Efficacy of premixed versus sequential administration of clonidine as an adjuvant to hyperbaric bupivacaine intrathecally in cesarean section.

BACKGROUND: Density of the drugs injected intrathecally is an important factor that influences spread in the cerebrospinal fluid. Mixing adjuvants with local anesthetics (LA) alters their density and hence their spread compared to when given sequentially in seperate syringes. AIMS: To evaluate the efficacy of intrathecal administration of hyperbaric bupivacaine (HB) and clonidine as a mixture and sequentially in terms of block characteristics, hemodynamics, neonatal outcome, and postoperative pain. SETTING AND
DESIGN: Prospective randomized single blind study at a tertiary center from 2010 to 2012.
MATERIALS AND METHODS: Ninety full-term parturient scheduled for elective cesarean sections were divided into three groups on the basis of technique of intrathecal drug administration. Group M received mixture of 75 μg clonidine and 10 mg HB 0.5%. Group A received 75 μg clonidine after administration of 10 mg HB 0.5% through separate syringe. Group B received 75 μg clonidine before HB 0.5% (10 mg) through separate syringe. STATISTICAL ANALYSIS USED: Observational descriptive statistics, analysis of variance with Bonferroni multiple comparison post hoc test, and Chi-square test.
RESULTS: Time to achieve complete sensory and motor block was less in group A and B in which drugs were given sequentially. Duration of analgesia lasted longer in group B (474.3 ± 20.79 min) and group A (472.50 ± 22.11 min) than in group M (337 ± 18.22 min) with clinically insignificant influence on hemodynamic parameters and sedation.
CONCLUSION: Sequential technique reduces time to achieve complete sensory and motor block, delays block regression, and significantly prolongs the duration of analgesia. However, it did not matter much whether clonidine was administered before or after HB.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

There has been growing interest in obstetric anesthesia, particularly in subarachnoid space, in the use of combination of drugs which would reduce the individual dosages, thereby obtaining greater analgesic effect with a lower incidence of side effects. Various analgesic additives to local anesthetics (LA) can improve the quality of analgesia both intra- and postoperatively. Intrathecal clonidine is being extensively evaluated as an alternative to neuraxial opioids for control of pain and is free of at least some of the opioid related side effects.[1] It is known to increase both sensory and motor block of LA.[23]

Many factors contribute to the spread and action of anesthetic solution in vivo. These include temperature of the solution, patient position during and after spinal injection, pH and density of the solution, volume of the drug injected, and height of the patient.[4] We commonly mix adjuvants with hyperbaric bupivacaine (HB) in a single syringe before injecting intrathecally because of its ease of administration. This may alter the density of both the drugs, thus influencing their spread in the cerebrospinal fluid (CSF).[5]

We hypothesized that administering LA and the adjuvants separately in different syringes may minimize the effect of the changes in densities and pH of both the drugs, thereby producing their maximum effect. On reviewing the literature there was paucity of data comparing the sequential and premixed administration of α2-agonist with HB. Therefore, we designed the study to investigate the efficacy of sequential versus premixed administration of clonidine with HB for cesarean sections (CSs) in terms of block characteristics, maternal hemodynamic neonatal outcome, and postoperative pain.

MATERIALS AND METHODS

After approval by the Institutional Ethics Committee (HIHTU/HIMS/ETHICS/2012/61, dated 1/9/2012) and written informed consent, 90 parturient with singleton pregnancy, American Society of Anesthesiologists (ASA) I and II scheduled for elective CSs under subarachnoid block (SAB), were enrolled in this single blind prospective randomized controlled trial. Patient having severe pregnancy induced hypertension (PIH), intrauterine deaths or known fetal anomaly, contraindication to SAB, patients on cardiovascular medications, and those with history of hypersensitivity to clonidine and LA were excluded from the study. The patients were allocated to following three groups using computer generated random table numbers to receive the drugs either as a mixture or in a sequential manner.

Group M (control group) patients received mixture of 2 ml of 0.5% HB plus 75 μg clonidine intrathecally, prepared in a single syringe. Group A received 2 ml of 0.5% HB followed by 75 μg clonidine through a separate syringe. Group B received 75 μg clonidine followed by 2 ml of 0.5% HB through a separate syringe.

The two drugs used in our study were kept same throughout the study to avoid manufacturer's difference. HB used was HEAVY ANAWINTM® and clonidine used was CLONEONTM® manufactured by Neon Laboratories Limited, 28 Mahal Ind. Est., M. Caves Rd., Andheri (East), Mumbai, India.

Parturients were kept fasting orally for 8–10 h and were premedicated with oral ranitidine 150 mg at night and repeated in the morning prior to surgery. The patients were familiarized with the concept of visual analog scale (VAS) for pain assessment with 0 = no pain and 10 = worst possible pain. Patient's characteristics like age, weight in kg, and height in cm was noted.

In the operating room, a good intravenous access was secured and monitoring devices were attached such as electrocardiogram (ECG), pulse oximeter (SpO2), noninvasive blood pressure (NIBP), and heart rate (HR). Baseline parameters were recorded. Preloading was done with 15 ml/kg of lactated Ringer's solution intravenously 15-20 min before spinal block. Oxygen was supplemented through nasal prongs. Under all aseptic precautions SAB was administered with 23 G Quincke needle via midline approach in sitting position. Drug was injected in L3-L4 space over 30 se (including the time for change of syringe in sequential administration) and the patient was made supine. Fluid therapy was maintained with lactated Ringer's solution 10 ml/kg/h. An experienced anesthesiologist, who was unaware of the drug given, evaluated the spinal block and other physiological parameters.

Hemodynamic parameters were monitored at every 2 min for the first 20 min and then every 5 min subsequently till 75 min or till completion of surgery. Any episodes of hypotension (systolic blood pressure below 90 mmHg or a fall in blood pressure by more than 20% of baseline values) and bradycardia (HR <50 beats/min or even higher, if clinical signs and symptoms were associated) in 24 h was noted. Hypotension was treated with a rapid infusion of crystalloids (200 ml) and a bolus of ephedrine 5 mg intravenous if hypotension persisted. Bradycardia was treated with injection atropine 20 μg/kg intravenously.

The onset of sensory block was assessed by loss of pin prick. Dermatomal level was assessed every 2 min until stabilized and time to reach maximum block height was noted. Also time of regression to T10 dermatome and time when patient demanded first rescue analgesia was noted. Motor block was assessed by modified Bromage scale as follows; I - free movement of legs and feet; II- just able to flex knees with free movement of feet; III - unable to flex knees but with free movement of feet; and IV - Unable to move legs and feet. Onset of motor block was assessed by time to reach Bromage II. Time to achieve complete motor block and its regression to Bromage I was noted.

Sedation score was assessed intraoperatively and until 2 h postoperatively according to Ramsay sedation score (RSS) as follows level 1 - awake, anxious, agitated, restlessness; level 2- awake, tranquil, cooperative; level 3-responds to commands; level 4- asleep, brisk response to stimuli; level 5- asleep, sluggish response to stimuli; and level 6 - asleep, no response to stimuli.[6]

Intraoperative pain was checked whenever the parturient complained of any discomfort or pain during operation and expressed as visual analogue scale by the parturient. Side effects like nausea, vomiting, dry mouth, respiratory depression (respiratory rate <10 breaths/min, SpO2 <92%) were noted. Newborn's APGAR scores were determined by a pediatrician not otherwise involved in the study at 1, 5, and 10 min. Postoperatively any incidence of bradycardia, hypotension, nausea/vomiting, prolonged sedation, postdural puncture headache (PDPH) and neurological deficit were noted and managed accordingly. Assessment of block characteristics and hemodynamics were the primary outcome and the intraoperative side effects and postoperative pain are secondary outcome measures.

Statistical analysis

A sample size of 30 patients per group was required to achieve a power of 80% and a level significance of 0.05 to be able to detect a difference between the groups. It was based on the assumption that an increase in the mean duration of analgesia by 60 min will be considered clinically significant. Interpretation of the data was analyzed using softwares Microsoft Excel and Statistical Package for Social Sciences (SPSS) version 19. Groups were compared using analysis of variance (ANOVA) with the Bonferroni multiple comparison post hoc test. The proportion of adverse effects was compared using Chi-square test and level of sedation was compared by Kruskal-Wallis H test. The level of significance was denoted as P < 0.05 - significant and P < 0.01 - highly significant.

RESULTS

All the groups were similar with respect to patient characteristic data, ASA physical status, and duration of surgery [Table 1]. The mean onset time of sensory and motor block and the highest level of sensory block achieved was comparable in all groups [Table 2]. Patients receiving clonidine sequentially (group A and B) took significantly less time to reach maximum sensory block height and complete motor block than in mixed group (group M). However it was comparable in group A and B. The total duration of analgesia lasted significantly longer in group B (474.3 ± 20.79 min) and in group A (472.50 ± 22.11 min) as compared to Group M (337 ± 18.22 min) (P < 0.001) [Table 2]. The resolution time of motor block back to Bromage I was significantly longer in Group A (288.67 ± 15.47 min) and in Group B (292.23 ± 15.24 min) than in Group M (189.50 ± 16.31 min) (P < 0.001) [Table 2]. Regression time of sensory block to T10 was also significantly longer in sequential groups compared to mixed group [Table 2].

Table 1

Patients’ demographic profiles

Table 2

Comparison of characteristics of sensory and motor block

Hemodynamic parameters showed a significant fall in HR among the groups after 8 min of giving SAB (P = 0.016) with the lowest values seen after 45 min of the administration of SAB [Figure 1]. There was an overall trend of fall in systolic blood pressure (SBP) and diastolic BP (DBP) in all the groups, except during the time intervals of 20 and 25 min (during delivery of baby) where there was rise [Figure 2]. The falling trend of blood pressures was more in the Group A and B than in group M. There was a fall in the mean arterial blood pressure from baseline to around 14% in Group M, 19% in Group A, and 18% in Group B; but was statistically insignificant (P = 0.345).

Figure 1

Trend line showing heart rates at different time interval

Figure 2

Trend line showing systolic and diastolic blood pressure at different time intervals

Incidence of intraoperative hypotension, bradycardia, respiratory depression, nausea/vomiting, dry mouth, and additional analgesic requirement were comparable in all the three groups [Figure 3]. There was no noticeable fall in the SpO2 in all the groups. Majority of patients had sedation scores 2 and 3 (interquartile range (IQR) =3.00 in all groups). One patient in group M, two in group A, and three in group B had sedation score of 4 [Figure 4]. One patient in Group M and two patients each Group A and B experienced nausea. None of the patients had respiratory depression and dry mouth, and none of them needed additional analgesic intraoperatively.

Figure 3

Incidence of intraoperative adverse effects

Figure 4

Incidence of sedation according to Ramsay sedation score

Postoperatively, 3% parturient experienced PDPH in Groups M and B which was not statistically significant. None of the patients had any other complications in the postoperative period.

DISCUSSION

Clonidine, an alpha-2 agonist when coadministered with HB intrathecally not only increases the duration of analgesia but also improves the quality of block.[78] The optimal dose in adults in terms of effects versus side effects of intrathecal clonidine by itself is controversial.[9] In the dose range of 150-450 μg, clonidine causes marked sedation and because of this clinically relevant side effect, there is a tendency toward the use of smaller doses (<150 μg).[10] Clinical research using clonidine in the dose range of 15-75 μg, however, has focused primarily on intrathecal use.[11] A recent study by Singh et al., on intrathecal clonidine with HB in lower segment CS (LSCS) showed that a dose of 75 μg of clonidine increased the duration of analgesia significantly without an increase in maternal side effect.[12] Similarly van Tuijl et al., demonstrated that addition of 75 μg clonidine to HB prolongs spinal analgesia and the motor block in CS without clinically relevant maternal or neonatal side effects.[13] Therefore, we used 75 μg clonidine and found that it helps achieving a faster block and longer duration of action without worrisome hemodynamic variability or side effects.

A number of factors affect the spread of drug in the CSF. Imbelloni et al., conducted a study involving assessment of the densities of LA and their combination with adjuvants. They stated that relative density of a LA in relation to that of CSF is one of the most important physical properties that affect the level of analgesia obtained after subarachnoid administration of the drug.[14]

Richardson and Wissler studied mean CSF densities in pregnant and non-pregnant humans and found out that CSF density in term pregnant females at 37°C is 1.0030 ± 0.00004 (mean ± standard deviation (SD) g/ml). At 37°C; morphine, sufentanil, and clonidine are hypobaric in relation to CSF.[15] The densities of the drugs that we used in this study (HB and clonidine) were 1.0260 and 0.9930, respectively. The density of the mixture of 2ml (10 mg) of HB and 0.5 ml (75 μg) clonidine was estimated to be 1.0189. In this study, we wished to investigate whether the inrathecal administration of clonidine and HB through two seperate syringes would improve the block characteristics without increasing the side effects.

Desai et al., administered HB with fentanyl and morphine in a sequential manner. They hypothesized that HB and hypobaric morphine and fentanyl produce the maximal effects at their original densities. Mixing them reduces the spread of morphine intrathecally and also reduces the duration of analgesia.[5] Sequential administration allows the drugs to take their own course of spread and subsequently the expected action.

In our study, the onset time of sensory and motor block and the time to reach maximum sensory block height and complete motor block was less in Group B followed closely by Group A. It was more in group M. This may be because of the fact that baricity of both drugs was better maintained when given sequentially. Mixing of the drugs alters the density and distribution of drugs and thus reduces their effect. On comparing group A with group B, in which clonidine was administered after and before HB, no statistical difference was found.

The sequential groups also showed the advantage of delayed sensory block regression and motor block resolution than the mixed group. Statistical analysis showed a significant difference when Group M was compared to Group A and B, while there was no significant difference between Groups A and B.

Similarly the mean duration of analgesia lasted longer in groups A and B in which drugs were given sequentially. Furthermore, clonidine given before HB improves the duration of analgesia as compared to clonidine given after HB, but not significantly.

Gray et al., studied the effect of administering intrathecal morphine with normal saline (hypobaric) and with dextrose saline (hyperbaric).[16] They found that the duration of analgesia after thoracotomy was prolonged when morphine was injected with normal saline He inferred that dextrose in a HB solution slowed the movement of morphine molecules in the CSF, reducing the exposure of supraspinal centers to morphine. Clonidine also being a hypobaric drug acting on both spinal and supraspinal receptors, might exhibit similar properties when administered with or without HB.[17]

Clonidine decreases HR by a presynaptic mediated inhibition of norepinephrine release and by a direct depression of atrioventricular nodal conduction after systemic absorption.[18] In our study we observed a significant difference in the fall in HRs when Group A and B were compared to Group M (P < 0.001). The maximum fall in the HR when compared to the baseline was 28% in Group B; whereas, it was 23% in Group A, and it was only 13% in Group M. In our study two patients in Group A had bradycardia and were managed with injection atropine 20 μg/kg intravenous.

A similar observation made by Baker et al., who in 2004 postulated that isobaric clonidine causes a more pronounced decrease in HR than hyperbaric clonidine.[18]

Hemodynamic effects of clonidine begin after 30 min of neuraxial or systemic administration, reaches maximum within 1-2 h, and last approximately 6-8 h after a single injection.[19] Maternal hypotension, the most frequent complication of spinal anesthesia, can be associated with severe nausea and vomiting which can pose risk to mother and baby. A number of strategies are followed to reduce the incidence of hypotension. Preloading and coloading is done with crystalloids and colloids. Among the vasopressors phenylephrine is the most effective and safe vasopressor for CS.[20] Left uterine displacement by inserting a wedge under the right lower back and physical interventions such as leg wrapping to minimize venous pooling of blood in the legs can be done.[2122]

We observed hypotension in 13% patients each in Group M and A, and 16% patients in Group B. Neither was the difference among the groups statistically significant nor was this incidence clinically important as vasopressors were needed for only 1, 4, and 3% parturients in Groups M, A, and B, respectively. In a study done by Yurtlu et al., spinal anesthesia performed with 10 mg of HB, isobaric bupivacaine, or a sequential injection in half doses of a hyperbaric-isobaric bupivacaine combination did not cause a difference in hypotension frequency.[23]

Clonidine produces sedation and analgesia by its action on spinal cord and locus ceruleus. Analgesia produced by clonidine is both because of sympatholysis at peripheral level and due to decrease catecholamine release in brain.[10] In our study, sedation provided by intrathecal (IT) clonidine (RSS 2 and 3) irrespective of the technique used, was acceptable and beneficial owing to its anxiolytic role. It decreased the requirement of additional intravenous drugs.

None of the patients needed any additional analgesics during the intraoperative period and the quality of anesthesia experienced by the patient and judged by the surgeon was excellent in all the groups. The APGAR scores in our study were statistically similar in all the three groups at 1, 5, and 10 min time intervals.

The limitation of our study was that we did not measure the temperature of drugs when injected, which also affects the spread of drugs in CSF. Secondly, it was impossible to blind the operator giving spinal block. One of the drawbacks of sequential administration is spillage of drugs while changing the syringes which was minimized by reducing the time of change over. The strength of the study were performance of surgery by one or two consultants of similar experience and the data collection was done by single blinded investigator.

We concluded that sequential administration of clonidine reduces the time to achieve complete sensory and motor block, delays both sensory block regression and motor block resolution, and significantly prolongs the total duration of analgesia. Addition of clonidine to HB provided a dense surgical anesthesia irrespective of the technique of administration. Sequential technique did not have any effect on level of sedation and incidence of hypotension or bradycardia as compared to the administration of mixture of clonidine and HB. Newborn's outcome also remained unaffected.

We also observed that, although the sequential technique offered certain benefits as compared to mixed drug administration technique, it did not matter much whether clonidine was administered before HB or after that.