Cesarean delivery is a common surgical procedure and rates are increasing.1 Postoperative pain is the greatest concern for women during and after cesarean delivery, as demonstrated by a recent survey conducted by Carvalho et al.2 It may be severe, last at least 48 to 72 hours, and may also impair early postoperative rehabilitation and recovery. Pain relief and patient satisfaction are still inadequate in many cases. Multimodal analgesia is therefore required, usually combining acetaminophen, nonsteroidal antiinflammatory drugs (NSAID), and opioids, with their related undesirable side effects and limits.3,4 Recently, chronic pain (lasting more than 3 months after caesarean delivery and even requiring treatment) has emerged as a problem in more than 10% of individuals.5,6 Interestingly, recall of severe acute postoperative pain appears to be a factor involved in development of chronic postoperative pain after cesarean delivery.7
Local anesthetic wound infusion is now widely recognized as a useful and safe adjunct in a multimodal approach to postoperative pain management in different surgical settings.8 This relatively simple technique in which the surgeon directly places a catheter to infuse local anesthetic or NSAID into wounds at the end of the procedure can be widely used, is technically efficient and safe, offers the potential to provide complete analgesia or to substantially reduce the need for opioids and their related side effects, can be used for several days, and can, with the introduction of new portable pumps, be used in an ambulatory setting.
Four randomized, double-blind, controlled studies9–12 conducted after cesarean delivery have yielded very interesting results that are further confirmed by Bamigboye et al13 in a recent Cochrane collaborative systematic review. Local anesthetic and NSAID infusions were of benefit as adjuncts to regional or general anesthesia in cesarean delivery by reducing opioid consumption and improving pain relief.
An important issue before wider use of continuous wound infusion for cesarean delivery is to determine the optimal site of drug administration. In the aforementioned studies, catheters were inserted above the fascia, resulting in subcutaneous spreading of local anesthetic or NSAID, thereby restricting the blockade of parietal nociceptive inputs to the superficial layer of the abdominal wall. By contrast, insertion of the catheter below the fascia may allow nociceptive blockade of both fascia of the abdominal muscles and peritoneum, resulting in better efficacy, as demonstrated recently by Beaussier et al14 in colorectal surgery. Such a hypothesis needs to be more clearly addressed during cesarean delivery.
We hypothesized that administration below the fascia would be more effective than above. We therefore conducted a randomized double-blind study to evaluate in which anatomical layer (above the fascia or below the fascia) continuous wound infusion of local anesthetic combined with NSAID through a multiorifice catheter had the best effectiveness during the first 48 hours on postoperative pain intensity after elective cesarean delivery. Persistence of pain at 1 and 6 months after completion of the study was also analyzed and compared.
MATERIALS AND METHODS
This prospective, randomized, double-blind, controlled study was approved by the Committee for the Protection of Human Subjects in Biomedical Research. All individuals signed a written informed consent form. The study was conducted from October 2007 to December 2008.
Fifty-six healthy parturient individuals American Society of Anesthesiology (ASA) I or II at more than 37 weeks of gestation scheduled to undergo elective cesarean delivery using a Pfannenstiel incision under spinal anesthesia were included in the study from October 2007 to September 2008. Individuals were excluded in case of known allergy to NSAID, ASA III or higher, or refusal to participate. The patient and the staff involved in perioperative management and data collection were not aware of the group assignment. Individuals were instructed regarding the analgesic system they would use after surgery, the continuous wound instillation device, the patient-controlled analgesia (PCA) pump, and how to use the visual analog scale (VAS; 0 mm=none and 100 mm=maximal).
The individuals were randomly allocated using computer-generated random numbers to two groups, depending on the site of insertion of the multiholed catheter, either above the fascia or below the fascia. Group allocation was concealed in sealed opaque envelopes that were opened only after written consent and just before closure of the fascia.
All individuals received a standard spinal anesthesia as usually performed in our institution with 2 mL of 0.5% hyperbaric bupivacaine (10 mg) combined with 5 micrograms sufentanil and 100 micrograms morphine. Maternal hypotension was prevented, treated, or both according to the most recent guidelines.15 Cesarean procedure was performed similarly using the Joel Cohen technique without peritoneal closure.16 On completion of surgery, the surgeon was informed before fascia closure where to insert the catheter by the instrumentalist, and this information was only shared between them; the anesthesiologist remained unaware of the location. The surgeon inserted a multihole 20-gauge catheter (PAINfusor 7.5 cm) below the fascia or above the fascia, according to randomization. The catheter was positioned below the fascia between the unclosed parietal peritoneum and the underside of the transversalis fascia before its closure, along the full length of the wound. In the above-the-fascia position, the catheter was set above the superficial abdominal fascia. Thereafter, the surgeon closed the skin and secured the infusion catheter on the skin using a sterile tape without any difference regarding group allocation. When the wound was closed, a 10-mL bolus of sterile saline was administered through the catheter. The catheter then was connected to an elastomeric pump set to deliver 5 mL per hour for 48 hours containing 450 mg ropivacaine and 200 mg ketoprofene in 240 mL isotonic saline. The NSAID dose was chosen based on the doses of ketoprofene currently used intravenously for postoperative analgesia after cesarean delivery in our institution. Mixture of ropivacaine and ketoprofene was realized uneventfully under sterile conditions by the nurse anesthetist. No precipitation or incompatibility between these two drugs occurred in contrast with what was observed with ropivacaine and diclofenac.
No other analgesics were administered systematically, by contrast with our usual multimodal protocol. An intravenous PCA device was immediately begun in the postanesthesia care unit and set to deliver 1.5 mg morphine per demand with a 7-minute lockout time and a maximum allowed dose of 20 mg per 4 hours. Analgesic regimens, continuous wound infusion, and PCA devices were supplied during the first 48 postoperative hours.
All of the postoperative data were collected by an anesthesiologist not involved in intraoperative patient care and blinded to the group assignment. Evaluation started on arrival at the postanesthesia care unit (H0).
Early postoperative pain was assessed using the parameters of cumulative dose and postoperative pain intensity. Cumulative dose of morphine consumption (PCA use) needs at 3, 6, 12, 24, 36, and 48 hours was assessed. Total 48-hour morphine was the primary major end point of this study. Postoperative pain intensity on admission to the postanesthesia care unit, at 3, 6, 12, 24, 36, and 48 hours after delivery using a VAS (0–100 mm) was assessed. Worst VAS for pain, at rest and mobilization, on coughing and leg rising before the first postoperative 24 hours, and after when changing from supine to sitting and standing position were recorded. Because we hypothesized that the different sites of catheter insertion would result in different patterns of pain, either parietal pain (wound pain) or visceral pain (uterine cramping, pain related to return of gastrointestinal function) were recorded.
Adverse effects of treatments and other outcome parameters were also recorded, including occurrence of nausea, vomiting, and itching, using a categorical scoring system (none, 0; mild, 1; severe, 2). Nausea or vomiting was defined as nausea or vomiting score more than zero at any postoperative time point. Rescue antiemetics were offered to any patient who experienced nausea or vomiting. Sedation scores were assigned by the investigator using sedation scale (awake and alert, 0; asleep but easily roused, 1; deep sleep, 2). The presence of sedation was defined as sedation score more than zero at any postoperative time point.
Close attention was given to the wound healing by both surgeons and nurses involved in postoperative care to detect any excessive inflammatory reaction or infection. Time for recovery in terms of first occurrence of flatus, feces, and days of hospital stay were recorded. In addition, we recorded patient satisfaction with the analgesia provided using a verbal numerical scale from 0 (poor) to 10 (excellent).
To study the diffusion of the local anesthetic and NSAID according to the catheter position, either below or above the fascia, one patient of each group who had excellent results on pain relief underwent a magnetic resonance imaging study just before removal of the catheter. Magnetic resonance was performed on a 1.5-T Siemens Sonata magnetic resonance system (maximum gradient amplitude=40 mT/m; slew rate=200 mT/m/ms). Individuals were positioned supine, without cardiac triggering and free breathing. Localization of uterus was obtained with fast-gradient echo. Transverse and sagittal images were acquired using T2-weighted sequence before and after injection of 15 mL of sterile saline solution through the catheter.
The incidence of postoperative residual pain or discomfort was evaluated at 1 and 6 months after surgery, according to the questionnaire published by Lavand'homme.12 This inquiry was performed by telephone call and confirmed by mail or e-mail.
The calculation of the sample size was based on the primary end point, ie, morphine consumption during the first 48 hours. Taking into account preliminary pilot data from our institution (48-hour morphine consumption evaluated as 22±8 mg), a sample size of 25 individuals in each group was required to detect as clinically significant a reduction in morphine requirements of 30% in the below-the-fascia group, with an alpha risk of 0.05 and a beta risk of 0.2.
Normality was evaluated by the Kolmogorov-Smirnov test. When normality was observed, t test or analysis of variance were used, and nonparametric tests were used otherwise. Categorical data were analyzed using χ2 contingency table. For nonnormally distributed data (morphine consumption), between-group comparisons at each time point were made using Wilcoxon rank-sum test. Two-way analysis of variance for repeated measures for analysis of different VAS scores between groups and for each time interval were performed. Normally distributed data are presented as mean±standard deviation, nonnormally distributed variables are presented as median (interquartile range), and categorical variables are presented as raw data and frequencies. Statistical analysis was performed using Staview. The threshold for statistical significance was set at P<.05.
Fifty-six individuals were enrolled, and 50 completed the study. Six individuals were excluded, four after early disconnection or dysfunction of the device (two individuals in each groups) and two for important wound leakage in the above-the-fascia group. Of the remaining 50 individuals, 25 individuals were randomized to either the below-the-fascia or the above-the-fascia group. Demographic data, as well as intraoperative parameters, were similar among the two groups (Table 1). Sensory level of spinal anesthesia reached the T4 level in all the parturient individuals included in the study, allowing surgery without pain. The duration of the surgical procedure and the duration of spinal anesthesia did not differ among groups (data not shown).
Below-the-fascia administration of ropivacaine and ketoprofene significantly reduced the postoperative consumption of morphine by PCA compared with the similar drug regimen administered above the fascia (P<.05 compared with above the fascia at 12, 24, 36, and 48 hours after surgery; Fig. 1). Total PCA morphine requirement was 15.7 mg (95% confidence interval 9.7–20.7 mg) in the below-the-fascia group compared with 26.4 mg (95% confidence interval 18.1–34.7 mg) in the above-the-fascia group.
For the first 48 hours after surgery, individuals with catheter below the fascia reported significantly less VAS pain intensity scores at rest during the first 36 hours, but no differences were recorded between groups for pain at movement (Fig. 2). We could not make any difference between visceral (uterine cramping, pain at first flatus and feces) and somatic pain in and between individuals of the two groups. The most frequent symptom was, however, related to somatic pain, mainly pain at the two suture edges of the fascia of the abdominal muscles.
No major adverse event occurred during the study. No sign or symptom indicative of systemic toxicity was noted. The incidence of undesirable side effects (nausea or vomiting, itching, sedation), and time before first flatus, feces, first oral intake, and hospital stay did not differ between groups (Table 2). Neither scar infection nor delay in wound repair occurred in individuals in the study. Finally, overall satisfaction was excellent, especially in women having already experienced previous cesarean delivery, and did not differ between the two groups (Table 2).
Magnetic resonance imaging allowed a better understanding of the catheter location. On T2-weighted images, hyperintensity remained in the Retzius space after saline injection and showed the below-the-fascia position of the catheter, indirectly (Fig. 3A). By contrast, in the above-the-fascia position, saline was trapped in the deep layer of the abdominal wall above the fascia (Fig. 3B).
All individuals answered questionnaires regarding residual pain by phone call and mail. At both 1 and 6 months after cesarean delivery, groups did not differ in residual pain located at the scar. The incidence of chronic postsurgical pain defined as pain, hypoesthesia, or mechanical allodynia at 6 months after completion of surgery was only 4%.
This randomized, double-blind, controlled trial demonstrates that continuous administration of combined NSAID and local anesthetic after elective cesarean delivery below the fascia is more effective than above the fascia, leading to a significant reduction in pain at rest and morphine consumption over the first 48 postoperative hours. We could not observe any difference in the incidence of morphine-induced undesirable side effects between the two groups, but the latter are probably related to intrathecal morphine rather than to systemic effects. Moreover, the study was not designed to address this issue. Although this study was not powered to evaluate the incidence and severity of residual pain after cesarean delivery, our results indicate an average incidence of 4% for residual pain at 6 months, which is equivalent between the two groups and less frequent than reported in the literature.5,7,17
Our current study demonstrates the better efficacy of wound infusion below the fascia compared with above after cesarean delivery. It also constitutes new evidence that continuous wound infusions are an interesting complement or even an alternative to multimodal analgesia after cesarean delivery. In this postoperative obstetric context in which women want to recover quickly to take care of their newborns, a very effective, safe, and opioid-sparing analgesic technique might be beneficial and hasten recovery. Because our study did not include groups with saline continuous infusion either below or above the fascia as control, we can only compare our current study in term of opioid-sparing effects with numerous other studies conducted with the same design and surgical technique. When using spinal anesthesia with both lipophilic opioids and hydrophilic morphine for elective cesarean delivery, mean requirements of rescue systemic morphine for the first 48 postoperative hours, combined with other analgesic drugs or not, range from 50 to 70 mg.18–23 Nausea and vomiting and other morphine-related undesirable side effects, such as sedation and respiratory depression, may also constitute an important issue.4 These observations strikingly contrast with the 48-hour morphine requirements of 15 and 26 mg in the two groups of our study, respectively, and the very low incidence of undesirable side effects. Seven of our 50 individuals did not require even 1 mg morphine in the postoperative period and were without any other multimodal analgesic regimen.
The identification of the optimal route for continuous wound infusion after cesarean delivery is an important issue. Numerous positive studies have demonstrated safety and effectiveness of continuous wound infusions in different settings, including cesarean delivery.8,13 However, this technique is not used commonly. Besides undisputable randomized studies9–12 reporting analgesic efficacy, either as reduced pain scores or as reduced opioid use, some studies have reported less significant success, mainly as a result of differences or even flaws in methodology (Table 3).24–26 A variety of continuous delivery methods were used, including patient-controlled analgesia, continuous infusion, and intermittent bolus. Control groups were inadequate, comparing, for instance, wound infusion with prolonged epidural analgesia. Among the other possible explanations for some limited results, the catheter placement must also be considered. The majority of wound catheters were placed between muscle fascia and subcutaneous tissues, delivering local anesthetic or NSAID subcutaneously, restricting the blockade of parietal nociceptive inputs to the superficial layer of the abdominal wall. Only one study tested the infusion below the fascia and led to interesting results.25 More recently, Bamigboye et al27 reported efficacy of peritoneum spraying combined with infiltrations of all layers of the anterior abdominal wall with ropivacaine. Even if not administered as continuous wound infusion, the authors could demonstrate significant reduction in pain and in NSAID and opioid requirements.27
Our current study has clearly demonstrated that continuous wound infusion below the fascia is more effective than above the fascia in the context of cesarean delivery. Recently, these results have been challenged in another surgical setting. Hafizoglu et al28 have reported better efficacy of above-the-fascia infusions when compared with below-the-fascia infusions after abdominal hysterectomy. There are many differences between this study and the current one that are mainly related to the catheter (epidural catheter compared with multiholed infusion catheter), the kind of anesthesia and surgery, and the drugs used (local anesthetic compared with local anesthetic plus NSAID), which makes comparison difficult. Pain after abdominal hysterectomy, as after cesarean delivery, can be multifactorial, and the relative contribution of somatic and visceral pain is difficult to elucidate. It is possible that pain of somatic origin is the major cause of postoperative pain after abdominal hysterectomy (better controlled by subcutaneous infusions), whereas pain after cesarean may be visceral origin and subsequently better treated by subfascial and peritoneal infusions. One other important difference between the study by Hafizoglu and our study is the use of NSAID, which may reduce visceral pain as much as the somatic wound pain relief obtained with local anesthetic and morphine.
We hypothesize that the results of our study can be explained by several reasons. First, below the fascia infusion may result in less leakage outside the wound, as frequently observed in the subcutaneous location. Second, it may be effective both at a superficial and at a more profound level of the scar, as suggested by different studies after abdominal surgery.14,29,30 Third, a better efficacy of both local anesthetic and NSAID when administered in this site may be observed, probably because of an increased local antiinflammatory effect. Both fascia of the abdominal muscles and peritoneum, which are richly innervated tissues, are injured by the surgical incision, which contributes to postoperative pain and primary mechanical hyperalgesia.31 It may also be involved in several pathophysiologic repercussions, such as prolonged paralytic ileus and pain at return of bowel function. Altogether, nociceptive and inflammatory mediators are produced in the surgical wound, as recently measured by Carvalho et al32 after cesarean delivery. Local wound cytokine concentrations are significantly higher than systemic levels, and there is a lack of correlations between their local and systemic concentrations. Ropivacaine and ketoprofene may exert an interesting and greater antiinflammatory effect when administered locally compared with systematically, as already demonstrated by Lavand'homme,12 and they are probably better below the fascia than above. The magnetic resonance imaging study could demonstrate that once infused below the fascia, the solution injected remains in the deep layer of the abdominal wall, in close vicinity to the peritoneal injury, where it has been shown to be the most effective.14 One may also hypothesize that the blunted proinflammatory response will result in less hyperalgesia and chronic pain, and that the incidence of adhesions found in future re-operations, mainly new cesarean deliveries, will be significantly reduced.
In summary, continuous wound infusion data consistently demonstrate analgesic benefits across a wide range of surgical procedures, locations of catheters, and dosing regimens, accompanied by low incidences of catheter-related complications.8 However, the appropriate use of continuous wound infusion seems to vary according to the type of the surgical procedure and location of the wound catheter. We show here that local anesthetic combined with NSAID are more effective for postoperative pain control after cesarean delivery when administered below the fascia rather than above. The mechanism of action requires further investigation, but the next studies comparing different analgesic modalities will have to integrate this current result.
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