| ||||||||||||||
|
|
|||||||||||||
From the Department of Anaesthesia, Monash Medical Centre, Victoria, Australia
Address correspondence and reprint requests to Adam P. Tucker, MBChB, DA, DRACOG, FANZCA, Department of Anaesthesia, Monash Medical Centre, 246 Clayton Road, Victoria 3168, Australia. Address email to adam.tucker{at}med.monash.edu.au
| Abstract |
|---|
|
|
|---|
IMPLICATIONS: Treatment of labor pain with epidural injections of local anesthetic is complicated by decreases in arterial blood pressure and leg weakness. This study showed that a mixture of two drugs, fentanyl and midazolam, could provide powerful pain relief when the drugs were given together spinally without such side effects.
| Introduction |
|---|
|
|
|---|
Although local anesthetic blockade is effective in the management of severe pain, it causes vasodilation and, subsequently, hypotension in the mother. Furthermore, the potential loss of lower limb and pelvic muscle power can affect the bearing down reflex and result in muscle relaxation, which require the use of oxytocin. As knowledge of the nociceptive processes in the spinal cord has grown, so too has the possibility of the use of regional analgesics other than local anesthetics. Such drugs that do not cause hypotension or muscle paralysis that have been advocated by some authors include morphine, pethidine, fentanyl, and sufentanil, as well as intrathecal fentanyl and sufentanil (6,7). However, neuraxial opioids may cause sedation, respiratory depression, nausea, emesis, pruritus, and in some circumstances may cause fetal compromise (8).
Novel intrathecal non-opioid drugs have therefore been investigated in the management of labor pain. Clonidine and neostigmine have both been studied. Clonidine has been shown to produce antinociception when administered intrathecally but it has also been associated with hypotension and sedation (9). The use of intrathecal neostigmine has been associated with nausea and vomiting (10). In the non-obstetric setting, intrathecal midazolam produced segmental antinociception in rats and humans, but published clinical experience with this drug given intrathecally is limited (1114).
Some of the preclinical literature has focused on the potential association between intrathecal midazolam and markers of neurotoxicity. Whereas the majority of these studies have not associated neurotoxicity with intrathecal midazolam (1520), some studies have described adverse effects in large proportions (up to half) of the subject animals studied (2124). The current clinical usage of intrathecal midazolam has therefore provided investigators the opportunity to determine whether this phenomenon occurs in patients or is primarily a preclinical laboratory finding. The results of a cohort study of 1100 patients investigating adverse neurological effects of intrathecal anesthesia with or without intrathecal midazolam has found no association between intrathecal midazolam and neurologic symptoms (25). Therefore, this study was conducted to investigate the efficacy of intrathecal midazolam. Specifically, this study tested the hypothesis that the administration of intrathecal midazolam causes potentiation of the analgesic effect of intrathecal fentanyl in laboring parturients. The term "potentiation" was used to describe the effect of a drug being increased by the concurrent action of another drug at a dose that does not have an effect alone. In additional, the incidence of adverse effects was assessed in the patients who received intrathecal midazolam in addition to fentanyl.
| Methods |
|---|
|
|
|---|
To optimize each patients ability to make an informed choice regarding entry into the trial, information regarding the trial was published in a booklet and given to all women attending antenatal classes. In the labor ward, only women with an accompanying adult were recruited to the study. The study was discussed and written information was supplied using language with a Flesch-Kincaid readability level of grade 10. A description of the serious risks of neurological damage was included. Written consent was obtained only after the information was read by both the parturient and the accompanying adult and a short time was allowed for both adults to discuss the study alone.
Each patient was randomized to receive either preservative-free intrathecal midazolam (Hypnovel 2 mg; Roche, Basel, Switzerland), fentanyl (Sublimase 10 µg; Janssen, Titusville, NJ), or both combined, as part of a CSE technique. The dose of fentanyl was chosen from earlier dose-response studies of its effect on labor pain (26,27). Ten micrograms of fentanyl was chosen because of its association with a modest analgesic effect and minimal side effects such as pruritus and nausea. Two milligrams of intrathecal midazolam was chosen because of a lack of adverse effects associated with its use as demonstrated by a large prospective cohort study (25).
Each parturient was hydrated with 500 mL of Hartmanns solution IV and placed in the sitting position. An 18-gauge Tuohy and a 27-gauge pencil-point spinal needle were used (CSEcure 100/491/718; Portex, Hythe, UK). The epidural space was located at the vertebral level of L2-3 or L3-4 using the loss of resistance to air technique. A single space needle-through-needle technique was used to position the tip of the spinal needle in the intrathecal space. After the free flow of cerebrospinal fluid had confirmed the intrathecal location, a single injection of the study drug was given slowly over 10 s. The study drug was diluted in normal saline to a total volume of 2 mL in all cases. After the intrathecal injection, the spinal needle was withdrawn and the epidural catheter was threaded 35 cm into the epidural space. The catheter was then flushed with 2 mL of normal saline over 10 s to prevent later catheter occlusion. The parturient was placed into the supine position with left uterine displacement once the epidural catheter had been secured. No analgesic or local anesthetic drugs were administered through the catheter until the patient requested supplemental pain relief.
Data were collected by a research assistant who, in common with the patient, was unaware of the nature of the study drug. Pain scores were recorded immediately before and at 5-min intervals after the intrathecal injection using a verbal 11-point numerical rating score (NRS) (0 = no pain, 10 = worst pain imaginable) and a 10 cm visual analog score (VAS) (0 mm = no pain, 100 mm = worst pain imaginable). The occurrence and severity of the side effects were assessed at the same times, in addition to 2 assessments (15 and 30 min after injection) of segmental changes in sensation to ice and alteration of motor function using a modified Bromage score published previously (28).
During this investigation, a blinded observer asked the patient to grade the intensity of nausea, pruritus, and headache using a four-point scale (0 = none, 1 = mild, 2 = moderate, and 3 = severe) after administration of the study drugs. The number of times a parturient vomited since the previous assessment was also recorded. In the event of vomiting or the presence of any of these symptoms, the patient was offered treatment. Sedation was rated by the observer using a four-point scale (1 = responds readily to name spoken in a normal tone, 2 = lethargic response to name spoken in a normal tone, 3 = responds only after name is called loudly or repeatedly, and 4 = responds only after mild prodding or shaking). The measurement of the parturients arterial blood pressure, heart rate, and respiratory rate was performed manually. Hypotension was defined as a systolic blood pressure <100 mm Hg or a 20% decrease from baseline and was treated with a fluid bolus and IV ephedrine as required.
Uterine contractions were monitored by external tocodynamometry and the FHR was monitored by external Doppler or fetal scalp clip. The cardiotocograph (CTG) was assessed by Fetal Monitoring Unit technicians who were unaware of the nature of the administered study drug. The CTG trace for 30 min after the intrathecal injection was examined. The definitions of CTG changes used by this unit were adopted unchanged for the purposes of this study. Therefore, a FHR of 120160 bpm was considered normal and baseline variability of
6 bpm was considered normal. Normal fetal reactivity was described as FHR accelerations of
15 bpm lasting for
15 s and occurring twice or more every 20 min. These were signs of fetal well being. Periodic changes that are commonly considered to signify hypoxia include late FHR deceleration (FHR <120 bpm) that occurs later than 10 s after the start of a contraction and within 30 s after the end of a contraction. Early FHR decelerations occur concurrently with uterine contractions and variable fetal heart rate decelerations are not apparently related to the timing of uterine contractions. The causes of these two patterns of decelerations are thought to be increased vagal tone coincident with fetal skull compression and umbilical cord compression respectively. Variable decelerations may be classified as mild (the FHR remains more than 80 bpm) and severe (FHR <60 bpm). Therefore, the occurrence of late FHR decelerations was chosen as the primary marker of fetal distress. The Apgar scores were measured by the attending midwife who was unaware of which study drug had been administered to the mother.
Patients were informed that the intrathecal injection might take as long as 15 min to reach its maximum effect. The patients participation was considered complete if she requested further pain relief after 15 min. The parturient was permitted to withdraw from the study at any time from the time of enrollment. On request for further analgesia, an epidural local anesthetic block was instituted using the indwelling epidural catheter and the patient was managed according to normal clinical routine for the remainder of her labor.
The parturients were examined for any neurological symptoms 2 days after the intrathecal injection. The presence of back, leg, or buttock pain, in addition to the presence of leg numbness or weakness, was assessed. Other symptoms, including urinary incontinence or difficulty emptying the bladder, faecal incontinence or difficulty emptying the bowel, anogenital numbness or burning, and the presence of a headache, were also sought. A telephone assessment was conducted 1 mo later to detect symptoms with a delayed onset and to monitor the course of symptoms that were present at 48 h.
Statistical calculations were conducted using SPSS for Windows (Release 10.0.7). The demographic and obstetric variables were presented as proportions or mean ± SD and were analyzed by one-way analysis of variance (ANOVA) and the
2 test as appropriate. The variation of rostral segmental sensory changes seen within each group was analyzed by grouping the number of parturients with sensory changes within evenly spaced dermatomal bands (T12-11, T10-9, T8-7, and T6-5) and testing the difference in the proportions between the study groups using the
2 test. The pain scores (NRS and VAS) were analyzed by nonparametric tests on all occasions. The data were expressed as medians and the interquartile range (25th75th percentiles). The correlation between the scores was tested with Spearmans rank correlation. The lowest median pain score recorded by a study group after the intrathecal injection was compared with the median baseline pain score of the same group using a single Wilcoxons signed-ranks test. The NRS recorded from the combination drug group and the fentanyl group was compared for the same time period using a single Mann-Whitney U-test. The time to request supplemental analgesia was analyzed with the Students t-test. The comparison of the changes in the cardiorespiratory variables between the intrathecal fentanyl group and the midazolam-fentanyl group were tested using one-way ANOVA. The occurrence of adverse effects were presented in a tabular form for the readers own consideration where the numbers of patients affected were small and were tested by the
2 test where the numbers were sufficiently large. The type I error rate was controlled by the Ryan-Holm step-down Bonferroni procedure where indicated. P
0.02 was regarded as statistically significant during the interim analysis.
| Results |
|---|
|
|
|---|
The groups did not differ with respect to age, weight, ASA physical status, parity, gestation, cervical dilation, or the proportion of patients in each group who received oxytocin (Table 1). A segmental sensory change to ice was unable to be determined in five patients (three in the fentanyl, one in the midazolam, and one in the combination group). There was no significant difference in the distribution of the segmental levels achieved among the patients in the three groups (P = 0.87).
|
|
The maximal reduction of NRS among the parturients who received midazolam monotherapy occurred 5 min after the intrathecal injection and was not statistically significant (Fig. 1). In contrast, the maximum decrease in NRS after fentanyl occurred after 10 min, and although it was highly statistically significant (P = 0.007), the extent of the decrease in the NRS was modest (5/10). Although the 2 mg of midazolam alone was ineffective, when it was added to fentanyl a large reduction of the NRS resulted after 10 min that was both statistically significant (P = 0.005) and clinically successful (2/10). Comparison of the fentanyl monotherapy group with the combination group showed that the pain relief score was significantly lower in the combination group after 10 min (P = 0.02). Consistent results were found when the subgroup that reported VAS data was studied using the same method. Specifically, midazolam given alone did not cause a significant decrease in VAS, and its combination with fentanyl reduced the VAS at 10 min more so than fentanyl alone (P = 0.01).
|
|
The addition of intrathecal midazolam to fentanyl did not confer any additional adverse effect as demonstrated by CTG trace and neonatal Apgar scores. Normal baseline variability was absent in 2 neonates (1 in the fentanyl group and 1 in the combination group; 95% confidence interval [CI], 0.170.19) and normal reactivity was absent for 9 (5 in the fentanyl group and 4 in the combination group; 95% CI, 0.500.42). Four neonates exhibited severe variable decelerations (3 in the fentanyl group and 1 in the combination group; 95% CI, 0.350.22). The number of neonates who were graded with the same Apgar scores was similar for both the fentanyl monotherapy group and the drug combination group (Table 3). All neonates scored 910 at 5 min after delivery.
|
One parturient reported persistent right leg pain and weakness subsequent to an antenatal fall, which resolved after 1 mo. A parturient who received intrathecal fentanyl alone recalled "sore legs" at the 1-mo assessment that had occurred for "a few days" postpartum before resolving spontaneously.
Several patients recalled leg numbness and weakness at the assessment 2 days postpartum. However these symptoms occurred in association with epidural local anesthetic infusions and all had resolved by the time of the assessment. A member of the fentanyl group reported de novo leg weakness at 1 mo, specifically, weakness of the toes bilaterally that made walking upstairs difficult. The symptoms resolved 12 mo later.
Bladder and bowel function were commonly affected. The most common complaint was constipation, which tended to resolve over time. After 1 mo, one parturient in each of the fentanyl and the combination groups had mild constipation. These symptoms resolved completely within 6 mo.
| Discussion |
|---|
|
|
|---|
Unfortunately, labor is commonly associated with neurological sequelae irrespective of the use of regional anesthesia. The birthing process is said to result in a 5-fold increase in neurological complications compared with the risk of neurological complications after regional anesthesia (30). Back pain is a frequent consequence of labor irrespective of the intervention of regional techniques. A randomized and controlled study of 369 women concluded that 20%35% of parturients report backache at 3 months postpartum and 16%35% report backache after 1 year (31). Other studies have reported a more frequent incidence of backache soon after delivery (43%53% day one postpartum) with a tendency to diminish over time (32). The incidence of backache seen in this investigation was consistent with that reported in the medical literature.
Headache was also commonly seen in this investigation and did not appear dependent on any of the study drugs used. The incidence of postpartum headaches has been associated with the use of the loss of resistance to air technique for locating the epidural space as well as dural puncture (33).
The small sample size used in this study cannot establish the safety of the use of intrathecal midazolam. However, the incidence of adverse events was not more than the incidence of adverse events reported in the medical literature after childbirth nor in the fentanyl group and in all cases, resolution of the symptoms occurred over time.
We conclude that the administration of intrathecal midazolam causes potentiation of the analgesic effect of intrathecal fentanyl in laboring parturients. It is most likely that this enhanced drug action occurs because of the combined action of two receptor-based systems in the spinal cord that may both act in concert to provide profound analgesia. This approach to pain therapy may hold the promise that favorable outcomes such as successful analgesia may be achieved without an increase in the occurrence of adverse effects such as pruritus and nausea. Further work aimed at the co-activation of the endogenous opioid and the gamma-aminobutyric acid A benzodiazepine spinal systems may provide new methods of improving current analgesic techniques to the benefit of our patients.
| Acknowledgments |
|---|
| References |
|---|
|
|
|---|
This article has been cited by other articles:
![]() |
Y. K. Batra, R. Mahajan, S. Kumar, S. Rajeev, and M. Singh Dhillon A Dose-Ranging Study of Intraarticular Midazolam for Pain Relief After Knee Arthroscopy Anesth. Analg., August 1, 2008; 107(2): 669 - 672. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. A. Duncan Labour pains Can Fam Physician, January 1, 2008; 54(1): 28 - 29. [Full Text] [PDF] |
||||
![]() |
S. L. Shafer Anesthesia & Analgesia's Policy on Off-Label Drug Administration in Clinical Trials Anesth. Analg., July 1, 2007; 105(1): 13 - 15. [Full Text] [PDF] |
||||
![]() |
J. P. Rathmell, T. R. Lair, and B. Nauman The Role of Intrathecal Drugs in the Treatment of Acute Pain Anesth. Analg., November 1, 2005; 101(5S_Suppl): S30 - 43. [Abstract] [Full Text] [PDF] |
||||
![]() |
K. Jarbo, Y. K. Batra, and N. B. Panda Brachial plexus block with midazolam and bupivacaine improves analgesia: [Le bloc du plexus brachial avec du midazolam et de la bupivacaine ameliore l'analgesie] Can J Anesth, October 1, 2005; 52(8): 822 - 826. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. K. Lin More on the Dilemma of Intrathecal Midazolam Anesth. Analg., February 1, 2005; 100(2): 604 - 604. [Full Text] [PDF] |
||||
![]() |
A. P. Tucker, J. Mezzatesta, R. Nadeson, and C. S. Goodchild Intrathecal Midazolam: Adverse Effects and Sources of Bias Anesth. Analg., February 1, 2005; 100(2): 605 - 605. [Full Text] [PDF] |
||||
![]() |
G. A. Van Norman, S. K. Palmer, and S. H. Jackson The Ethical Role of Medical Journal Editors Anesth. Analg., February 1, 2005; 100(2): 603 - 604. [Full Text] [PDF] |
||||
![]() |
L. Walker Intrathecal Midazolam: Adverse Effects and Sources of Bias Anesth. Analg., February 1, 2005; 100(2): 604 - 605. [Full Text] [PDF] |
||||
![]() |
M. J. Cousins and R. D. Miller Intrathecal Midazolam: An Ethical Editorial Dilemma Anesth. Analg., June 1, 2004; 98(6): 1507 - 1508. [Full Text] [PDF] |
||||
![]() |
T. L. Yaksh and J. W. Allen Preclinical Insights into the Implementation of Intrathecal Midazolam: A Cautionary Tale Anesth. Analg., June 1, 2004; 98(6): 1509 - 1511. [Full Text] [PDF] |
||||
![]() |
T. L. Yaksh and J. W. Allen The Use of Intrathecal Midazolam in Humans: A Case Study of Process Anesth. Analg., June 1, 2004; 98(6): 1536 - 1545. [Abstract] [Full Text] [PDF] |
||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|