Evaluation of pre-emptive intramuscular phenylephrine and ephedrine for reduction of spinal anaesthesia-induced hypotension during Caesarean section

Transcription

1 British Journal of Anaesthesia 86 (3): 372±6 (2001) Evaluation of pre-emptive intramuscular phenylephrine and ephedrine for reduction of spinal anaesthesia-induced hypotension during Caesarean section B. T. Ayorinde, P. Buczkowski, J. Brown, J. Shah and D. J. Buggy* University Department of Anaesthesia, University Hospitals of Leicester NHS Trust, Leicester General Hospital, Leicester LE4 5PW, UK *Corresponding author Pre-emptive intramuscular (i.m.) vasopressors were evaluated in 108 patients undergoing elective Caesarean section under spinal anaesthesia, assigned to four groups in a randomized, double-blind, placebo-controlled study. Group 1 received pre-emptive phenylephrine 4 mg i.m., group 2 received phenylephrine 2 mg i.m., group 3 received ephedrine 45 mg i.m., while controls received an i.m. injection of saline, all given immediately after induction of spinal anaesthesia. Hypotension was de ned as a 25% decrease in mean arterial pressure (MAP). Rescue intravenous (i.v.) boluses of ephedrine were given if the patient was hypotensive or reported nausea, vomiting or dizziness. The incidence of hypotension was 33% in the phenylephrine 4 mg group compared with 70% in the control and phenylephrine 2 mg groups (P=0.03), and 48% in the ephedrine 45 mg group. The phenylephrine 4 mg and ephedrine 45 mg groups had a signi cantly lower percentage reduction in MAP (±21 (SD 14)% and ±22 (14)%) compared with controls (±32 (18)%, P=0.04). They also had a lower total dose of rescue i.v. ephedrine (15.7 (15.7) mg and 15.8 (15.6) mg) compared with controls (28.8 (20.6) mg, P=0.02). We conclude that pre-emptive i.m. phenylephrine 4 mg and ephedrine 45 mg reduce the severity of hypotension and the total dose of rescue i.v. ephedrine during spinal anaesthesia for Caesarean section. Br J Anaesth 2001; 86: 372±6 Keywords: anaesthetic techniques, subarachnoid; anaesthesia, obstetric; sympathetic nervous system, pharmacology, ephedrine; sympathetic nervous system, pharmacology, phenylephrine Accepted for publication: November 1, 2000 The incidence of hypotension during spinal anaesthesia for Caesarean section is reported to be as high as 80%, despite uid preload, lateral uterine displacement and use of vasopressors. 1 Maternal hypotension is associated with the distressing symptoms of dizziness, nausea and vomiting, and may also interfere with the surgical procedure. 2 Lateral uterine displacement using a 15 tilt is essential in parturients to prevent the `supine hypotensive syndrome' whereby compression of the inferior vena cava by the gravid uterus leads to reduced venous return and subsequent hypotension. Although uid preloading is still widely used, its place in the management of hypotension induced by spinal anaesthesia has been questioned. 3 The management of choice of this common problem is the use of intravenous (i.v.) vasopressors as required. Ephedrine, an indirectly acting sympathomimetic amine, is probably the vasopressor of choice in obstetric anaesthesia. Although ephedrine has mixed a- and b-adrenoreceptor activity, it maintains arterial pressure mainly by increases in cardiac output (CO) and heart rate as a result of its predominant activity on b 1 - adrenoreceptors. 4 Phenylephrine, an a 1 -adrenergic agonist whose action would be expected to counteract the decrease in systemic vascular resistance induced by spinal anaesthesia, has been found to be safe and effective when given in bolus i.v. doses to patients undergoing Caesarean section. 5 The usual approach to the use of vasopressors in this clinical setting is reactive rather than proactive; spinal anaesthesia-induced maternal hypotension is allowed to develop and is then treated accordingly. Given the frequency with which it occurs, a more logical approach to its prevention may be the administration of pre-emptive vasopressors. Intramuscular (i.m.) ephedrine 37.5 mg has been found to be safe for the fetus; however, it is associated with a persistently high incidence of maternal hypotension. 6 The effect of ephedrine 45 mg i.m. has not been reported. No previous study has investigated the use of i.m. Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2001

2 Intramuscular vasopressors for spinal hypotension phenylephrine for the prevention of hypotension during spinal anaesthesia for Caesarean section, but it has been safely given via this route to healthy non-pregnant volunteers, including the elderly, in doses of 0.15 mg kg ±1 (up to 10 mg). 7 8 In this randomized, double-blind, placebocontrolled study, we have evaluated phenylephrine 2 mg and 4 mg i.m., in comparison with ephedrine 45 mg i.m. and saline, given immediately after induction of spinal anaesthesia, in terms of haemodynamic stability, requirement for rescue i.v. vasopressor therapy and neonatal umbilical cord ph values. Patients and methods After obtaining hospital Ethics Committee approval and written informed consent, we studied 108 women, ASA status I or II, undergoing elective Caesarean section under spinal anaesthesia. Known hypertensive patients or those with a resting arterial pressure greater than 160/90 mm Hg were excluded from the study. The patients were randomized by a coded, opaque, sealed envelope technique into one of four groups: group 1 received phenylephrine 4 mg i.m. (P4), group 2 received phenylephrine 2 mg i.m. (P2), group 3 received ephedrine 45 mg i.m. (E45), while group 4, the control group (C), received saline 0.9%. All study medication was made up to 2 ml with 0.9% saline and administered by an anaesthetist not involved in the care of the patient or collection of data. A second anaesthetist, blind to the identity of the study medication, managed the patient. Baseline non-invasive arterial pressure and heart rate readings were recorded at 1 min intervals by an automated non-invasive oscillometer (Criticon-DinamapaÈ) with data storage and printout facility, for 10 min before the start of the anaesthetic and continuing until surgery was completed. A 16-gauge i.v. cannula was sited in the non-dominant hand and 500 ml of Ringer's lactate solution given as a preload. Combined spinal±epidural anaesthesia (CSE) was instituted in the sitting position at L2±3 or L3±4, with a 26-gauge Sprotte spinal needle and 16-gauge Tuohy epidural needle, using a needle-through-needle technique. The i.m. injection of the study medication was given into the left vastus lateralis muscle immediately after the subarachnoid injection was completed. The time of i.m. injection was taken as time zero. The spinal injection contained 2.2 ml of 0.5% hyperbaric bupivacaine and fentanyl 20 mg, giving a total volume of 2.6 ml. The patient was then placed in the supine position, with a 15 left lateral tilt, after positioning of the epidural catheter to a depth of 3±4 cm in the epidural space. Block height was assessed with ethyl chloride spray at 5 and 15 min. Rescue i.v. bolus doses of ephedrine 6 mg were given if the patient became hypotensive or reported nausea, vomiting or dizziness. Hypotension was de ned as a 25% decrease in mean arterial pressure (MAP) from baseline, which was taken as the lowest MAP recorded in the 10 min before receiving the study medication. (The lowest MAP value was chosen to minimize the in uence of anxiety in patients with high initial MAP values.) The percentage change in MAP was calculated from the difference between baseline and the lowest recorded MAP, which occurred within the study period. The baseline heart rate was taken as the highest recorded heart rate before administration of the study drug. A printout of the haemodynamic data was obtained at the end of the operation. Neonatal Apgar scores at 1 and 5 min, and umbilical cord venous blood ph at delivery were also recorded. Top-ups for analgesia were not given via the epidural component of the CSE until the recording of data had been completed. The number of patients required for enrolment in the study was calculated prospectively by assuming an incidence of hypotension of 80% in the untreated control group. We took a 35% reduction in the incidence of hypotension as being clinically signi cant. Therefore, taking a=0.05 and b=0.2, n=27 patients were required in each group to demonstrate these differences. Haemodynamic data, timing and dose of ephedrine required, together with physical characteristics were compared using analysis of variance with Dunnet's post-hoc test for difference between the groups compared with control. Interval data (parity, dermatomal sensory levels, Apgar scores) were compared using the Kruskal-Wallis test. Categorical data (incidence of hypotension and incidence of use of rescue i.v. ephedrine therapy) were compared after constructing contingency tables and applying the chi-squared test or Fischer's exact test as appropriate. Data were analysed using GraphPad PrismÔ 2.0 on a personal computer running Microsoft Windows 98. A value of P<0.05 was considered statistically signi cant. Results All patients completed the study. Physical characteristics, baseline haemodynamic data and dermatomal sensory levels are given in Table 1. All groups were similar in terms of age, weight, parity, baseline haemodynamic data and dermatomal sensory levels. All the patients had adequate surgical anaesthesia. The incidence of hypotension is shown in Table 2. The incidence of hypotension was 33% in the phenylephrine 4 mg group, 48% in the ephedrine 45 mg group and 70% in the phenylephrine 2 mg group and control group. The incidence of hypotension was signi cantly lower in the phenylephrine 4 mg compared with controls (P=0.03). No patient in any group developed hypertension (MAP >25% increase from baseline) after the study medication. Figure 1 shows the percentage decrease in MAP. Patients who received phenylephrine 4 mg i.m. and ephedrine 45 mg i.m. had a signi cantly lower percentage reduction in MAP compared with controls and phenylephrine 2 mg i.m. (P=0.04). These two groups also required signi cantly lower doses of rescue i.v. ephedrine (P=0.02, Table 2). Patients in the phenylephrine 2 mg group required less rescue i.v. ephedrine than the control group, but this did not reach statistical signi cance (P=0.1). The incidence of 373

3 Ayorinde et al. Table 1 Patient characteristics, haemodynamic data and dermatomal sensory levels. Age, weight, MAP and heart rate are expressed as mean (SD). Parity and block height are expressed as median (interquartile range). There was no signi cant difference between the groups. MAP=mean arterial pressure; T=thoracic dermatome; P4=phenylephrine 4 mg; P2=phenylephrine 2 mg; E45=ephedrine 45 mg P4 group n=27 P2 group n=27 E45 group n=27 Control n=27 Age (yr) 30.1 (18±41) 31.3 (22±38) 30.0 (22±37) 30.7 Weight (kg) 81.5 (11.4) 79.8 (11.3) 74.8 (13.1) 76.8 (15.1) Parity 1.0 (0±2) 1.0 (0±2) 1.0 (0±1) 2.0 (1±2) Baseline MAP (mm Hg) 81.5 (9.3) 88.1 (13.3) 81.5 (10.5) 86.0 (12.1) Baseline heart rate (14.8) (15.9) (15.4) (13.1) Block height (5 min) T8 (T6±10) T7 (T5±8) T6 (T4±8) T8 (6±10) Block height (15 min) T4 (T2±4) T3 (T3±4) T4 (T3±5) T3 (T3±4) Table 2 Incidence of hypotension and requirement for rescue i.v. ephedrine, with dose and time to rst administration. Requirement of rescue i.v. ephedrine, with dose and time to rst administration are expressed as mean (SD). Incidence of hypotension is expressed as number (%). n=27 in each group. *P=0.02 for P4 and E45 compared with controls. **P=0.03 for P4 compared with controls. P4=phenylephrine 4 mg; P2=phenylephrine 2 mg; E45=ephedrine 45 mg P4 group P2 group E45 group Control Incidence of ephedrine requirement 21 (77%) 22 (81%) 21 (77%) 23 (85%) Dose of rescue i.v. ephedrine (mg) 15.7 (15.7)* 17.9 (15) 15.8 (15.6)* 28.8 (20.6) Incidence of hypotension 9 (33%)** 18 (70%) 13 (48%) 18 (70%) Time to rst ephedrine (min) 8.7 (7.6) 6.3 (4.7) 6.4 (6.1) 7.5 (4.8) Table 3 Neonatal data. Cord ph is expressed as mean (SD) and Apgar scores as median (range). There was no signi cant difference between the groups. P4=phenylephrine 4 mg; P2=phenylephrine 2 mg; E45=ephedrine 45 mg P4 group P2 group E45 group Control Cord ph 7.31 (0.06) 7.31 (0.04) 7.29 (0.08) 7.28 (0.09) Apgar score (1 min) 9 (9±9) 9 (8±9) 9 (9±10) 9 (9±9) Apgar score (5 min) 10 (9±10) 10 (9±10) 10 (9±10) 10 (9±10) Fig 1 Percentage decrease in MAP from baseline. Values are mean (SD). *P<0.05 in the P4 and E45 groups versus control. P4=phenylephrine 4 mg; P2=phenylephrine 2 mg; E45=ephedrine 45 mg; C=control; MAP=mean arterial pressure. patients requiring rescue i.v. ephedrine was high in all groups (77±85%), but was not different between the groups. The time to rst requirement for rescue i.v. ephedrine therapy was also similar between the groups (Table 2). There was no signi cant difference between the groups with respect to umbilical cord venous blood ph and Apgar scores (Table 3). The percentage change in heart rate (Fig. 2) did not show any signi cant difference between the groups. No patient developed bradycardia (heart rate <60 beats min ±1 ). Fig 2 Percentage increase in heart rate. Values are mean (SD). There was no signi cant difference between the groups. P4=phenylephrine 4 mg; P2=phenylephrine 2 mg; E45=ephedrine 45 mg; C=control. Discussion This is the rst report to our knowledge to show that phenylephrine 4 mg i.m. and ephedrine 45 mg i.m., given pre-emptively at induction of spinal anaesthesia for Caesarean section, reduce the severity of hypotension and the total dose of rescue i.v. ephedrine required compared with controls or phenylephrine 2 mg i.m. However, the incidence of the use of rescue i.v. ephedrine was not signi cantly different between the groups. The prevention and treatment of maternal hypotension associated with spinal anaesthesia for Caesarean section remains a dif cult problem, with no consensus as to the 374

4 Intramuscular vasopressors for spinal hypotension optimal mode of management. Hypotension is de ned arbitrarily in most studies, with values ranging from a 20±30% reduction from baseline systolic arterial pressures (SAP) to absolute values less than 90±100 mm Hg The incidence of hypotension clearly depends on its de nition and on the trigger for rescue ephedrine use. The trigger for rescue i.v. ephedrine use in our study was not only a 25% reduction in MAP, but also the presence of nausea, vomiting or dizziness which is the standard practice in our institution. Hence, we observed a high incidence of requirement for some rescue i.v. ephedrine therapy in all groups. However, our data demonstrated a reduction both in the severity of hypotension (in terms of percentage decrease in MAP) and the total dose of rescue i.v. ephedrine given. We chose the lowest MAP value in the 10-min stabilization period to allow anxious patients to settle and avoid spuriously high MAP values, which might have in uenced the baseline measurement. Measurement of SAP and MAP using non-invasive automated oscillometry has been found to be a valid method for non-invasive measurement of arterial pressure. 9 We chose MAP rather than SAP, as this is the component of arterial pressure that is most accurately determined by this method. Continuous invasive arterial pressure measurement is a more sensitive method of detecting hypotension, but is not usually indicated in a healthy population and would not be used in routine obstetric anaesthesia practice. In this study, we investigated the effect of i.m. vasopressors, given before the onset of hypotension, and found a therapeutically useful effect. We did not measure the effect of these agents on CO and derived systemic vascular resistance index (SVRI). However, this has been done in other studies. Phenylephrine effectively restores SAP, MAP and diastolic arterial pressure, but decreases heart rate and CO when given by infusion to patients undergoing elective surgery under spinal anaesthesia. 10 Another study found a 58% incidence of bradycardia (heart rate <60 beats min ±1 ) when phenylephrine was given as an i.v. bolus after the induction of spinal anaesthesia. 5 None of the patients in the present study developed bradycardia. This may have been because of the overriding chronotropic effect of ephedrine when it was given as a rescue vasopressor. Alternatively, the absence of bradycardia may have been because of a baroreceptor-mediated re ex tachycardia in response to the reduction in systemic vascular resistance after the induction of spinal anaesthesia. Metaraminol, another a- agonist, has also been shown to be effective in restoring SAP and SVRI within 10±15 min, when given by continuous infusion in an elderly population. 11 Ephedrine is not a potent arterial vasoconstrictor; it maintains SAP mainly by increases in CO and heart rate. 4 All groups showed an increase in heart rate. As expected, the greatest increase was in the group receiving ephedrine 45 mg (Fig. 2), which can be explained by its b 1 -adrenoreceptor activity. The place of i.v. vasopressors for treatment of hypotension during Caesarean section is well established. However, giving i.m. vasopressors before a spinal anaesthetic is more controversial because of concerns about reactive hypertension and adequacy of placental perfusion if the subarachnoid block fails. 14 We justi ed delaying the administration of i.m. vasopressors until the induction of spinal anaesthesia because of these concerns. A study comparing ephedrine 37.5 mg i.m., with placebo showed improved cardiovascular stability in the ephedrine group, but with a persistent 50% incidence of hypotension. 6 Sternlo and colleagues found ephedrine 0.6 mg kg ±1 i.m., was effective in reducing the incidence of hypotension in patients undergoing hip arthroplasty under spinal anesthesia. 15 In spite of the differing patient populations, this dose is consistent with the ndings in our i.m. ephedrine 45 mg group. Although, we have shown a reduction in the severity of spinal anaesthesia-induced hypotension with i.m. vasopressor therapy, there is still a persistently high incidence of hypotension. Perhaps earlier vasopressor administration or a larger dose may have reduced this further. The timing of i.m. drug administration to achieve optimum ef cacy can be unpredictable. Pharmacokinetic studies have suggested that the peak effect of i.m. phenylephrine or ephedrine is 10±15 min after administration. 16 The onset of subarachnoid block in this study occurred simultaneously with administration of the i.m. vasopressors, yet despite this, signi cant reductions in MAP were observed within a few minutes of establishment of the block. Nonetheless, we have demonstrated a reduction in the severity of hypotension, but no difference in the time to rst requirement for rescue i.v. ephedrine. This suggests that giving i.m. vasopressors immediately after the intrathecal injection is not too late to achieve a bene cial effect. In addition, no hypertension was observed 30 min after i.m. vasopressor administration, when a peak vasopressor effect might have been expected, because of the continuing in uence of spinal anaesthesia. There was no impact on the fetus of any of our vasopressor therapy regimes in terms of umbilical cord venous blood ph and Apgar scores, but we did not undertake neurobehavioural studies. In conclusion, we have shown that phenylephrine 4 mg i.m., and ephedrine 45 mg i.m., reduce the severity of hypotension and the total dose of rescue i.v. ephedrine therapy during spinal anaesthesia for Caesarean section. Further studies are warranted to determine the optimum dosage and timing of i.m. phenylephrine and ephedrine in terms of ef cacy and safety before they can be recommended for routine clinical use in obstetric anaesthesia. References 1 Rout CC, Rocke DA, Levin J, Gouws E, Reddy D. A re-evaluation of the role of crystalloid preload in the prevention of hypotension associated with spinal anesthesia for elective Cesarean section. Anesthesiology 1993; 79: 262±9 2 Pan PH, Moore C. Intra-operative antiemetic ef cacy of 375

5 Ayorinde et al. prophylactic ondansetron versus droperidol for Cesarean section patients under epidural anesthesia. Anesth Analg 1996; 83: 982±6 3 Jackson R, Reid JA, Thorburn J. Volume preloading is not essential to prevent spinal-induced hypotension at Caesarean section. Br J Anaesth 1995; 75: 262±5 4 Critchley LAH, Stuart JC, Conway F, Short TG. Hypotension during subarachnoid anaesthesia: haemodynamic effects of ephedrine. Br J Anaesth 1995; 74: 373±8 5 Thomas DG, Robson SC, Redfern N, Hughes D, Boys RJ. Randomized trial of bolus phenylephrine or ephedrine for maintenance of arterial pressure infusion during spinal anaesthesia for Caesarean section. Br J Anaesth 1996; 76: 61±5 6 Webb AA, Shipton EA. Re-evaluation of i.m. ephedrine as prophylaxis against hypotension associated with spinal anaesthesia for Caesarean section Can J Anaesth 1998; 45: 367±9 7 Korkuschko OW, Sarkisow KG, Schatilo WB, Moros GS, Mistrjokow WM, Tarasenko OB. Hemodynamic effects of stimulation of alpha 1-adrenoreceptors in healthy elderly and aged persons. Z Gerontol 1992; 25: 88±93 8 Korkushko OV, Fedirko MI, Shatilo VB, Mistriukov VM. Analysis of the effect of the alpha 1-adrenostimulator mezaton on plasma renin activity in healthy people of varying age. Fiziol Zhurnal 1991; 37: 25±30 9 Hutton P, Dye J, Prys-Roberts C. An assessment of the Dinamap 845. Anaesthesia 1984; 39: 261±7 10 Brooker RF, Butterworth JF, Kitzman DW, Berman JM, Kashtan HI, McKinley AC. Treatment of hypotension after hyperbaric tetracaine spinal anesthesia. A randomized, double-blind, crossover comparison of phenylephrine and epinephrine. Anesthesiology 1997; 86: 797± Critchley LAH, Conway F. Hypotension during subarachnoid anaesthesia: haemodynamic effects of colloid and metaraminol. Br J Anaesth 1996; 76: 734±36 12 Chan WS, Irwin MG, Tong WN, Lam YH. Prevention of hypotension during spinal anaesthesia for Caesarean section: ephedrine infusion versus uid preload. Anaesthesia 1997; 52: 908±13 13 Hall PA, Bennet MP, Wilkes MP, Lewis M. Spinal anaesthesia for Caesarean section: comparison of infusions of phenylephrine and ephedrine Br J Anaesth 1994; 73: 471±4 14 Rout CC, Rocke DA, Brijball R, Koovarjee RV. Prophylactic intramuscular ephedrine prior to Caesarean section. Anaesth Intens Care 1992; 20: 377±8 15 Sternlo JE, Rettrup A, Sandin R. Prophylactic ephedrine in bupivacaine spinal anaesthesia. Br J Anaesth 1995; 74: 517±20 16 ABPI Compendium of data sheets and summaries of product characteristics 1999±2000. London: Datapharm Publications,