tracheal intubation. Anaes­thesia during the study period was maintained with 66% nitrous oxide in oxygen, and lungs were ventilated me­chanically. The study was terminated at this point and subsequent anaesthesia proceeded according to the surgical requirements. The time to intubation was taken from introduction of laryngoscope to tracheal tube placement. Patients in whom more than one attempt or more than 15sec were required for tracheal intubation were excluded from the study.

Statistical analysis: Data are expressed as mean ± SD. Statistical analysis within each group was per­formed with repeated measures analysis of variance (ANOVA) test and where significance was observed, Bonferroni test was applied for comparison with baseline values. Independent sample't' test was used to compare numerical data between two groups. P value less than 0.05 was inferred as significant.

   Results Top

A total of 120 patients were enrolled in the study, of which 22 (12 from control and 10 from phenytoin group) were excluded, either because time taken for intubation exceeded 15sec or multiple attempts were needed for intubation. Therefore, data were analyzed from 98 patients (48 of control and 50 of phenytoin group).Two groups were comparable in respect of age, sex and weight [Table 1]. Patients of the phenytoin group lost eye-lash reflex at a significantly smaller dose of thiopentone compared with the control group. Time taken to intubate trachea was comparable in the two groups [Table 2].

BIS: Baseline BIS was comparable in two groups. Compared with baseline it decreased significantly in both groups in response to thiopentone administration, the decrease being comparable in two groups. In both groups tracheal intubation resulted in significant increases in BIS which persisted throughout the study duration. Greatest increases in BIS were observed 120 sec post intubation in both the groups. The increases in BIS were significantly less pronounced in the phenytoin group, at each time point [Table 3].

MBP: Baseline MBP was comparable in two groups. Thiopentone administration produced no al­teration in MBP in either group. Tracheal intubation in­creased MBP in both the groups at 30, 60 and 90 sec. compared with baseline. Maximal increases in MBP in both groups were recorded 30 sec post tracheal intu­bation. The increases in MBP were significantly lesser in the phenytoin group [Table 4].

HR: Baseline HR was similar in two groups. There were significant increases of HR in both groups in re­sponse to thiopentone administration and tracheal intu­bation compared with baseline throughout the study pe­riod. Maximal increases in HR were observed 30 sec post intubation in both groups. The magnitude of increases of HR was significantly lesser in the phenytoin group at each time point, except 90 sec post intubation, when it was comparable in both groups [Table 5].

   Discussion Top

Induction of anaesthesia expectedly decreased BIS in both the groups but the impact on BIS was greater in the phenytoin group, presumably because of potentiation of hypnotic effect of thiopentone by pheny­toin. A significant smaller dose of thiopentone required to abolish eye-lash reflex in the phenytoin group gives credence to this potentiation theory. Previous studies have demonstrated that tracheal intubation is associ­ated with increase in BIS value. [3],[6] In agreement with those studies, we too observed increase in BIS values following tracheal intubation in both the groups but the increase was less marked in the phenytoin group com­pared to the control group throughout the study pe­riod. We excluded patients in whom laryngoscopy and /or tracheal intubation required more than one attempt or when the duration of LTI exceeded 15 sec. The pro­cedure of tracheal intubation is usually accomplished within 10 to 15 sec, while duration longer than this de­notes difficult airway which might alter anaesthetic depth, thereby, our observations.

Earlier studies by Turner et al, [2] Stoelting, [7] and Bucx et al [8] have demonstrated that degree of reflex response to laryngeal stimulation appears to vary with the depth of anaesthesia, the duration and difficulties encountered during laryngoscopy and tracheal intuba­tion. Guignard and colleagues [9] reported that maximal increase in BIS value as well as haemodynamic values occurred during first 120 sec following orotracheal in­tubation, therefore we limited our observations to 120 sec post intubation. Our observations on BIS follow­ing laryngoscopy and tracheal intubation further strengthen our hypothesis that in the phenytoin group a greater depth of anaesthesia was responsible for a smaller increase in BIS value compared to the control group in spite of significantly smaller dose of thiopen­tone required for induction of anaesthesia in the former group. BIS is a predictor of depth of anaesthesia/hyp­nosis and arousal reaction during induction of anaes­thesia and tracheal intubation. An attenuated BIS in­crease in the phenytoin group reflects a greater sup­pression of cortical activity and thereby, the level of consciousness. Increased gamma amino butyric acid (GABA) in brain may also result in deeper plains of anaesthesia. However, at normal phenytoin concentra­tions no changes of spontaneous activity or response to iontophoretically applied GABA are detected. At concentrations five to ten folds higher, multiple effects of phenytoin are evident including reduction of sponta­neous activity and enhancement of response to GABA. [10] Therefore, it is unlikely that GABA played any role in increasing the anaesthetic depth in the phenytoin group. Laryngoscopy and tracheal intubation are known to increase blood catecholamine levels. [11] The impor­tance of adrenergic system for the modulation of con­sciousness has been known since long. [12] Previous stud­ies have demonstrated that exogenously administered adrenaline causes clinical signs of arousal associated with an increase in BIS in deeply sedated patients [13] but not in presence of deep anaesthesia. [14] Further­more, Hirota and colleagues have demonstrated that BIS levels are significantly correlated with plasma nore­pinephrine concentrations after oral diazepam premedi­cation. [15] Thus one more reason of relatively smaller increase in BIS in the phenytoin group could be the blunting of the action of endogenously released cat­echolamines on the cerebral cortex or suppression of release of catecholamines during LTI since the intensity of reflex response to laryngeal stimulation tends to vary with the depth of anaesthesia. The same factors were probably responsible for a smaller increase in BIS in the phenytoin group over the next two minutes post tracheal intubation.

Many drugs, including the recently reported gabapentin [16] and landiolol, [17] have been shown to be effective in attenuating haemodynamic responses as­sociated with LTI in healthy patients. Even deepening of anaesthesia has also been recommended to blunt these responses. [18] Importance of avoidance of blood pressure fluctuations during anaesthesia induction, and tracheal intubation cannot be overemphasized. Abrupt increase in BP during tracheal intubation has been re­ported to cause myocardial ischaemia, [19] and rupture of intracranial aneurysm in susceptible patients. [20] Since tachycardia appears to be associated more frequently with myocardial ischaemia than does hypertension, most common approach towards blunting haemodynamic re­sponse to laryngoscopy and tracheal intubation is use of beta-adrenergic antagonist. [21] However, excessive negative chronotropic and inotropic action of beta blockers may be harmful in susceptible cardiac patients. [22] We have no explanation for the exact mechanism by which phenytoin attenuates the pressor responses of laryngoscopy and tracheal intubation but as mentioned above it may do so by increasing the anaesthetic depth and thereby, resulting in suppression of endogenous catecholamine release. Stability of haemodynamic vari­ables in the phenytoin group suggests that these pa­tients blunt the insult of laryngoscopy and tracheal intu­bation better.

Phenytoin is absorbed slowly by oral route and a steady state of plasma concentration is achieved after at least one week of continuous treatment. [23] For this reason we included patients who were taking this medi­cine for more than a week. Oral administration of pheny­toin generally causes few side effects unless the patient has severe underlying cardiac disease. Intravenous ad­ministration at a rate exceeding 50 mg/min can have potentially catastrophic haemodynamic results. [24] It has stabilizing effect on neuronal membrane by inhibiting voltage sensitive sodium channels. This affects both the nerves and also the cardiac muscles. It inhibits seizure activity without causing generalized central nervous sys­tem depression.

There are certain limitations of our study. The design of the study did not permit us blinding, thereby, enhancing the chances of bias in our observations. We avoided volatile agents over the study period to pre­vent their influence on haemodynamic and BIS value because different patient population in two groups might respond differently to these agents. Since maximal haemodynamic and BIS changes are observed within the first 120 sec after intubation we didn't deem it nec­essary to continue the study beyond this period.

In conclusion, patients on oral phenytoin 200 to 300 mg, daily dose for more than 7 days and who were also given 100mg of the drug intravenously, 90 min prior to anaesthesia induction, require a relatively lesser dose of thiopentone for induction of anaesthesia compared with the controls. Moreover, because of greater an­aesthetic depth (as seen by BIS monitoring) the haemodynamic insult of LTI is blunted in them. Whether a single oral / intravenous dose administered on the day of surgery would attenuate the haemodynamic response to laryngoscopy and tracheal intubation requires fur­ther evaluation.

   References Top

1.King BD, Harris LC, Greifenstein FE, Elder JD, Dropps RD. Reflex circulatory responses to direct laryngoscopy and tracheal intubation performed during general anes­thesia. Anesthesiology 1951; 12:556-566.  Back to cited text no. 1      
2.Turner DAB, Shribman AJ, Smith G, Achola KJ. Effect of halothane on cardiovascular and plasma catecholamine response to tracheal intubation. Br J Anaesth 1986; 58:1356 - 1370.  Back to cited text no. 2      
3.Nakayama M, Ichinose H, Yamamoto S, Kanaya N, Namiki A. The bispectral index response to tracheal in­tubation is similar in normotensive and hypertensive patients. Can J Anesth 2002;49: 458-460.  Back to cited text no. 3  [PUBMED]    
4.Sebel PS, Lang E, Rampil IJ, et al. A multicenter study of bispectral electroencephalogram analysis for monitor­ing anesthetic depth. Anesth Analg 1997;84:891-899.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]  
5.Oda Y, Nishikawa K, Hase I, Asada A. The short acting Beta 1 adrenoceptor antagonists esmolol and landiolol suppress bispectral index response to tracheal intuba­tion during sevoflurane anesthesia. Anesth Analg 2005;100:733-737.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]  
6.Slavov V, Motamed C, Massou N, Rebufat Y, Duvaldestin P. Systolic blood pressure,not BIS, is associated with movement during laryngoscopy and intubaiton. Can J Anesth 2002;49:918-921.  Back to cited text no. 6  [PUBMED]    
7.Stoelting RK. Circulatory changes during direct laryn­goscopy and tracheal intubation. Influence of duration of laryngoscopy with or without lidocaine. Anesthesi­ology 1977;47:381-384.  Back to cited text no. 7      
8.Bucx MJL, Van Geel RTM, Scheck PAE, Stijnen TP. Car­diovascular effects of forces applied during laryngos­copy. The importance of tracheal intubation. Anaesthe­sia 1992;47: 1029-1037.  Back to cited text no. 8      
9.Guignard B, Meningaux C, Dupont X, Fletcher D, Chauvin M. The effect of remifentanil on the bispectral index change and hemodynamic responses after orotracheal intubation. Anesth Analg 2000;90:161-167.  Back to cited text no. 9      
10.McNamara JO. Pharmacotherapy of the epilepsies. In: Brunton LL, Lazo JS, Parker KL,eds, Goodman and Gillman's The Pharmacological basis of therapeutics. McGraw Hill New York (USA) 2006; 508-510.  Back to cited text no. 10      
11.Derbyshire DR, Chmielewski A, Fell D, Vater M, Achola KJ, Smith G. Plasma catecholamine responses to tracheal intubation. Br J Anaesth 1983;55:855-860.  Back to cited text no. 11      
12.Berredge CW, Foote SL. Enhancement of behavioural and electroencephalographic indices of waking follow­ing stimulation of noradrenergic B-receptors within the medial septal region of the basal forebrain. J Neurosci 1996;16:6999-7009.  Back to cited text no. 12      
13.Andrzejowski J, Sleigh JW, Johnson IA, Sikiotis L. The effect of intravenous epinephrine on the bispectral in­dex and sedation. Anaesthesia 2000;55:761-763.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]  
14.Shin HW, Ban YJ, Lee HW, Lim H J, Yoon SM. Arousal with epinephrine depends on the depth of anesthesia. Can J Anesth 2004;51:880-885.  Back to cited text no. 14      
15.Hirota K, Matsunami K, Kudo T, Ishihara H, Matsuki,K. Relation between bispectral index and plasma catechola­mines after oral diazepam premedication. Eur J Anaesthesiol 1999;16:516-518.  Back to cited text no. 15      
16.Fassoulaki A, Melemani A, Paraskeva A, Petropoulos G. Gabapentin attenuates the pressor response to direct laryngoscopy and tracheal inutabtion. Br J Anaesth 2006;96:769-773.  Back to cited text no. 16      
17.Goyagi T, Tanaka M, Nishikawa T. Landiolol attenuates the cardiovascular response to tracheal intubation. J Anesth 2005;19:282-286.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]  
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20.Fox E, Sklar G, Hill C, Villanueva R, King BD. Complica­tions related to the pressor response to endotracheal intubation. Anesthesiology 1977;47:524-525.  Back to cited text no. 20      
21.Thomson IR. The haemodynamic response to intuba­tion. : a perspective. Can J Anesth 1989; 36 : 367 - 369.  Back to cited text no. 21  [PUBMED]    
22.Prys-Roberts C, Greene LT, Meloche R, Foex P. Studies of anaesthesia in relation to hypertension. Haemodynamic consequences of induction and endot­racheal intubation.Br J Anaesth 1971; 43:531-547.  Back to cited text no. 22      
23.Graheme-Smith DG, Aronson JK. Pharmacopoeia. In: Graheme-Smith DG, Aronson JK, eds. Oxford text book of clinical pharmacology and Drug Therapy. 3 rd ed. Oxford University press, New York (USA) 2002; 571.  Back to cited text no. 23      
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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