Anaesthesia induction with sevoflurane and propofol in children: Evaluation of QT and QTc durations

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Anaesthesia Induction with Sevoflurane and Propofol in

Children: Evaluation of QT and QTc Durations

SUMMARY

Aim: The present study aims to compare the effects of anesthesia induction in children with sevoflurane and propo-fol on QT and corrected QT (QTc) interval durations.

Material and Method: A total of 40 paediatric patients were included in this prospective study. Control electro-cardiograms (ECG) were recorded before induction. In the sevoflurane group (Group S), anaesthesia was induced by sevoflurane. In the propofol group (Group P), induction was performed using propofol. In all patients, ECGs were ob-tained at the first and third minutes of induction, 3 minutes after administration of muscle relaxant and 5 minutes after initiation of intubation. QT durations were measured directly from ECG records, while QTc intervals were estimated using Bazett formula.

Results: There was no significant difference in QT and QTc duration of control ECG records in groups S and P. In Group S, QTc estimates obtained 3 minutes after induction, 3 minutes after administration of the muscle relaxant and 5 minutes after the intubation were significantly longer than those of Group P (p<0.05).

Conclusion: In our study, we found that QTc durations were significantly prolonged in the paediatric patients that received anaesthesia induction with sevoflurane rather than propofol. We conclude that propofol could be first preference for the induction of paediatric patients with a predisposition to preoperative arrhythmia and those with prolonged QTc durations.

Key words: QT, QTc, anaesthesia induction, sevoflurane, propofol, children ÖZET

Çocuklarda Sevofluran ve Propofol ile Anestezi İndüksiyonu: QT ve QTc Süresi Üzerine Etkilerinin Değerlendirilmesi Amaç: Çalışmamızda, çocuklarda sevofluran ve propofol kullanılarak uygulanan anestezi indüksiyonunun QT ve dü-zeltilmiş QT (QTc) süreleri üzerine etkilerinin karşılaştırılması amaçlandı.

Gereç ve Yöntem: Prospektif çalışmamıza toplam 40 çocuk alındı. Anestezi indüksiyonu öncesi kontrol elektrokardi-yografi (EKG) kayıtları alındı. Sevofluran grubunda (Grup S), anestezi indüksiyonu sevofluran kullanılarak gerçekleştirildi. Propofol grubunda (Grup P), anestezi indüksiyonunda propofol kullanıldı. Tüm hastaların indüksiyonun birinci ve üçüncü dk.’sında, kas gevşetici ajanın verilmesi ardından 3 dk. sonra ve entübasyonun ardından 5 dk. sonra EKG kayıtları alındı. Tüm EKG kayıtlarında QT süresi ölçüldü. Olgulara ait EKG kayıtlarında QTc süresi Bazett formülü ile belirlendi.

Bulgular: Gruplara alınan olguların kontrol EKG kayıtlarında QT ve QTc süreleri açısından anlamlı farklılık bulunma-maktaydı. Grup S’de, indüksiyonun 3 dk. ardından, kas gevşetici ajanın verilmesinin 3 dk. ardından ve entübasyonun 5 dk. ardından yapılan EKG kayıtlarında hesaplanan QTc süreleri Grup P’den anlamlı olarak uzundu (p<0.05).

Sonuç: Çalışmamızda, sevofluranla anestezi indüksiyonu uygulanan çocuklarda QTc sürelerinin propofol ile yapılan indüksiyona göre anlamlı olarak uzadığını belirledik. Operasyon öncesi dönemde QTc süreleri uzamış bulunan çocuk-larda propofolün anestezi indüksiyonunda seçilebileceğini düşünmekteyiz.

Anahtar kelimeler: QT, QTc, anestezi indüksiyonu, sevofluran, propofol, çocuk J Turk Anaesth Int Care 2010; 38(4):285-292

Bu çalışmanın bir kısmı, Antalya’da 28 Ekim-1 Kasım 2009 tarihleri arasında düzenlenen Türk Anesteziyoloji ve Reanimasyon Derneği 43. Ulusal kongresi’nde poster olarak sunulmuştur.

Alındığı Tarih: 10.10.2009 Kabul Tarihi: 16.12.2009

Yazışma adresi: Dr. Volkan Hancı, Zonguldak Karaelmas Üniversitesi Tıp Fakültesi Anesteziyoloji ve Reanimasyon Anabilim Dalı, Zonguldak

e-posta: vhanci@gmail.com

Klinik Araştırma

Volkan Hancı*, Varım Numanoğlu**, Ethem Pişkin***, Serhan Yurtlu*, Hilal Ayoğlu*, Gülay Erdoğan*, Rahşan Dilek Okyay*, Işıl Özkoçak Turan*

Zonguldak Karaelmas Üniversitesi *Anesteziyoloji ve Reanimasyon Anabilim Dalı, **Çocuk Cerrahisi Anabilim Dalı, ***Çocuk Sağlığı ve Hastalıkları Anabilim Dalı

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INTRODUCTION

Anesthetic agents can show proarrhyth-mic or antiarrhythproarrhyth-mic activity by affect-ing electrical activity with certain mecha-nisms.(1)_{Prolongation of QT and corrected} QT (QTc) interval were thought to be re-lated to many anesthetic drugs.(2)

Sevoflurane is a widely used inhalation agent that is convenient for fast anesthe-sia induction by inhalation due to its low blood/gas solubility.(3)_Propofol (2,6-diiso-propylphenol) is an intravenous anesthet-ic agent widely used for fast intravenous induction.(4)

The present study aims to compare the ef-fects of anesthesia induction with sevoflu-rane and propofol on QT and QTc dura-tions in pediatric patients.

MATERIALS and METHODS

After obtaining the approval of the hos-pital ethics committee of Zonguldak Ka-raelmas University, a total of 40, ASA I paediatric patients with 20 in each group within the age range of 3 to 13, whose elective non-cardiac surgeries were sched-uled to take place between January 2008-July 2009 were included in this study. Exclusion criteria included past and actual presence of nephrotic syndrome, diabe-tes mellitus, hypothyroidism, hyperthy-roidism, arrhythmia, valvular disease and medicine usage leading to extended QT intervals.

The family consent of patients included in the study was obtained with the ‘Family Informed Consent Form’. Demographic data and age of the patients were recor-ded.

Thirty minutes prior to induction, all pa-tients were premedicated orally with 0.5 mg kg-1_{midazolam in cherry juice.} Maxi-mum midazolam dose was limited to 15 mg. In the operation room, a 24-gauge cannula was used for intravenous ac-cess and isolyte-P infusion was adminis-tered. The baseline mean arterial pres-sure (MAP), peripheral oxygen saturation (SpO2) and electrocardiograms (ECG) of the patients were obtained with standard monitorization.

In the operating room, on all patients standard 12- derivation ECG monitoriza-tion was performed (Hewlett Packard, Pagewriter 300pi ECG device) and control ECGs were recorded at 50 mm s-1_paper speed with an amplitude of 1 mV cm-1 pri-or to induction.

After control ECGs were recorded, pa-tients were randomly divided into two groups using a random samples table. In the sevoflurane group (Group S, n=20), anaesthesia was induced using tidal vo-lume inhalational induction technique at a fresh gas flow rate of 6 L min-1_{with volume} breathing of 8 % sevoflurane. During anaesthesia induction, administration of anaesthesia was continued for 2 minutes with 8 % sevoflurane. Two minutes later, anaesthesia was maintained using 3 % sevoflurane.

In the propofol group (Group P, n=20),

in-duction was performed using 2.5 mg kg-1

propofol. Anaesthesia was maintained using propofol infusion at a rate of 6 mg kg-1_hr-1_{. In both groups, after} maintain-ing muscle relaxation was maintained with 0.15 mg kg-1_{vecuronium at the third} minutes of induction, and intubation was performed three minutes later.

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In both groups, throughout the entire study, 60 % oxygen - 40 % air mixture was used as carrier gas.

Patients were ventilated with end-tidal CO2 values of 35-40 mmHg.

After obtaining control ECGs, second and third ECG tracings were recorded at the first and third minutes of induction and also following the administration of mus-cle relaxant. The fourth ECG records were read 3 minutes after the injection of the muscle relaxant. Five minutes after intu-bation performed with a tube of appro-priate size, fifth ECGs were obtained. All patients’ heart rates (HRs), mean blood pressures (MBPs), peripheral oxygen satu-rations (SpO2), and end-tidal carbondi-oxide values (ETCO2) were recorded con-currently with ECG monitorization. Five minutes after anaesthesia induction, all measurements and calculations related to our study was finalized and the surgical intervention was initiated.

In the electrocardiograms, heart rates were calculated using mean RR time. The QT was defined as the interval between the beginning of QRS complex and mo-ment where T waves descend onto the TP isoelectric line. When a U wave interrupt-ed the T wave before returning to base-line, the QT interval was measured from the lowest point of the curve between the T and U waves. The QTc interval was calculated using Bazett formula; QTc (ms) = QT measured / √RR (where RR is the RR interval). Extended QTc interval was defined as duration of QTc lasting more than 440 ms.(5)

Subjects who had less than nine deriva-tions assessed in their ECGs were

exclud-ed from the study. All ECG measurements were evaluated three times by two experts who were blind to the allocation of the groups, and the mean values accepted. Statistical Package for the Social Sciences (SPSS) 11.5 was used in the analysis of data. Mann Whitney-U test was used for the comparative analyses of patients’ age, weight, QT and QTc intervals, HRs, MAPs, ETCO2, SpO2 values, Wilcoxon test to com-pare intragroup repeated measures; and chi-square test for the comparison of data used in the frequency distribution charts such as gender. Numerical data were given as median (min.-max.). Categorical variables were shown as percentages (%). A value of p<0.05 was considered as a sig-nificant difference.

Using previously published data about statistical evaluation of QTc values(1,6,7) _for the interpretation of an effect in either direction, at a significance level of 0.05 and power of 80 %, a sample size of 19 per group was deemed to be appropri-ate.

RESULTS

Groups were similar in terms of gender distribution, age and weight (Table I). There was no significant difference in terms of variations in mean heart rates among groups (p>0.05). When intragroup variations in HRs were analyzed, it was observed that in Group S, HRs measured 3 minutes after induction (p<0.001) and 3 minutes after the administration of muscle relaxant (p=0.018) were significantly low-er compared to the control values (Tab-le II). Similarly in Group P, HRs recorded 1 (p=0.004), and 3 minutes (p<0.001) af-ter induction and 3 minutes afaf-ter the

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ad-ministration of muscle relaxant (p<0.001) were significantly lower compared to the control values (Table II).

A significant difference in terms of mean arterial pressure variations among groups could not be found either (p>0.05). When Table I. Demographic data of groups.

Age (year) (Median), (min-max).

Group S (n=20)

Sex (F / M) (n)

8.00 (3.5-13) 12 / 8 Weight (kg) (Median), (min-max). 24.00 (15-57)

Group P (n=20) 8.0 (3-13) 11 / 9 30.00 (15-48) F: Famele M: Male Min: minumum Max: maximum

Table II. Heart rate values of groups (beats min-1_{), (Median), (min-max).}

Control Group S (n=20) Induction 1 min 101.00 (78-118) 98.50 (75-115) † Induction 3 min 92.50 (66-124) † Group P (n=20) 103.50 (84-123) 97.00 (78-119) ‡ 89.00 (75-114) ‡

Induction 1 min: 1 minute after anesthesia induction Induction 3 min: 3 minute after anesthesia induction

Muscle relax 3 min: 3 minute after muscle relaxation (vecuronium) Intubation 5 min: 5 minute after endotracheal intubation

† p<0.05 (compared control value in Group S), Wilcoxon test ‡ p<0.05 (compared control value in Group P), Wilcoxon test Min: minumum

Max: maximum

Muscle Relax 3 min 90.50 (74-128) †

Intubation 5 min 98.00 (85-126)

90.50 (80-115) ‡ 100.50 (84-118)

Table III. Mean arterial pressure values of groups (mmHg), (Median) (min-max).

Control Group S (n=20) Induction 1 min 78.00 (64-102) 76.00 (61-91) Induction 3 min 69.50 (53-81) † Group P (n=20) 80.50 (65-115) 74.50 (61-106) ‡ 67.00 (55-84) ‡

Max: maximum

Muscle Relax 3 min 72.00 (56-94) †

Intubation 5 min 76.50 (59-99)

69.50 (60-82) ‡ 80.00 (66-102)

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intragroup variations in MAPs were ana-lyzed, it was observed that in Group S, mean arterial pressure values 1 (p=0.002), 3 minutes (p=0.002) after after induction and 3 minutes after the administration of muscle relaxant (p=0.005) were signifi-cantly lower compared to the control va-lues (Table III). Similarly in Group P, MAPs measured 1 (p=0.006), and 3 minutes (p=0.001) after inductionand 3 minutes after the administration of muscle rela-xant (p=0.001) were significantly lower

compared to the control values (Table III).

During the study, no patients required at-ropine or ephedrine.

The statistical analyses among and within groups revealed no significant difference in terms of variations in SpO₂ and ETCO₂ (p>0.05).

All patients included in the study had si-Table IV. QT interval values of groups (ms), (Median), (min-max).

Control Group S (n=20) Induction 1 min 320.00 (251-367) 327.00 (271-373) Induction 3 min 352.00 (300-406) † Group P (n=20) 311.00 (273-380) 300.00 (273-394) 329.50 (296-379) ‡

Max: maximum

Muscle Relax 3 min 363.00 (312-395) †

Intubation 5 min 357.00 (302-386) †

343.00 (298-386) ‡ 345.00 (286-392) ‡

Table V. QTca_{interval values of groups (ms), (Median), (min-max).}

Control Group S (n=20) Induction 1 min 414.00 (380-435) 421.00 (379-496) Induction 3 min 424.50 (386-498) * Group P (n=20) 413.50 (368-448) 411.00 (344-466) 408.50 (364-462)

* p < 0.05 (between Group S and Group P), Mann Whitney U test † p < 0.05 (compared control value in Group S), Wilcoxon test ‡ p < 0.05 (compared control value in Group P) , Wilcoxon test

a QTc reflects the heart rate adjusted QT interval by using Bazett’s formula. Min: minumum

Max: maximum

Muscle Relax 3 min 435.50 (378-485) †* Intubation 5 min 441.50 (405-472) †* 418.00 (345-446) 421.50 (357-461) p 0.818 0.208 0.020 0.016 0.019

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nus rhythms. No patients had atrioven-tricular or bundle-branch blocks, atrial or ventricular premature beats.

Among the control ECG recordings of the groups, there was no significant dif-ference in terms of QT and QTc durations (p=0.914 and p=0.818, respectively). There was no significant difference in terms of QT variations among groups (p>0.05).

In Group S, where inhalation induction was performed using sevoflurane, QTc intervals in ECGs obtained 3 minutes after induc-tion (p=0.020), 3 minutes after the admin-istration of muscle relaxant (p=0.015) and 5 minutes after the intubation (p=0.018) were significantly longer than those in Group P where anaesthesia induction was performed with IV propofol (Table IV-V). When intragroup variations in QT dura-tions were analyzed, in Group S, QT inter-vals measured 3 minutes after induction (p=0.002), 3 minutes after the administra-tion of muscle relaxant (p=0.003) and 5 minutes after intubation (p=0.002) were significantly longer compared to the con-trol values (Table II). Similarly, in Group P, QT intervals observed 3 minutes after in-duction (p=0.049), 3 minutes after the ad-ministration of muscle relaxant (p=0.003) and 5 minutes after intubation (p=0.018) were significantly longer compared to the control values (Table IV).

When intragroup variations in QTc vals were analyzed, in Group S, QTc inter-vals recorded 3 minutes after the adminis-tration of muscle relaxant (p=0.007) and 5 minutes after intubation (p=0.001) were significantly longer compared to the con-trol values. In Group P, there was no

sig-nificant from the control values in terms of any ECG record times (p>0.05) (Table V).

DISCUSSION

In our study, we found that QTc intervals were significantly prolonged in the pae-diatric patients who received anaesthesia induction with sevoflurane rather than propofol.

Most anaesthetic agents affect the dura-tion of QT and QTc intervals. Halothane and isoflurane, which are frequently used inhalation anaesthetics during anaesthe-sia, prolong QTc interval.(1,7)_{In patients} with acquired, congenital or idiopathic long QT syndrome, the use of anaesthetics that prolong QT interval increases the risk of development of polymorphic ventricu-lar tachycardia and torsades de pointes. (6,8-11)_{In case reports, sevoflurane is held} re-sponsible for the development of torsades de pointes in cases with long QT syndrome. (12,13)

Experimental studies, focused on the effects of sevoflurane on QT interval, showed that sevoflurane prolongs action potential peri-od, QT and QTc intervals.(14-17)_{However, the} mechanism with which this effect works was not clearly explained. It was also emphasized that sevoflurane inhibits (I (Ks)) slow K(+) channels which are activated slowly in con-centrations used clinically but does not have an effect on fast (I (Kr)) potassium channels. (14-17)

However; the results of prospective con-trolled studies on the effects of sevoflu-rane on QT and QTc intervals in children are controversial.(7,9,18)_{Whyte et al.}(7) sho-wed that sevoflurane prolongs QTc in-terval compared to preoperative control

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values with irrespective of MAC values in children. However two studies found that sevoflurane was not cause of prolonged QTc duration in children.(9,18)_{In our study,} we found that there was a significant pro-longation in QT and QTc intervals when compared with control values during the induction performed with a concentra-tion of 8 % sevoflurane without nitrous oxide. We are in the opinion that the differences among the studies can be at-tributed to premedication status of chil-dren’s, sevoflurane concentrations that were used, nitrous oxide and adjuvant drugs and the duration of anaesthesia in which the study was carried out.

So far studies have focused on the effects of propofol on QT and QTc intervals with reaching any consensus.(8)_{In a case report,} it is stated that in a patient with idiopath-ic QT and QTd prolongation, propofol shortened the QT interval and QTd dura-tion.(19)_{It was emphasized that} anaesthe-sia was performed smoothly using total intravenous anaesthesia with propofol in patients with congenital long QT syn-drome.(20,21)_{In a study conducted with 60} children who were not premedicated, pro-pofol plasma concentrations of 3 µg mL-1_, 4,5 µg mL-1_{and 6 µg mL}-1_{were reportedly} had no effect on QTc. This study empha-sizes that propofol used in clinical doses does not affect myocardial repolarization in children and that propofol is a good choice in children with repolarization ab-normality.(8)_{Likewise, in our study,} propo-fol was not found to prolong QTc interval and in contrast it significantly shortened QTc interval when compared with control values recorded at specific times in our paediatric patients. Studies similar to ours which compare the effects of anaesthesia induction with propofol and sevoflurane on QT intervals are limited.(6)_{Whyte et}

al.(6)_{showed that, sevoflurane} significant-ly prolonged the QTc durations compared with the preoperative values. However they emphased that propofol did not prolonged QTc intervals when compared with the preoperative values.(6)

Similarly in our study, we found that QTc values were significantly prolonged in pa-tients who underwent sevoflurane induc-tion in comparison to the propofol group. Also we detected that the QTc duration was significantly prolonged in compari-son to control values in the sevoflurane group. We concluded that propofol could be first preference in the induction of anaesthesia in paediatric patients whose QTc intervals were found to be prolonged in the control ECGs.

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