Gztepe Tp Dergisi 27(1):22-29, 2012 doi:10.5222/J.GOZTEPETRH.2012.

022

ISSN 1300-526X

KL NK ARATIRMA

Anesteziyoloji ve Reanimasyon

Comparison of intrathecal hyperbaric bupivacaine and levobupivacaine with fentanyl for caesarean section
Dilek Suba (*), Osman Eknc (*), Yldz Kuplay (*), Tolga Mftolu (**), Berna Terzolu (***)
SUMMARY Background: Use of levobupivacaine as pure S(-) enantiomer of bupivacaine is progressively increased due to lower cardiotoxicity and neurotoxicity and shorter motor block duration.. The aim was to compare the efficacy of lower dose local anesthetics use together with higher opioid dose to decrease side effects of drugs. We compared sensorial, motor block levels and side effects of equal doses of hyperbaric bupivacaine and levobupivacaine with intrathecal fentanyl addition in elective caesarean cases. Methods: After hospital ethics committee approval and getting written informed consent from patients, eighty patients with ASA I-II aged 18-45 were included in the study. They were randomized to either Group BF receiving 7.5 mg (1.5 ml) hyperbaric bupivacaine and 25 mcg (0.5 ml) fentanyl, or Group LF receiving 7.5 mg (1.5 ml) hyperbaric levobupivacaine and 25 mcg (0.5 ml) fentanyl. Results: ASA II cases were higher in Group LF. Hemodynamic parameters such as 45th min mean arterial pressure of Group BF was found to be lower (p<0.05). Max. motor block level, motor block level, found to be higher in Group BF (p<0.05). In Group LF, max sensorial block level and postoperative VAS scores were higher (p<0.05). Arterial blood gas PCO2 was higher and PO2 was lower in Group BF (p<0.05). Onset of motor block time, time to max motor block, time to T4 sensorial block, reversal of two dermatome, first analgesic need were similar in both groups. Conclusion: Intrathecal hyperbaric levobupivacaine-fentanyl combination is good alternative to bupivacaine-fentanyl combination in cesarean surgery as it is less effective in motor block, it maintains hemodynamic stability at higher sensorial block levels. ZET Sezaryende intratekal fentanil ilavesi ile birlikte hiperbarik bupivakain ve levobupivakainin karlatrlmas Ama: Bupivakainin saf S (-) enantiyomeri olan levobupivakainin kullanm daha az kardiyotoksisite ve nrotoksisitesi ile daha ksa motor blok sresi olmas nedeniyle giderek artmaktadr. almann amac, ilalarn yan etkileri azaltmak iin daha yksek opioid dozu ile birlikte dk doz lokal anesteziklerin etkinliini karlatrmaktr. Elektif sezaryen olgularnda intratekal fentanil ilavesi ile eit dozlarda hiperbarik bupivakain ve levobupivakainin duyusal, motor blok seviyesi ve yan etkilerini karlatrdk. Yntem: Hastane etik kurul onay ve hastalardan yazl bilgilendirilmi onam alndktan sonra 18-45 ya, ASA I-II olan seksen hasta almaya dahil edildi. Hastalar 7.5 mg (1.5 ml) hiperbarik bupivakain ve 25 mcg (0.5 mL) fentanil alan Grup BF ya da 7.5 mg (1,5 ml) hiperbarik levobupivakain ve 25 mcg (0.5 mL) fentanil alan Grup LFye randomize edildi. Bulgular: ASA II vakalar Grup LFde daha fazlayd. Grup BFde 45. dk. ortalama arter basnc gibi hemodinamik parametrelerinin daha dk olduu tespit edildi (p<0.05). Maks. motor blok seviyesi, motor blok seviyesi Grup BFde daha yksek bulundu (p<0.05). Grup LFde, maksimum duyusal blok seviyesi ve postoperatif VAS skorlar daha yksekti (p<0.05). Grup BFde arter kan gaz PCO2 deeri yksek ve PO2 daha dkt (p <0.05). Motor blok balama sresi, maksimum motor bloa ulama sresi, T4 duyusal bloa ulama sresi, iki dermatomda gerileme ve ilk analjezi ihtiyac her iki grupta da benzer bulundu. Sonu: ntratekal hiperbarik levobupivakain-fentanil kombinasyonu sezaryenda daha az motor blok etkisi olmas nedeniyle bupivakain-fentanil kombinasyonuna iyi bir alternatiftir, daha yksek duyusal blok seviyelerinde hemodinamik stabilite salar. Anahtar kelimeler: Bupivakain, levobupivakainin, fentanil, spinal anestezi, sezaryen

Key words: Bupivacaine, levobupivacaine, fentanyl, spinal anesthesia, caesarean section

Spinal and epidural administration of local anesthetics during caesarean section produce analgesia,

anesthesia and motor block, depending on the volume, concentration, and doses of drug used (1,2).

Geli tarihi: 09.02.2012 Kabul tarihi: 27.02.2012 Haydarpaa Numune Research and Training Hospital Department of Anesthesiology and Reanimation*; Haydarpaa Numune Research and Training Hospital Department of General Surgery**; Haydarpaa Numune Research and Training Hospital Pharmacology and Toxicology Unit***

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D. Suba ve ark., Comparison of intrathecal hyperbaric bupivacaine and levobupivacaine with fentanyl for caesarean section

For the local anesthetics selection, it is known that the agents onset and duration of action, sensorial block level to motor block level and cardiac toxicity should be considered. 0.5 % heavy bupivacaine is more commonly used for spinal anesthesia for Caesarean section (3). Levobupivacaine, being the S enantiomer of bupivacaine, is less cardiotoxic and less neurotoxic in cases of accidental intravascular injection and has shorter duration of motor block than racemic bupivacaine, its use increased progressively (4,5). There is the clinical profile of potency for motor block for the pipecolylxlidines when administered spinally: low, intermediate, and high for ropivacaine, levobupivacaine, and bupivacaine, respectively (1,6). The use of low doses anesthetics and opioids in spinal anesthesia were reported to have advantages such as faster onset of action, better efficacy with minimum toxic effect and selective sensorial block (4). Fentanyl can be combined with local anesthetics for spinal anesthesia, and when used in this way it prolongs the duration of action and spread of sensory block as well (7). Fentanyl has been combined with bupivacaine for lower limb surgery and also for inguinal herniorrhaphy and caesarean section (7-10). We planned to compare the onset and duration of action, sensorial, motor block levels and side effects of equal doses of hyperbaric bupivacaine and levobupivacaine with intrathecal fentanyl addition in spinal technique in elective cesarean cases. Our aim was to compare the efficacy of low dose local anesthetics use together with higher opioid dose to decrease side effects of drugs. MaterIals and Methods This prospective double-blinded randomized study is performed in between February and December 2009. The study was approved by institutional ethics committee and patients provided written

informed consent before inclusion. The study was conducted in adherence with ICH/GCP and local regulations. Total of eighty patients aged between 18-45 years, classified as ASA I-II and undergoing elective cesarean surgery were included in the study. Patients with history of allergy to any study drug, with any contraindication to regional anesthesia, pregnancy associated hypertension and placenta previa were not included in the study. The injector with the drug was prepared by the study coordinator according to software which was carefully designed to prevent duplicate injections. The injectors were numbered and given to the staff who did not know the content. Also, patients did not know which agent they were given. All patients were evaluated initially by medical history and a complete physical examination. No premedication was administered. After iv prehydration with 500 mL of 0.9 % isotonic NaCl infusion hemodynamic variables were monitored with ECG, systolic and diastolic blood pressure, cardiac heart rate and oxygen saturation (SpO 2). Mean arterial pressure (MAP) decrease of 30 % of MAP before block, accepted as hypotension. It was treated with 5 ml/kg fluid replacement and iv 5 mg ephedrine. Total ephedrine use was recorded. All cases in sitting position were administered 3 ml (60 mg) 2 % lidocaine infiltration anesthesia through L3-4 after disinfected with antiseptic solution. After infiltrating epidural space with resistance loss technique via 18 gauge Tuohy needle, intrathecal space is reached with 27 gauge spinal needle. They are randomized to either Group B receiving 7.5 mg (1.5 ml) hyperbaric bupivacaine (Marcaine; Zentiva) and 25 mcg (0.5 ml) fentanyl, or Group L receiving 7.5 mg (1.5 ml) hyperbaric levobupivacaine (Chirocaine, Abbott Laboratories) and 25 mcg (0.5 ml) fentanyl. After administration of drugs into intrathecal space, patients were placed in the supine position with left uterine displace23

Gztepe Tp Dergisi 27(1):22-29, 2012

ment and 10-150 elevation of the head of the bed. Surgery is started when sensorial block level reached T4. The hemodynamic parameters were monitored at 1st, 3rd and 5th min and recorded every 5 min until it had resolved. Sensorial-motor block was recorded at 1st, 3rd and 5th min and it was recorded every 15 min until reversal of motor block. Pin-prick test is used for sensorial block evaluation. Highest dermatome level as maximum sensorial block level, time duration to T 4 dermatome block after drug administration, time duration to onset of T4 sensorial block, sensorial block reversal time in two dermatome and time to first analgesic need were recorded as first analgesia time. The most frequently used measure of motor block is the Bromage scale. In this scale, the intensity of motor block is assessed by the patient's ability to move their lower extremities (0=Free movement of legs and feet; 1=Just able to flex knees with free movement of feet; 2=Unable to flex knees, but with free movement of feet; 3=Unable to move legs or feet). Onset of motor block is recorded as when Bromage scale is 1 after administration of local anesthetics, onset of highest motor block is recorded as time to reach highest scale of motor block, motor block time is recorded as time to complete termination of motor block, maximum motor block level is recorded as highest motor block scale that is reached. Duration of baby birth is recorded as time to clamping of umbilical cord after administration of local anesthetics. Operation duration is recorded as time until end of operation after administration of local anesthetics. Pain intensity was recorded during skin incision, uterus incision, and closure of periton, postoperative 30 min, and postoperative 60 min and when
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there is pain. In assessment of pain intensity, 10 cm visual analogue scale (VAS) is used. Before operation, VAS was explained to patients as; 0 no pain, 10 intolerable pain. During operation, in cases where analgesia was insufficient (VAS: 3-4), local anesthetics was applied and patients were excluded from the study in BF group. Newborn 1 min and 5 min apgar scores and umbilical vein blood gases were recorded. Side effects such as pruritus, nausea, vomiting, anxiety, respiratory depression, and headache were followed. Statistical analysis is performed by SPSS (Statistical Package For Social Sciences) for windows 17.0 program. All data were expressed as means, standard deviation, and frequency. Statistical significance was accepted as p<0.05. The comparisons between groups were tested using independent t-test. The comparisons within groups were tested using Fishers Exact Test and chi-square test. Results Demographical data of study population Total of eighty patients were included in the study. However, in two patients, due to insufficient regional anesthesia, additional local anesthetics were given and patient was excluded from the study as the doses were changed. No significant differences were detected among
Table 1. Demographical data of study population. Group LF Mean SD Age (year) Height (cm) Weight (kg) Gestational age (day) 28.754.41 160.906.66 76.4011.09 270.958.64 n (%) ASA I II 22 (55 %) 18 (45 %) Group BF Mean SD 29.213.98 160.164.42 74.749.98 271.746.33 n (%) 8 (21 %) 30 (79 %) P value 0.735 0.686 0.626 0.749 P value 0.048*

Group LF: 7.5 mg (1.5 ml) hyperbaric levobupivacaine and 25 mcg (0.5 ml) fentanyl, Group BF: 7.5 mg (1.5 ml) hyperbaric bupivacaine and 25 mcg (0.5 ml) fentanyl

D. Suba ve ark., Comparison of intrathecal hyperbaric bupivacaine and levobupivacaine with fentanyl for caesarean section

the groups with respect to age, weight, height, and gestational age. In Group BF, ASA II cases were higher (p<0.05), where there was no difference in Group LF (Table 1). Hemodynamic Parameters Basal heart rate of Group LF was 93.1014.14 rate/min and 89.2112.78 rate/min in Group BF. There was no significant difference between heart rate of groups both preoperatively and postoperatively (p>0.05). Preoperative mean arterial pressure of Group LF was 94.2014.33, and mean arterial pressure of Group BF was 91.6809.27. There was significant difference between mean arterial pressure (MAP) of groups at 45th min (p=0.017). MAP of Group LF (86.3008.80) was significantly higher than Group BF (79.3208.90). At other time measurements, there was no difference between MAP of groups (p>0.05; Figure 1).
100 95 90 85 80 75 70 65 60 55 50 1. min 3. min 5. min 10. min 15. min 20. min 25. min 30. min 35. min 40. min 45. min 60. min Preop Mean Arterial Pressure (mmHg)

ve 30th min and 60th min VAS distribution of groups were significantly different between groups (p<0.05; Figure 2). In Group BF, VAS with 0 was in 84 % of patients at postoperative 30th min measurement, in Group LF, VAS with 0 was in 41 % of patients, VAS was predominantly 0 (42 %) and 1 (37 %) at postoperative 60th min measurement in Group BF also.
1,4 1,2 0,8 0,4 0,2 0,0 Perition Closure Postop 30. min Postop 60. min 0,6 1,6

1,0

Group BF Group BM

Figure 2. Visual Analogue Scale scores of the groups.

Anesthesia determination parameters There was no statistically significant difference between groups at 1 st min motor block level (p>0.05), however 3rd and 5th min motor block levels were significantly different between groups (p<0.05; Table 2). The Bromage score at 3rd min in Group LF was predominantly 1 and it was 2 in Group BF. The Bromage score at 5th min was predominantly 2 in Group LF and 3 in Group BF.
Table 2. Motor block level of groups. Time Bromage score 0 1 2 0 1 2 3 1 2 3 Group LF n (%) 22 (55 %) 14 (35 %) 4 (10 %) 6 (15 %) 20 (50 %) 10 (25 %) 4 (10 %) 6 (15 %) 22 (55 %) 12 (30 %) Group BF n (%) 12 (32 %) 14 (36 %) 12 (32 %) 0 (0 %) 6 (15 %) 20 (53 %) 12 (32 %) 0 (0 %) 10 (26 %) 28 (74 %) P value

Grup K Grup P

Figure 1. Mean arterial pressure measurements of the groups.

SpO2 measurements were not different between groups (p>0.05). Visual Analogue Scale Postoperative VAS was found to be higher in Levobupivacaine group (Group LF; p<0.05). VAS of skin incision and uterus incision of all individuals in both groups were recorded as 0. There was no significant difference between periton closure VAS scores of groups. However postoperati-

1st min 3th min

0.178 0.015

5th min

0.015

Group LF: 7.5 mg (1.5 ml) hyperbaric levobupivacaine and 25 mcg (0.5 ml) fentanyl, Group BF: 7.5 mg (1.5 ml) hyperbaric bupivacaine and 25 mcg (0.5 ml) fentanyl

Max. motor block level and time to end of motor block were found to be higher in Bupivacaine (Group BF) group (p<0.05).
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Gztepe Tp Dergisi 27(1):22-29, 2012

Onset of motor block time, time to max motor block, time to T4 sensorial block, reversal of two dermatome, first analgesic need were similar in both groups (Table 3). Reversal of motor block was significantly different between groups, being mean value of Group BF was significantly higher than Group LF (p<0.05).
Table 3. Anesthesia determination parameters of groups. Group LF meanSD Onset of motor block (sec) Onset of maximum motor block (sec) Two dermatome regression (min) First analgesic need (min) Onset of T4 sensorial block (sec) Intrathecal injection birth (min) Operation (min) 135.0075.70 288.0068.41 89.8516.29 Group BF meanSD 97.8942.82 250.2685.59 82.7407.13 P value 0.069 0.136 0.089 0.245 0.279 0.079 0.899

Side effect distribution of groups are presented in Table 5 (p<0.05). Newborn apgar scores were similar in each group. The umbilical vein blood gas PCO2 was higher and PO2 was lower in bupivacaine group (p<0.05).
Table 5. Side effect distribution of groups. Group LF n (%) Hypotension Nausea Vomiting Ephedrine need Bradycardia Sedation Pruritus Headache 24 (60 %) 22 (55 %) 14 (35 %) 14 (35 %) 14 (35 %) 14 (35 %) 26 (65 %) 4 (10 %) Group BF n (%) 20 (53 %) 10 (26 %) 4 (11 %) 18 (47 %) 6 (16 %) 4 (11 %) 18 (47 %) 0 (0 %)

162.5537.30 173.0510.74 345.00134.69 304.26110.99 22.003.76 67.2012.87 19.1106.02 67.7413.39

Group LF: 7.5 mg (1.5 ml) hyperbaric levobupivacaine and 25 mcg (0.5 ml) fentanyl, Group BF: 7.5 mg (1.5 ml) hyperbaric bupivacaine and 25 mcg (0.5 ml) fentanyl

Group LF: 7.5 mg (1.5 ml) hyperbaric levobupivacaine and 25 mcg (0.5 ml) fentanyl, Group BF: 7.5 mg (1.5 ml) hyperbaric bupivacaine and 25 mcg (0.5 ml) fentanyl

DIscussIon Recent trends of obstetric anesthesia show increased popularity of regional anesthesia among obstetric anesthetists. General anesthesia is associated with higher mortality rate in comparison to regional anesthesia (11). Regional anesthesia has some risks; deaths are primarily related to excessive high regional blocks and toxicity of local anesthetics. Reduction in doses and improvement in technique to avoid higher block levels and heightened awareness to the toxicity of local anesthetics have contributed to the reduction of complications related with regional anesthesia (12). Over the last decade, spinal anesthesia has been refined with the addition of opioids to local anesthetic solutions. It was reported that use of only local anesthetics in cesarean operation under spinal anesthesia, is not sufficient in prevention of nausea and visceral pain during uterus manipulation and periton closure, short duration of action and has disadvantages such as early need for analgesia (1113). The addition of morphine significantly prolongs post operative analgesia to 18-24 h, whereas the more lipophilic opioid such as sufentanil and fentanyl improve and prolong intraoperative anal-

There was significant difference between maximum sensorial block levels between groups (p<0.05). In Group LF, sensorial block level was T2 and T4, in Group BF, it was T3 and T4 (Table 4). Sensorial block level distribution of groups at 1st, 3rd and 5th min were not different between group (p>0.05).
Table 4. Comparison of maximum block level of groups. Group LF n (%) Sensorial T2 T3 T4 T5 1 2 3 20 (50 %) 0 (0 %) 18 (45 %) 2 (5 %) 6 (15 %) 12 (30 %) 22 (55 %) Group BF n (%) 2 (6 %) 18 (47 %) 18 (47 %) 0 (0 %) 0 (0 %) 4 (11 %) 34 (89 %) P value

0.001

Motor

0.044

Group LF: 7.5 mg (1.5 ml) hyperbaric levobupivacaine and 25 mcg (0.5 ml) fentanyl, Group BF: 7.5 mg (1.5 ml) hyperbaric bupivacaine and 25 mcg (0.5 ml) fentanyl

There was significant difference between maximum motor block levels between groups (p<0.05). Besides, in group BF, max motor block level was predominantly 3 by Bromage score (Table 4).
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D. Suba ve ark., Comparison of intrathecal hyperbaric bupivacaine and levobupivacaine with fentanyl for caesarean section

gesia and reduce the amount of local anesthetics required to perform a sufficient dermatome spread and block intensity necessary for Caesarean section. By adding opioids to spinal anesthesia, a reduction in local anesthetic dose is possible. This reduction in local anesthetic requirements reduces the intensity and duration of motor blockade and allows patients to ambulate faster. Initial reports on low-dose spinal anesthesia suggest that this may also reduce maternal hypotension (14). Today, 0.5% heavy bupivacaine is most commonly used for spinal anesthesia for caesarean section (3). Recent studies have claimed successful anesthesia with very low doses of intrathecal bupivacaine (5-9 mg) when co administered with opiods (7,15,16). Kiran and Singal advocated the use of 7.5 mg bupivacaine for Caesarean section as this dose was associated with a decreased incidence of hypotension ,but again, a large number of patients rated the analgesic quality as poor (17). Ginosar et al. reported ED50 and ED95 of hyperbaric bupivacaine in cesarean section with combined spinal epidural technique is 7.6 mg and 11.2 mg, respectively (18). In our study, anesthesia was 95 % successful with 25 mcg fentanyl added to 7.5 mg hyperbaric bupivacaine. Only in two patients, it was not sufficient and local anesthetics were administered. Due to lower cardiovascular side effect and central nervous system toxicity, use of levobupivacaine as pure S(-) enantiomer of bupivacaine is progressively increased (5,19). Epidural levobupivacaine has the advantage of decreased cardio toxicity in cases of accidental intravascular injection (20). Parpaglioni et al reported minimum intrathecal levobupivacaine dose to be 10.58 mg in cesarean section (21). Alley et al evaluated three intrathecal doses of levobupivacaine and bupivacaine (4, 6 and 8 mg) in healthy volunteers and found no differences in clinical profile of sensory and motor blocks and recovery from spinal anesthesia (22). In some studies, levobupivacaine and racemic bupivacaine showed undistinguishable clinical profile in spinal anesthesia (23,24).

In selection of local anesthetics, it is desired that the agents onset of action is short, duration of action is longer and sensorial block level to motor block level is higher. Camorcia et al. reported that intrathecal 0.5 % levobupivacaine had weaker motor block potency than 0.5 % bupivacaine in elective cesarean cases with CSE anesthesia technique (6). Similarly Vercauterenet et al. performed a study on patients who received either 0.125 % levobupivacaine or 0.125 % racemic bupivacaine and found that levobupivacaine led to less motor impairment compared to racemic bupivacaine in intrathecal labor analgesia (25). In our study, levobupivacaine had lesser motor potency. Bromage score at 3rd and 5th min were 1-2 in levobupivacaine and 2-3 in bupivacaine. On the other hand, max sensorial block level was found to be higher in levobupivacaine group. In levobupivacaine group, T 2 was predominant at sensorial block, and in bupivacaine group, T 3 was more. Preoperative VAS scores were similar in both groups, whereas postoperative 30th and 60th min VAS scores were lower in bupivacaine group. Hypotension incidence in cesarean cases were reported to be 45 % and in its prevention, fluid replacement, left lateral decubitus position and use of vasoconstrictors were recommended (26,27). In our study, it was 60 % in levobupivacaine and 53 % in bupivacaine group. Sympathetic block due to supine position and patients head down position were probably affected in our study. Intrathecal opioids administration has side effects such as nausea, vomiting, pruritus, sedation, respiratory depression and urinary retention (28). Highly lipid soluble opioids cause temporary pruritus whereas intrathecal morphine causes long acting and intensive pruritus (28). In our study, pruritus incidence was higher in LF group, however it was not intense to be treated. There was significantly higher number of ASA II cases in group BF. This difference is due to inclusion of ASA II cases with respiratory system disor27

Gztepe Tp Dergisi 27(1):22-29, 2012

ders without requirement for any treatment which is a factor for regional anesthesia preference. It was reported that fentanyl or morphine added to intrathecal bupivacaine did not affect apgar score and newborn blood gas values in cesarean cases. Umbilical cord blood pH and acid-base balance is objective predictor of neonatal well-being (29). In our study, apgar score analysis was not significantly different between groups, umbilical vein pCO2 was higher in bupivacaine group and pO2 was lower. However these values were within normal ranges. Thus, we concluded that administration of green mask O2 support to all cases in cesarean cases with regional anesthesia will be better for newborns even though SpO2 values are within normal ranges. In the study of Bremerich et al. fixed doses of intrathecal hypertonic levobupivacaine 0.5 % (10 mg) and bupivacaine 0.5 % (10 mg) combined with either intrathecal fentanyl (10 and 20 microg), or sufentanil (5 microg) were compared in terms of sensory and motor block characteristics. However we compared lesser 7.5 mg hyperbaric levobupivacaine and 7.5 mg bupivacaine combined with higher fentanyl dose (25 mcg) than that was used in study of Bremerich et. al. (30). Also in the study of Gautier P et al, different doses than that of our study were used (24). Intrathecal 7.5 mg hyperbaric levobupivacaine and 25 mcg fentanyl combination is good alternative to 7.5 mg bupivacaine - 25 mcg fentanyl combination in cesarean surgery as it is less effective in motor block, but it maintains hemodynamic stability at higher sensorial block levels. Acknowledgement: We would like to thank Assistant Prof. Dr. Halil Turgut from Marmara University Educational Faculty for his statistical analysis support for the project.

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D. Suba ve ark., Comparison of intrathecal hyperbaric bupivacaine and levobupivacaine with fentanyl for caesarean section

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