INTRODUCTION:

Aminophylline (Theophylline ethylenediamine) is a methylxanthine derivative that is widely used in the treatment of respiratory and cardiovascular diseases. Theophylline and other methylxanthines are known to exert a variety of important physiological and biochemical effects. The major therapeutic application of theophylline is to promote bronchial smooth muscle relaxation in the clinical setting of acute or chronic bronchospasm, but it also has a diuretic effect that can be useful in the treatment of heart failure, particularly acute pulmonary edema. This effect on kidney is thought to be secondary to an increase in renal blood flow¹. The 3 xanthines; caffeine, theophylline, and theobromine are found naturally in plants like tea, coffee, cocoa, chocolate, and cola nut.

· Theophylline and caffeine are found in tea.

· Caffeine found in coffee.

· Theobromine and caffeine in cocoa and chocolate.

· Cola nut (cola drink) contains caffeine. They are quantitatively similar but are markedly different in potency.

Caffeine and theophylline have complex and incompletely explained actions, which include:

· Inhibition of phosphodiesterase enzyme which is responsible for the breakdown of cyclic adenosine monophosphate(c AMP).

· Effect on intracellular calcium distribution².

· They have been reported to stimulate the release of epinephrine and nor epinephrine from the sympathoadrenal system. They exert both positive inotropic and chronotropic effect on the heart, while peripheral vascular resistance is reduced. The metabolic effects include stimulation of gastric acid secretion and an increase in plasma free fatty acids¹.

Caffeine is more potent than theophylline but both drugs stimulate mental activity when it is below normal. They do not raise it above normal, thoughts are more rapid and fatigue is removed or its onset is delayed. The effect on mental and physical performance varies according to the mental state and personality of the subject. Reaction time is reduced. Intellectual performance may be assisted when it has been reduced by fatigue or boredom. Caffeine affects sleep of older more than it does of younger people, onset of sleep (sleep latency) is delayed, movement of the body are increased, total sleep time is reduced and there are increased awakenings². Aminophylline partially reverses the effect of anesthetics such as benzodiazepines, barbiturates, and volatile anesthetics^3-5. Aminophylline is a phosphodiesterase inhibitor that centrally antagonizes the effect of adenosine⁶.

Adenosine is present in all cells and its receptors are distributed in all brain cells. Adenosine is a central nervous system neuromodulator^7-8. The hypnotic effect of systemic and central administration of adenosine has been demonstrated in humans^9,10. Microdialysis of adenosine in the basal forebrain promotes sleepiness, whereas perfusion of A1 adenosine receptor selective antagonists such as caffeine or theophylline increases wakefulness¹¹. Infusion of adenosine in low doses can potentiate the hypnotic effect of anesthetics. Conversely, administration of aminophylline produces some resistance to anesthesia¹². Changes in adenosine function may be one of the mechanisms of action for this effect of theophyllines. There are 4 subtypes of adenosine receptors in the CNS; A1, A2A, A2B, and A3. A1 and A2A receptors modulate cortical acetylcholine release, behavioral arousal, and sleep¹³.

The mechanism for the antihypnotic effect of aminophylline is thought to be suppression of adenosine receptors in the CNS¹⁴. Meanwhile some authors have reported that caffeine, which is structurally similar to aminophylline, decreases GABA neurotransmitter¹⁵. Theophylline metabolism occurs in the liver by cytochrome P450 system, so caution needs to be taken when using other drugs that are metabolized by the cytochrome system. Conditions such as hepatic dysfunction and heart failure can reduce the elimination of theophyllines, and low albumin states reduces the amount of protein bound drugs in the blood, so in these situations, aminophylline should be used with caution. When using aminophylline in recovery of anesthesia, these effects must be evaluated carefully and precautions must be taken in the speed of the injection¹⁶.

Bispectral (BIS) index:

It is considered the most validated form of monitoring of brain function or level of consciousness used in the field of anesthesia and sedation care. BIS index values are the result of 2 innovations; bispectral analysis and the BIS algorithm.

· Bispectral analysis is a signal processing methodology that assesses relationships among signal components and captures synchronization within signals like the EEG. By quantifying the correlation between all the frequencies within the signal, bispectral analysis yields an additional EEG facet of brain activity¹⁷.

· BIS algorithm was developed to combine the EEG features (bispectral and others) that were highly correlated with sedation/hypnosis in the EEGs from more than 5000 adult subjects¹⁸.

The bispectral index ranges from 0 to 100. A score of 95 to 100 correlates with an awake state, and Zero score shows no EEG activity. During general anesthesia, a BIS index of less than 55 is recommended^19-21. Intense surgical stimulation causes increase in BIS ²².

Fig. 1: BIS index range in relation to clinical condition of the patient

Methods

This study was conducted in the period of August 2015 till November same year in Hawler teaching hospital/ Hawler city/Iraq, and the study included 50 patients aged 18 to 45 years old and ASA physical status I and II, who were to be operated upon for orthopedic procedures that last less than one hour. The study was designed as a double blind controlled study. The patients were divided into two groups; group P who receive placebo, and group A who receive aminophylline.

Exclusion criteria include:

Hypersensitivity to aminophylline (or other methylxanthines), egg, and soybean.

History of consumption of or addiction on opioid.

Administration of sedative/hypnotic or psychoactive drugs in the last one year.

Chronic use of aminophylline or other methylxanthines.

And positive history of cardiac arrhythmia, palpitation, and convulsion.

On arrival in the operating room; ECG, non-invasive arterial blood pressure, heart rate, ETCo2 and SpO2 were monitored. BIS monitoring electrode was placed on the patient's forehead after careful cleaning of the skin and reading was continuously recorded.

Pic.1: BIS sensor applied on forehead of the patient

Anesthesia was induced with propofol 2.5 mg/kg and remifentanil 1.5 mcg/kg as a bollous.

Without any muscle relaxant tracheal intubation was done. Anesthesia was maintained with propofol 100 mcg/kg/min, remifentanil 0.2 mcg/kg/min and 100% O2, with controlled mechanical ventilation, stable BIS readings in the range of 40 – 60 and stable ETCo2 of 35 – 45 cm H2O. At the end of surgery, after skin closure, TIVA was discontinued, and the test drug injected. Patients received either aminophylline 4 mg/kg within 2 minutes or same volume of normal saline.

Pic. 4: Aminophylline ampoule

Recovery was observed; BIS values (until reach to 95) , heart rate , blood pressure were recorded in all patients before administration and every 3 minutes after injection of the test drug for 20 minutes.

Pic. 5: Portable BIS monitor

The following variables were measured in both groups;

· Time to eye opening ,

· Time to extubation after injection of test.

· and Time needed to reach BIS reading of 95.

N.B: The issue of hypothermia was not perfect for academic study purposes.

Statistical analysis

Data w expressed as mean ± SD. Analysis of BIS values, and clinical recovery parameters was performed by a t-test for independent groups. Statistical analysis was performed using SPSS software for windows version 19. We used Excel Microsoft Software for data input and making of graphs. A probability value of less than 0.001 was considered to be statistically significant.

RESULTS:

After injection of the test drug, BIS values were measured every 3 minutes and comparison was made between the two groups. P-value for each reading was measured and found to be less than 0.001. BIS score of 95 was reached in a statistically significantly shorter period of time in group A (P- value <0.001). Time to eye opening and extubation time were used as a measurement of clinical recovery, and there was a significant reduction in those values (p-values less than 0.01) Heart rate and blood pressure were found to be higher after injection of aminophylline compared with placebo group.

Table 1: Clinical recovery and BIS values

	Tim o ime to eye opening	Extubation T.	BIS 95
Group P	13.413.4±1.8	17.1±2.7	20.4±220.4±2.8
Group A	10.810.8±3.1	14±3.8	1616.8±3.4
P value	0.0007	0.0004	0.0002

Fig. 2: Changes in clinical and BIS recovery values

Fig. 3: Changes in BIS values

DISCUSSION:

In this study, propofol was used for maintenance of anesthesia, and remifentanil (which is an ultra short acting opioid) for analgesia. No muscle relaxant was used in order to avoid its interference with clinical recovery values. The main result of this study was that aminophylline administration led to shortening in the time of recovery parameters and an increase in BIS values after total intravenous general anesthesia.

There was a decrease (of about 2 minutes) in the time required for eye opening after discontinuation of intravenous propofol and remifentanil infusion and administration of aminophylline compared with the time required after placebo administration. Extubation time after aminophylline administration was shortened by about 3 minutes compared with that after placebo administration. The result of improvement in recovery parameters (eye opening and extubation time) goes with other studies demonstrating that aminophylline decreases recovery times.

An article published in the European Journal of Anesthesiology June 2002 by Turan et al,²³ demonstrating that Aminophylline hastened recovery after sevoflurane anesthesia. El Tahan MR²⁴. in 2011 demonstrated that administration of Aminophylline enhances postoperative cognitive recovery from anesthesia with sevoflurane. Ghaffaripour S. et al.,¹⁶ in 2014 demonstrated that Aminophylline administration shortens recovery time from intravenous anesthesia and caused an increase in BIS readings.

In our study we noticed that there was a significant increase in BIS readings after injection of Aminophylline compared with placebo. Hupfl M. et al.,²⁵ in 2008 demonstrated that administration of aminophylline causes significant increase in BIS readings till 10 minutes after aminophylline injection possibly due to its ability to partially antagonize the effect of G.A. While in our study we found an increase up to 20 minutes after injection. In 2009 Turan A. et al,²⁶ concluded in a study that Aminophylline decreases the sedative effect of Propofol.

CONCLUSION:

In this study we have shown 2 points:

1. Aminophylline administration decreases the time needed for clinical recovery in patients anesthetized with total intravenous general anesthesia, nevertheless, it should not be used routinely because of the potential arrhythmiogenecity specially if given simultaneously with other arrhythmiogenic anesthetic agents, in spite of the fact that we did not face such complication.

2. Higher BIS values were obtained after administration of aminophylline.

REFERENCES:

1. Pacifici GM. Clinical pharmacology of theophylline in preterm infants: effects, metabolism and pharmacokinetics. Curr Pediatr Rev. 2014; 10(4): 297-303.

2. Cappelletti S, Piacentino D, Sani G, Aromatario M. Caffeine: cognitive and physical performance enhancer or psychoactive drug? Curr Neuropharmacol. 2015; 13(1): 71-88.

3. Krintel JJ, Wegmann F. Aminophylline reduces the depth and duration of sedation with barbiturates. Acta anesthesiologica scandinavica. 1987; 352- 354.

4. Sibai AN, Sibai AM, Baraka A, Comparison of flumazenil with aminophylline to antagonize medazolam in elderly pts. Br J Anesthesia. 1991; 591-595.

5. Wu CC, Lin CS, Wu GJ. Doxapram and aminophylline on bispectral index under sevoflurane anesthesia; a comparative study. Euro J Anesthesiol. 2006; 937- 941.

6. Stone TW, Hollins C, Lloyd H, Methylxanthines modulates adenosine release from slices of cerebral cortex, Brain Res. 1981; 421-31.

7. Ribeiro A, Sebastiao AM. Caffeine and adenosine. J Alzheimer's Dis. 2010; 1379.

8. Basheer R, Stecker RE, Thakkar MM,McCarley RW. Adenosine and sleep-wake regulation. Prog Neurobiol. 2004; 379-396.

9. Segevdahl M,Ekblom A, Sandelin K, Wickman M, Sollevia A. aPreopertive adenosine infution reduces the requirement for; isoflourane and postoperative anaigesics. Anesthesia analgesia 1995; 1145-9

10. Neimand D, Martinell S, Arvidsson S, Svedmyr N, Ekstrom-Jodal B. Aminophylline inhibition of diazepam sedation; is adenosine blockade of GABA-receptors the mechanism ? Lancet 1984; 1265-8

11. Tung A, Herrera S, Szafran MJ, Kasza K, Mandelson WB. Effect of sleep deprivation on rightening reflex in the rat is partially reversed by administration of adenosine A1 and A2 receptors antagonists. Anesthesiology 2005; 1158-1164.

12. Kaputlu I, Sadan G, Ozdem S. Exogenous Adenosine potentiates hypnosis induced by iv anes. Anesth 1998; 496-500.

13. Van Dort CJ, Baghdoyan HA, Lydic R. Adenosine A1 and A2A resep in mouse prefrontal cortex modulate Ach rel and behavioral arousal. G Neuroscience 2009; 871-881.

14. Fredholm BB, Ijzerman AP, Jacobson KA, Klotz KN, Linden J. International union of pharma. Pharm review 2001; 527-552.

15. Takito M, Matsuda H, Yoshioka T. Calcium independent inhib of GABA. Brain Res. 2004; 229-239.

16. Ghaffaripour S, Khosravi MB, Rahimi A, et al. The effects of Aminophylline on clinical recovery and bispectral index in patients anesthetized with total intravenous anaesthesia. Pak J Med Sci. 2014; 30(6): 1351-1355.

17. Sigl JC, Chamoun NG.An introduction to bispectral analysis for the electroenceohalogram.J Clin Monit. 1994; 392-404.

18. Rampil IJ. A primer for EEG signal processing in anesthesia. Anesthesiology. 1998; 980-1002.

19. Gilbert TT, Wagner MR, Halukurike V, Paz HL, Garland A. Use of bispectral electroencephalogram monitoring to assess neurologic status in unsedated, critically ill pt.Critical care medicine . 2001; 1996-2000.

20. Struys M, Versichelen L, Byttebier G, Mortier E, Moerman A Rolly G. Clin. Usefulness of the BIS index for titrating propofol target effect -site conc. anesthesia. 1998; 4-12.

21. Khafagy HF, Ebied RS, Osman ES, Ali MZ, Samhan YM. Periop effects of various anesthetic adjuvants with total intravenous anesthesia guided by BIS index. Korean J Anes. 2012; 113-119.

22. Sandin M, Thorn SE, Dahlqvist A, Wattwil L, Axelsson K, Wattwil M. Effects of pain stim on BIS, HR, BP at diff MAC values of sevoflurane. Acta Anesth scand 2008; 420-426.

23. Turan A, Memis D., Karamanlioglu B, Colak A, Pamukcu Z, Turan N. Effect of aminophylline on recovery from sevoflurane anesthesia. Euro J Anesthesiology. 2002; 452-454.

24. El Tahan MR. Effects of aminophylline on cognitive recovery after sevoflurane anesthesia. J Anesth. 2011; 25(5): 648-56.

25. Hupfl M, Schmatzer I, Buzath A, Burger H, Horauf K, Ihra G, et al; The effect of aminophylline on BIS index during inhalational and total intravenous anesthesia. Anesthesia 2008; 63: 583-587.

26. Turan A, Kasuya Y, Govinda R, Obal D, Rauch S, Dalton JE, Akça O, Sessler DI. The effect of aminophylline on loss of consciousness, bispectral index, propofol requirement, and minimum alveolar concentration of desflurane in volunteers. Anesth Analg. 2010; 110(2): 449-54.

Received on 18.01.2021 Modified on 27.02.2021

Research J. Pharm.and Tech 2021; 14(11):6012-6016.

DOI: 10.52711/0974-360X.2021.01045

	TIVA- off time	3min.	6min.	10min.	15min.	20min.
GroupP	49±1.7	48±1.8	61±2.9	77±2.6	89±4	95±3.8
GroupA	50±2.1	51±2.9	64±2.7	80±3.1	92±2.6	98±2.9
P value	0.07	0.0008	0.0004	0.0005	0.0029	0.0029