Effect Of Dexamethasone On The Incidence Of Post-dural Puncture Headache After Spinal Anesthesia:a Randomized,Double-blind, Placebo-controlled Trial And A Meta-analysis

Part Ⅰ AbstractEffect of dexamethasone on the post-dural puncture headache in pregnancy with cesarean section:a randomized, double-blind, placebo-controlled trialBackgroundSpinal anesthesia, through injection of a local anesthetic into the subarachnoid space, is the most common method of pain control used in orthopedic, obstetric and gynecological operations. Nausea, vomiting, headache and retention of urine are the common complications of spinal anesthesia. Among them, post-dural puncture headache (PDPH) is one of the most important and usual complications. According to the Headache Classification Committee of the International Headache Society, PDPH is defined as "bilateral headaches that develop within seven days after a lumbar puncture and disappears within fourteen days. The headache worsens within fifteen minutes of resuming the upright position, disappears or improves within thirty minutes of resuming the recumbent position". Nowadays, the incidence of PDPH varies from 0.5% to 25%, and the high risk factors for PDPH include women, young age, the needle size and design, the needle bevel direction and a previous history of PDPH, especially in subjects with low body mass index or young pregnancy. Therefore, it might reduce the incidence of PDPH by using proper type and right direction of needles, replacement of the stylet and some medical therapies. The precise mechanism of PDPH has been not well understood. Some studies indicated that the generations of pain producing mediators (such as Prostaglandin 12, E2) in the process of spinal anesthesia might be an important mechanism of PDPH. However, other studies considered that the persistent leak of cerebro-spinal fluid from the "hole" in the dura after the puncture, resulting in a fall in intracranial cerebro-spinal fluid volume and cerebro-spinal fluid pressure, might be an pivotal mechanism. Based on the above mechanisms, previous studies have indicated that corticosteroids such as hydrocortisone could resolve PDPH symptoms, and dexamethasone, as one of the corticosteroids, was frequently used for treating headaches of various etiologies, especially cluster headaches and migraines. Therefore, researchers raised the question whether dexamethasone has protective effects against PDPH, and some trials have been conducted, but these trials have some limitations and got the different conclusions. A relatively large and more scientific design clinical trial is needed to clarify the effect of dexamethasone on the incidence of PDPH after spinal anesthesia.ObjectiveWe performed a randomized, double-blind, placebo-controlled and relatively large trial to investigate the effects of dexamethasone on PDPH during cesarean sections.MethodsThe present randomized, double-blind, placebo-controlled trial was performed at Qilu Hospital, Shandong University according to the CONSORT statement of randomized controlled trial and the Declaration of Helsinki. Informed consent was obtained from all participants following a protocol that had been approved by the Medical Ethics Department of the Medical School of Shandong University. The present trial has been registered in the database of Chinese Clinical Trial Registry (ChiCTR:ChiCTR-TRC-13003460).1. Inclusion and exclusion criteriaThe subjects were selected objectively based on the following inclusion criteria: 20-40 years of age; willing to participant in the trial; undergoing cesarean section under spinal anesthesia; and American Society of Anesthesiologists (ASA) grade of Ⅰ-Ⅱ. The subjects were excluded if they had a history of dexamethasone intolerance or past hypersensitivity reaction to it, a past history of chronic headaches or recent onset acute headaches, and/or a history of known emotional or mental illness. Patients that had experienced pre-eclampsia or skin infections at the site of needle insertion were also excluded.2. Randomization and treatment interventionsPatient eligibility was judged by anesthesiologists at the participating hospitals and consent prior to enrollment was obtained. Eligible participants were given unique subject numbers according to study criteria and were assigned to Group 1 or Group 2 by a research technician according to a computer-generated, randomization plan. Study medications were sent to each hospital from the coordinating center, according to the schedule. A list of subject identification numbers and corresponding treatment assignments was restricted to J-G.Y. and were concealed from other study personnel until interventions were assigned.3. DesignThe primary outcome was post-dural puncture headache after spinal anesthesia in the first seven post-operative days. For all patients, only one anesthesiologist performed the spinal anesthesia. Both the anesthesiologist and patients were not aware of the groups. At first, each subject received lactated Ringer’s solution for pre-loading. Spinal anesthesia was then performed by an anesthesiologist using a 25-gauge Quincke needle in the L3/4 or L4/5 interspaces. Routine monitoring (noninvasive arterial blood pressure, electrocardiogram and oxygen saturation) was applied for all patients. Immediately after delivery and clamping of the umbilical cord,8 mg dexamethasone (2 ml) or normal saline (2 ml) as placebo was intravenously injected. After the operation, patients were admitted to the women’s ward. The patients were questioned for possible occurrence of spinal anesthesia induced headache on the first, second, third and seventh postoperative days. A telephone follow-up call was used if the hospital stay was shorter than 7 days. The severity of PDPH was assessed using a 10-cm visual analog scale (VAS), in which 0 signifies no headache,1-3 indicates mild headache,4-7 indicates moderate headache and >7 indicates severe headache.4. Statistical analysisProspective estimation of the sample size for an outcome trial with 5% significance level (alpha) and 80% power was calculated. Therefore, the minimum number of patients required per arm was calculated to be 260. The primary outcome considered was the post-dural puncture headache after spinal anesthesia in the first seven post-operative days. Data analysis was performed using Statistical Package for the Social Sciences for Windows, version 13.0 (SPSS Inc., Chicago, Illinois, USA). Student’s two-tailed t-test was used for comparing the mean variables, whereas the chi-squared test was used for quality variables. A P value of less than 0.05 was considered statistically significant.ResultsTotally 720 women were enrolled from September 2013 to February 2014 in the initial stage, but 24 participants were excluded because they did not meet the inclusion criteria (n=17) or declined to participate the trial (n=7). Sixty women did not receive allocated intervention for more than one time for dural puncture, and another 20 participants were lost to follow up due to incomplete questionnaires or were reanesthetized. Finally, there were 307 participants in the dexamethasone group and 309 in the placebo group for analysis.There were no significant differences between the dexamethasone and placebo groups with respect to age, body mass index, systolic and diastolic blood pressure, blood lipid and glucose. The tea and coffee drinking habits and the use of oral glucocorticoids and previous history of cesarean sections were also similar in the two groups.In the study period (postoperative 7 days),31 participants from the dexamethasone group and 18 from the placebo group experienced PDPH, but the incidences of PDPH between the two groups was not significantly different (31 vs.18, P=0.054). However, in the first 24 hours after spinal anesthesia, a significant difference was detected between the two groups regarding the occurrence of PDPH (25 vs.11, RR 2.29; 95% CI:1.15 to 4.57, P=0.016).The severity of PDPH was assessed using the VAS score in the first 24 hours, and on postoperative days two, three and seven. All PDPH cases had a mild (VAS=1-3) to moderate (VAS=4-7) severity and none experienced severe PDPH (VAS=8-10). Although no significant statistical difference in the severity of pain between the dexamethasone and placebo groups was noted, the pain seemed more severe in the dexamethasone group in the first postoperative week.No critical adverse events could be found. The most common adverse effect was mild nausea, which was observed in five patients (four receiving dexamethasone, one receiving placebo).ConclusionsIn conclusion, the present study indicates that prophylactic administration of 8 mg dexamethasone after spinal anesthesia does not have any protective effects against PDPH and may even increase the incidence of PDPH in the first 24 hours in patients with spinal anesthesia. More well-designed trials with different doses of dexamethasone and objective indexes assessing the severity of headaches are needed to verify our results in the future.Part Ⅱ AbstractEffect of dexamethasone on the post-dural puncture headache in after spinal anesthesia:a meta-analysis of randomized, placebo-controlled trialsBackgroundSpinal anesthesia is a common method of pain control used in orthopedic, obstetric and gynecological operations. Post-dural puncture headache (PDPH) is one of the most important and usual complications. According to the Headache Classification Committee of the International Headache Society, PDPH is defined as "bilateral headaches that develop within seven days after an lumbar puncture and disappears within fourteen days. The headache worsens within fifteen minutes of resuming the upright position, disappears or improves within thirty minutes of resuming the recumbent position". The high risk factors for PDPH including women, young age, the needle size and design, the needle bevel direction and a previous history of PDPH lead to the the incidence of PDPH varying from 0.5% to 25%. The precise mechanism of PDPH has been not clear. Some studies indicated that the generations of pain producing mediators (such as Prostaglandin 12, E2) in the process of spinal anesthesia might be an important mechanism of PDPH. However, other studies considered that the persistent leak of cerebro-spinal fluid from the "hole" in the dura after the puncture, resulting in a fall in intracranial cerebro-spinal fluid volume and cerebro-spinal fluid pressure, might be an pivotal mechanism. Previous studies have indicated that corticosteroids such as hydrocortisone could resolve PDPH symptoms, and dexamethasone, as one of the corticosteroids, was frequently used for treating headaches of various etiologies, especially cluster headaches and migraines. Therefore, researchers raised the question whether dexamethasone has protective effects against PDPH, and some trials have been conducted. Yousefshahi et al. reported that prophylactic treatment with 8 mg of dexamethasone increased the severity and incidence of PDPH, but Hamzei et al. found that 8 mg of dexamethasone could significantly reduce the incidence of PDPH in the first 24 hours and the first week after spinal anesthesia. The inconsistent conclusions might be due to the fact that 4 anesthesiologists (not the same anesthesiologist) performed the dural puncture in the trial by Yousefshahi, and that Hamzei’s study was conducted as a single blind randomized controlled trial and the sample size was relatively small. As a result, the precise effect of dexamethasone on PDPH has not been established. In statistics, meta-analysis comprises statistical methods for contrasting and combining results from different studies in the hope of identifying patterns among study results, sources of disagreement among those results, or other interesting relationships that may come to light in the context of multiple studies. Meta-analysis can be thought of as "conducting research about previous research." In its simplest form, meta-analysis is done by identifying a common statistical measure that is shared between studies and calculating a weighted average of that common measure. The motivation of a meta-analysis is to aggregate information in order to achieve a higher statistical power for the measure of interest, as opposed to a less precise measure derived from a single study, in an effort to obtain a better understanding of how well the treatment works. In the present meta-analysis, we identified all randomized and placebo-controlled trials involving dexamethasone and conducted a meta-analysis to evaluate the effects of dexamethasone on PDPH after spinal anesthesia.ObjectiveWe identified all randomized and placebo-controlled trials involving dexamethasone and conducted a meta-analysis to evaluate the effects of dexamethasone on PDPH after spinal anesthesia. The present meta-analysis was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The protocol details of our present meta-analysis have been submitted to the PROSPERO register and this record has been published on the database at http://www.crd.york.ac.uk/prospero/. Our registration number is CRD42013006537.MethodsWe systematically searched PubMed (from 1950 to January,2014), Embase (from 1966 to January,2014), and the Cochrane Library (Cochrane Central Register of Controlled Trials) for published reports using the query "headache" paired with "dexamethasone". Reference lists of original and review articles were also manually analyzed.Studies were chosen for analysis if they met the following criteria:(i) the articles should be published in English; (ii) studies should be completed, published, randomized and placebo-controlled trials; (iii) spinal anesthesia should be used in the operation; (iv) PDPH should be investigated in the trial; (v) dexamethasone should be intravenously injected during the operation; (vi) the incidence of PDPH in the two groups should be reported in the study.The search, data extraction, and quality assessment were completed independently by two reviewers according to the inclusion criteria. Any discrepancies between the two reviewers were resolved through discussion until a consensus was reached. The extracted data included the study characteristics (authors, publication year, sample size, study design, study duration), population information (age, gender, the type of operation), and the incidence of PDPH in the two groups were all extracted from the included studies. The quality of the studies was judged by concealment of treatment allocation, quality of randomization, blinding, reporting of withdrawals, and generation of random numbers. Trials were given one point for each area addressed, with a possible score 0 to 5 (highest level of quality).We estimated the pooled risk ratio (RR) and 95% confidence interval (CI) of PDPH after spinal anesthesia using the random effects model. Statistic heterogeneity of treatment effects between studies was formally tested with Cochran’s test (P<0.1). The I2 statistic was also examined, and we considered an I2 value >50% to indicate significant heterogeneity between the trials. Publication bias was assessed with the Egger regression test and funnel plots [16]. Meta-analyses and statistical analyses were performed with Stata software (version 10.0; Stata Corporation, College Station, TX, USA) and REVMAN software (version 5.0; Cochrane Collaboration, Oxford, UK).ResultsA total of 427 articles were initially screened in a combined search, and 419 were excluded because they were not clinical trials or because the interventions were not relevant to the purpose of the current meta-analysis. Thus, eight potentially relevant articles were selected for detailed evaluation. After the detailed evaluation, five articles were excluded for the following reasons:four articles did not use dexamethasone for treating PDPH; one article was not a placebo-controlled trial. Finally, three eligible randomized, placebo-controlled trials and our present data were used for the meta-analysis.The characteristics of the trials are shown in Table 3. All the trials were randomized, placebo-controlled, and Hamzei’ trial was single-blind but the others were double blind. The study by Doroudian included orthopedic patients, while the other studies included the parturients for cesarean section. The study duration ranged from 3 to 7 postoperative days, and all the included studies used 8 mg dexamethasone as the intervention. Doroudian’s trial used a 22 G Quincke needle for dural puncture [8], and the other studies used a 25G Quincke needle for spinal anesthesia. The incidences of PDPH in the first 24 hours after spinal anesthesia and during the entire study period were all reported in the studies by Yousefshahi, Hamzei and our present studies, whereas the incidence in the first 24 hours was not shown in Doroudian’s article. The participants who underwent more than one attempt at spinal anesthesia were enrolled in the trials by Yousefshahi and Doroudian, but Hamzei’s and our trials excluded these subjects.Pooled analysis using the random-effects model showed that prophylactic intravenous administration of 8 mg dexamethasone did not have any effects on the incidence of PDPH in the study period when compared with the placebo-controlled group (RR 1.05; 95% CI:0.46 to 2.38; P=0.91). Significant heterogeneity between individual studies were detected (heterogeneity chi-square=20.20,I2=85%). The meta-analysis of trials reporting the data of the first 24 hours also showed no significant difference in PDPH incidence between the dexamethasone and placebo groups, but an increased trend in the dexamethasone group was observed (RR 1.33; 95%CI:0.40 to 4.46; P=0.65). Similarly, heterogeneity in the meta-analysis of the first 24 hours was also significant (heterogeneity chi-square= 10.48,12=81%).The Egger test and funnel plots were performed to detect the publication bias. No publication bias was found in the two meta-analyses (the meta-analysis of PDPH incidence in the entire study period:Egger test P=0.780; the meta-analysis of PDPH incidence in the first 24 hours:Egger test P=0.352).ConclusionsThe present meta-analysis indicates that prophylactic administration of 8 mg...