剖宫产后局部止痛 联合用药更有效

加州蒙特雷(EGMN)——在产科麻醉与围产医学会(SOAP)年会上报告的一项随机试验显示，在剖宫产后局部止痛和消炎方面，两药联用的效果优于单药。这项入组60名剖宫产产妇的试验表明，如果在布比卡因基础上加用非甾体抗炎药酮咯酸，可使坐位术后疼痛评分的曲线下面积减少约30%，追加阿片类药物的需求减少约40%，伤口渗出液炎症标志物白介素6和10的水平也更低。

参与这项试验的60名健康产妇均怀有足月单胎，均在脊椎麻醉下接受择期剖宫产。这些产妇的平均年龄为32岁，80%已有剖宫产史。研究者在切口皮下埋置弹性ON-Q泵，一边采集伤口渗出液和给药。这些产妇被随机均分为三组，均在术后持续皮下给药48 h：布比卡因10 mg/h(活性对照组)，布比卡因+酮咯酸0.6 mg/h，布比卡因+氢吗啡酮0.04 mg/h。研究者特意采用很小剂量，以避免全身效应对结果的干扰。在术后4、24和48 h，采用口头疼痛量表评估静息时和活动时的疼痛强度。同时采集伤口渗出液，检测多种细胞因子水平。

结果显示，活性对照组产妇坐位术后疼痛评分曲线下面积约为250，布比卡因+酮咯酸组产妇为175(P=0.018)。静息时疼痛评分无显著组间差异。与活性对照组相比，布比卡因+酮咯酸组产妇伤口渗出液的白介素6(P=0.012)和白介素10(P=0.004)的水平均更低。布比卡因+酮咯酸组产妇术后追加阿片类止痛药的剂量相当于25 mg吗啡，而单用布比卡因的产妇平均需追加相当于40 mg吗啡的阿片类药物。

受试者均未发生明显不良事件或研究相关并发症，未发生血肿、感染或伤口愈合延迟。1名产妇发生切口下液潴留。

第一作者、加州斯坦福Lucile Packard儿童医院的Brendan Carvalho博士指出：“外周加用小剂量酮咯酸兼具抗炎和镇痛作用，提示这是一种局部介导效应而非全身效应，甚至有可能由此形成直接对伤口使用极低剂量药物的观念。我们可能设计出直接作用于伤口的小剂量药物组合方案，在有效镇痛抗炎的同时避免全身性不良反应。”而在布比卡因基础上经皮下加用氢吗啡酮却不能改善结局。研究者称，基于既往关于外周给予阿片类和非甾体类药物的文献，这一结果并不令人意外。

一名与会者就研究中用于给药的导管向作者提问：“你是否考虑过导管这种异物的刺激可能与研究结果有关？”Carvalho博士承认这是一个好问题，但“为了能对部分患者在不留置导管的情况下继续随访，我们需要进行侵入性操作(打针)和取活检……还有很长的路要走，也许这一疑问会激励人们想出更好的办法”。

另一名与会者问道：“我想知道，如果手头没有ON-Q泵可用于给药，你会怎么做？是让产科医生对伤口使用酮咯酸进行浸润，还是将该药加入腹横肌平面(TAP)阻滞？”作者答复称：“现在给出答案还为时过早。在彻底了解药物作用机制之前，我并不建议外周给予非甾体抗炎药。”

Carvalho博士承认与I-Flow公司有关联，后者是该研究所用ON-Q泵的生产商。

MONTEREY, CALIFORNIA (EGMN) – Two drugs work better than one when it comes to reducing pain and inflammation with local therapy after cesarean delivery, researchers reported.

In a randomized trial of 60 women who used subcutaneous drug delivery, the area under the curve for postoperative pain scores while sitting was roughly 30% less and supplemental opioid requirements were roughly 40% less when the nonsteroidal anti-inflammatory drug ketorolac was added to bupivacaine. Wound exudate levels of the inflammatory markers interleukin-6 and -10 also were lower.

“Giving a low dose peripherally of nonsteroidal ketorolac has both an anti-inflammatory and an analgesic effect,” commented lead author Dr. Brendan Carvalho, an anesthesiologist at Lucile Packard Children’s Hospital in Stanford, California.

“This suggests that there is a local mediation effect – this is not a systemic effect – and it may give birth to the whole concept of being able to give very small doses directly in the wound,” he said at the annual meeting of the Society for Obstetric Anesthesia and Perinatology.

“You could even create a multimodal analgesic protocol with small doses of drugs that will not have the high side effects based on big systemic doses, and they can work exactly in the area that we know is most important for inflammation and pain propagation.”

In contrast, there were no significant improvements in study outcomes when subcutaneous hydromorphone was added to bupivacaine. “This probably could have been anticipated if you look at the balance of the literature, looking at the efficacy of opioids and nonsteroidals peripherally administered,” Dr. Carvalho said.

Session attendee Dr. David R. Gambling of the Sharp Mary Birch Hospital for Women in San Diego questioned the impact of the catheter used to deliver the drugs. “Do you think that having that foreign body in place affects the release of the mediators you were measuring, and if that’s the case, do you think patient movement and irritation of the foreign body could have had an effect on the result?” he asked.

The point is a good one, Dr. Carvalho acknowledged. However, “to be able to follow someone continuously [without a catheter in place] would require invasive [needle procedures] as well as punch biopsies. ... There’s sort of a long way to go, and maybe the whole idea behind this is to encourage people to think of better ways of doing this.”

Dr. Andrea Fuller of the University of Colorado Hospital in Aurora, who also attended the session, said, “I’m wondering clinically how to use this. If you don’t have an ON-Q pump [to deliver the drug], are you doing things like asking your obstetricians to put some ketorolac in infiltrate right at the site, or even putting it in a TAP [transversus abdominus plane] block – it might be close enough.”

“It’s way too early to say,” Dr. Carvalho replied. “I am not recommending the use [of a nonsteroidal agent peripherally] yet, until we truly understand what these drugs are doing. ... It’s a growing area, and I think a few years from now, a lot of the drug administration will be where it should be as opposed to systemically.”

The trial participants were 60 healthy women with term singleton pregnancies who underwent elective cesarean delivery with spinal anesthesia. The investigators placed elastomeric ON-Q pumps subcutaneously in the incisional wound to permit collection of wound exudate and instillation of agents.

The women were randomized equally into three groups given continuous subcutaneous instillation for 48 hours after surgery of bupivacaine at 10 mg/hr only (as an active control); bupivacaine plus ketorolac at 0.6 mg/hr; or bupivacaine plus hydromorphone at 0.04 mg/hr.

The drugs were intentionally “given in very small doses, which we believe would not be systemically effective, so it’s not a systemic absorption effect,” Dr. Carvalho noted.

Pain intensity was measured at 4, 24, and 48 hours post surgery, both at rest and during activity, using the verbal pain scale, on which values range from 0 to 10. Wound exudate was collected at the same time points and assayed for a wide variety of cytokines.

On average, the women were about 32 years old and had a parity of 1. Eighty percent had had a previous cesarean delivery.

Trial results showed that the area under the curve for postoperative pain scores while sitting was approximately 250 for women given bupivacaine only, versus 175 for women given bupivacaine plus ketorolac (P = .018), Dr. Carvalho reported. There were no significant differences in pain scores while at rest.

Compared with bupivacaine alone, bupivacaine plus ketorolac was associated with lower levels of interleukin-6 (P = .012) and interleukin-10 (P = .004) in wound exudate.

Postoperative supplemental opioid analgesic use was approximately 25 mg of morphine equivalents for women in the bupivacaine-ketorolac group, compared with 40 mg for their counterparts in the bupivacaine-only group (P = .020).

None of the women had significant adverse events or study-related complications, and there were no hematomas, infections, or delays in wound healing. One woman developed a subincisional fluid collection.

“The majority of patients we enrolled had had previous cesarean deliveries, which may [have introduced] bias, as patients having second C-sections may respond differently from someone who is undergoing a cesarean for the first time,” Dr. Carvalho acknowledged. Additionally, there was some “empiric guessing” involved in the selection of drug doses, and the study focused only on the acute inflammatory period.

“The next plan is to compare systemic versus peripheral administration of various other drugs, and to start understanding the mechanisms behind what is happening in the periphery,” he concluded. “We have a very delicate balance where if we inhibit inflammation too much, then we have delayed wound healing. If we accelerate it too much, we might get hypertrophic scarring. So it’s a delicate balance that we can intervene on and maybe improve analgesia, but we mustn’t affect the balance of wound healing.”

Dr. Carvalho disclosed that he has a relationship with I-Flow, manufacturer of the pump used in the study.