Richard M. Smiley

severity of acute pain after childbirth, but not type of delivery, predicts persistent pain and postpartum depression

Abstract Cesarean delivery rates continue to increase, and surgery is associated with chronic pain, often co‐existing with depression. Also, acute pain in the days after surgery is a strong predictor of chronic pain. Here we tested if mode of delivery or acute pain played a role in persistent pain and depression after childbirth. In this multicenter, prospective, longitudinal cohort study, 1288 women hospitalized for cesarean or vaginal delivery were enrolled. Data were obtained from patient interviews and medical record review within 36 h postpartum, then via telephone interviews 8 weeks later to assess persistent pain and postpartum depressive symptoms. The impact of delivery mode on acute postpartum pain, persistent pain and depressive symptoms and their interrelationships was assessed using regression analysis with propensity adjustment. The prevalence of severe acute pain within 36 h postpartum was 10.9%, while persistent pain and depression at 8 weeks postpartum were 9.8% and 11.2%, respectively. Severity of acute postpartum pain, but not mode of delivery, was independently related to the risk of persistent postpartum pain and depression. Women with severe acute postpartum pain had a 2.5‐fold increased risk of persistent pain and a 3.0‐fold increased risk of postpartum depression compared to those with mild postpartum pain. In summary, cesarean delivery does not increase the risk of persistent pain and postpartum depression. In contrast, the severity of the acute pain response to childbirth predicts persistent morbidity, suggesting the need to more carefully address pain treatment in the days following childbirth.

Distribution of β3-adrenoceptor mRNA in human tissues

The beta 3-adrenoceptor is a G protein-coupled receptor which mediates metabolic functions of the endogenous catecholamines epinephrine and norepinephrine. Questions exist regarding distribution of the beta 3-adrenoceptor in human tissue. In order to examine the distribution of beta 3-adrenoceptor mRNA in human tissues, we used sensitive and specific RNase protection assays without previous PCR amplification in an extensive list of human tissues. We confirm the presence of beta 3-adrenoceptor mRNA in human white fat from several locations, gall bladder, and small intestine, as well as extend the distribution of beta 3-adrenoceptor mRNA to previously uncharacterized human tissues such as stomach and prostate. The presence of beta 3-adrenoceptor mRNA in human white adipose tissue has important implications regarding possible use of beta 3-adrenoceptor selective agonists as anti-obesity agents, and the demonstration of beta 3-adrenoceptor mRNA in a number of gastrointestinal tissues and prostate raises the question of the role of the beta 3-adrenoceptor in motility and secretory processes.

Genetic variability of the μ-opioid receptor influences intrathecal fentanyl analgesia requirements in laboring women

Abstract Labor initiates one of the most intensely painful episodes in a woman’s life. Opioids are used to provide analgesia with substantial interindividual variability in efficacy. μ‐Opioid receptor (μOR, OPRM1) genetic variants may explain differences in response to opioid analgesia. We hypothesized that OPRM1 304A/G polymorphism influences the median effective dose (ED50) of intrathecal fentanyl via combined spinal–epidural for labor analgesia. Nulliparous women were prospectively recruited around 35 weeks gestation (n = 224), and genotyped for 304A/G polymorphism. Those requesting neuraxial labor analgesia were enrolled in one of the two double‐blinded trials: up‐down sequential allocation (SA, n = 50) and a separate confirmatory random‐dose allocation trial (RA, n = 97). Effective analgesia from intrathecal fentanyl was defined by ⩾60 min analgesia with verbal rating score ⩽1 (scale 0–10) and was compared between μOR 304A homozygotes (Group A) and women carrying at least one 304G allele (Group G). OPRM1 304G allele frequency f(−) was 0.18. Using SA, intrathecal fentanyl ED50 was 26.8 μg (95% CI 22.7–30.9) in Group A and 17.7 μg (95% CI 13.4–21.9) in Group G (p < 0.001; 304A homozygosity increased the ED50 1.5‐fold). RA confirmed that 304A homozygosity significantly increases intrathecal fentanyl ED50 (27.4 μg in Group A and 12.8 μg in Group G [p < 0.002; 2.1‐fold]). We demonstrate for the first time that the μOR 304G variant significantly reduces intrathecal fentanyl ED50 for labor analgesia, suggesting women with the G variant may be more responsive to opioids and require less analgesic drugs. These findings for intrathecal fentanyl pharmacogenetics may have implications for patients receiving opioids in other settings.

Arg389Gly β1-adrenoceptor polymorphism varies in frequency among different ethnic groups but does not alter response in vivo

There are marked interethnic differences in beta 1-adrenoceptor-mediated responsiveness, with sensitivity decreased in African-Americans and increased in Chinese compared with Caucasians. Therefore, the frequency of a common naturally occurring polymorphism of the human beta 1-adrenoceptor gene (Arg389Gly), which has functional importance in vitro, was determined in 194 African-Americans, 316 Caucasian-Americans, 221 Hispanic-Americans and 142 Chinese. African-Americans were found to have a significantly lower frequency of the Arg389 allele than the other three ethnic groups (all P < 0.01). In the populations studied, the order of the distribution of the Arg389 allele was: Chinese (74%) > Caucasians (72%) > Hispanics (67%) > African-Americans (58%). To determine the functional significance of the Arg389Gly beta 1-adrenoceptor polymorphism, in-vivo heart rate responses to exercise were compared in healthy subjects homozygous for the Arg (n = 9) and Gly (n = 8) alleles. Heart rate response to exercise was not affected by genotype (P = 0.4). Although ethnic differences in the frequency of the beta 1-adrenoceptor Arg389Gly polymorphism exist, the polymorphism does not appear to have functional significance in healthy subjects and therefore may not contribute to ethnic differences in response to drugs acting through the beta 1-adrenoceptor.

Serious Complications Related to Obstetric Anesthesia The Serious Complication Repository Project of the Society for Obstetric Anesthesia and Perinatology

Background:Because of the lack of large obstetric anesthesia databases, the incidences of serious complications related to obstetric anesthesia remain unknown. The Society for Obstetric Anesthesia and Perinatology developed the Serious Complication Repository Project to establish the incidence of serious complications related to obstetric anesthesia and to identify risk factors associated with each. Methods:Serious complications were defined by the Society for Obstetric Anesthesia and Perinatology Research Committee which also coordinated the study. Thirty institutions participated in the approximately 5-yr study period. Data were collected as part of institutional quality assurance and sent to the central project coordinator quarterly. Results:Data were captured on more than 257,000 anesthetics, including 5,000 general anesthetics for cesarean delivery. There were 157 total serious complications reported, 85 of which were anesthesia related. High neuraxial block, respiratory arrest in labor and delivery, and unrecognized spinal catheter were the most frequent complications encountered. A serious complication occurs in approximately 1:3,000 (1:2,443 to 1:3,782) obstetric anesthetics. Conclusions:The Serious Complication Repository Project establishes the incidence of serious complications in obstetric anesthesia. Because serious complications related to obstetric anesthesia are rare, there were too few complications in each category to identify risk factors associated with each. However, because many of these complications can lead to catastrophic outcomes, it is recommended that the anesthesia provider remains vigilant and be prepared to rapidly diagnose and treat any complication.

Burden of proof.

In early 2009, a two-day symposium on Obstetric Anesthesia had just ended, and my colleague and I stepped onto the tram in Basel, Switzerland, to begin our respective journeys home. One of the final discussions at the conference had concerned treatment/prevention of hypotension during spinal anesthesia for cesarean delivery, and I had spoken about the evidence in favor of phenylephrine infusions, and my personal practices in utilizing the drug. On the tram, I asked my colleague what he generally used to treat hypotension during cesareans and he responded “Boluses of ephedrine or phenylephrine, as does most of the rest of my group.” The following month, as I began a lecture at a CME course, I asked the audience, composed of a mixture of anesthesiologists and CRNAs, “What is your first-line drug to treat hypotension at cesarean section, ephedrine or phenylephrine?” Ninety percent responded ephedrine. The next week, one of our current departmental Fellows, who had done his residency in our institution and was quite familiar with both the evidence for and our practice in using phenylephrine infusions, and who was about to sit for his oral ABA Board examination asked me, “What do I say if they ask me what drug I would use for hypotension during cesarean section. Is phenylephrine an acceptable answer?” The response from the audience of predominantly non-obstetric anesthesia providers is perhaps not so shocking, despite the fact that there exists over a decade of fairly consistent evidence from well-designed, randomized, blinded studies in Europe, 1,2 the United States 3–5 and Asia 6,7 supporting the proposition that phenylephrine is at least as safe and effective and probably preferable to ephedrine for the treatment or prevention of hypotension at cesarean section. Not every anesthesiologist or CRNA reads every journal, interprets evidence correctly, is willing to change his or her practice based on the available information, or even believes in the principle of evidence-based practice. The question from the Fellow reflects the fear and insecurity that all of us felt as we approached our oral exam, even when we thought we knew the answer to a clinical question. We wondered what those Board examiners knew (or didn’t know) and what they would accept as answers. The comments of my colleague on the tram, however, were a bit more surprising, as they came from the Editor-in Chief of this Journal, whose clinical practice is and has been predominantly in obstetric anesthesia. A few weeks later Dr. Eisenach emailed me to tell me that he had started using phenylephrine infusions, had convinced several colleagues at his institution to also do so, and invited me to write this editorial.

Resolution of pain after childbirth.

Background:Chronic pain after surgery occurs in 10–40% of individuals, including 5–20% of women after cesarean delivery in previous reports. Pain and depression 2 months after childbirth are independently associated with more severe acute post-delivery pain. Here we examine other predictors of pain at 2 months and determine the incidence of pain at 6 and 12 months after childbirth. Methods:Following Institutional Review Board approval, 1228 women were interviewed within 36 h of delivery. Of these, 937 (76%) were successfully contacted by telephone at 2 months, and, if they had pain, at 6 and 12 months after delivery. The primary outcome measure was presence of pain which began at the time of delivery. We also generated a model of severity of acute post-delivery pain and 2 month pain and depression. Results:Pain which began at the time of delivery was remarkably rare 6 and 12 months later (1.8% and 0.3% [upper 95% confidence limit, 1.2%], respectively). Past history of pain and degree of tissue damage at delivery accounted for 7.0% and 16.7%, respectively, of one aspect in the variability in acute post-delivery pain. Neither of these factors was associated with incidence of pain 2 months later. Conclusions:Using a definition of new onset pain from delivery, we show a remarkably low incidence of pain 1 yr after childbirth, including those with surgical delivery. Additionally, degree of tissue trauma and history of chronic pain, risk factors for pain 2 months after other surgery, were unimportant to pain 2 months after cesarean or vaginal delivery.

β2-Adrenoceptor Genotype Affects Vasopressor Requirements during Spinal Anesthesia for Cesarean Delivery

Background: Maternal hypotension is common after spinal anesthesia for cesarean delivery. There is wide variability in the incidence and severity of hypotension and in the response to treatment. The &bgr;2 adrenoceptor (&bgr;2AR) possesses several polymorphic sites. Codons 16 (Arg16Gly) and 27 (Glu27Gln) have been shown to affect desensitization of the receptor. The goal of this study was to determine whether genetic variants of the &bgr;2AR alter incidence of hypotension or the amount of vasopressor treatment required during spinal anesthesia for cesarean delivery. Methods: One hundred seventy healthy women undergoing elective cesarean delivery were studied. Spinal anesthesia was performed with 12 mg hyperbaric bupivacaine, 25 &mgr;g fentanyl, and 200 &mgr;g morphine. Hypotension was treated with ephedrine and/or phenylephrine intravenously, and &bgr;2AR genotype at codons 16 and 27 was determined. Analysis of variance was used to compare variables between genotypes, with data expressed as mean ± SD. Results: Ephedrine or phenylephrine was used in more than 90% of patients, with no difference in the incidence of hypotension between &bgr;2AR genotypes. However, there was a significant effect of genotype on the amount of vasopressor required. Gly16 homozygotes received significantly less ephedrine (18 ± 14 mg) than Arg16 homozygotes (28 ± 13 mg) and Arg16Gly heterozygotes (30 ± 20 mg; P = 0.0005). Glu27 homozygotes required significantly less ephedrine than Gln 27 homozygotes (14 ± 13 vs. 30 ± 19 mg; P = 0.002). Gln27Glu heterozygotes received less ephedrine than Gln27 homozygotes (23 ± 16 vs. 30 ± 19 mg; P = 0.03). Conclusions: Glycine at position 16 and/or glutamate at position 27 of the &bgr;2AR leads to lower vasopressor use for treatment of hypotension during spinal anesthesia.

Fetal bradycardia and uterine hyperactivity following subarachnoid administration of fentanyl during labor: Case report

Background and Objectives. Changes in uterine tone have been postulated as the cause of fetal bradycardia following subarachnoid administration of fentanyl for labor analgesia. Such a case occurred in a 20‐year‐old parturient with an intrauterine pressure catheter in place. Methods. The patient was given intravenous terbutaline, after which contractions ceased for 20‐30 minutes and then resumed. Results. The patient underwent successful cesarean delivery. Retrospective analysis of the data revealed a significant increase in uterine tone and contractions following fentanyl administration. Conclusions. This case supports the view that changes in uterine tone, producing a hyperdynamic contractile state and a resulting decrease in utero‐placental perfusion, may explain the fetal bradycardia following subarachnoid opioid administration. Cases that do not resolve spontaneously may respond to intra‐venous terbutaline.

Persistent Alterations of the Autonomic Nervous System after Noncardiac Surgery

Background Changes in the sympathetic nervous system may be a cause of postoperative cardiovascular complications. The authors hypothesized that changes in both [Greek small letter beta]‐adrenergic receptor ([Greek small letter beta] AR) function (as assessed in lymphocytes) and in sympathetic activity (assessed by plasma catecholamines and by heart rate variability [HRV] measurements obtained from Holter recordings) occur after operation. Methods The HRV parameters were measured in 28 patients having thoracotomy (n = 14) or laparotomy (n = 14) before and for as long as 6 days after operation. Transthoracic echocardiography was performed before and on postoperative day 2. Lymphocytes were also isolated from blood obtained before anesthesia and again on postoperative days 1, 2, 3, and 5 (or 6). They were used to examine beta AR number (Bmax) and cyclic adenosine monophosphate (cAMP) production after stimulation with isoproterenol and prostaglandin E1. In addition, plasma epinephrine, norepinephrine, and cortisol concentrations were determined at similar intervals. Results After abdominal and thoracic surgery, most time and all frequency indices of HRV decreased significantly, as did Bmax and basal and isoproterenol‐stimulated cAMP production. The decrements in HRV correlated with those of Bmax and isoproterenol‐stimulated cAMP throughout the first postoperative week and inversely correlated with the increase in heart rate. Plasma catecholamine concentrations did not change significantly from baseline values, but plasma cortisol levels did increase after operation in both groups. Left ventricular ejection fraction was normal in both groups and unaffected by surgery. Conclusions Persistent downregulation and desensitization of the lymphocyte beta AR/adenylyl cyclase system correlated with decrements in time and frequency domain indices of HRV throughout the first week after major abdominal or thoracic surgery. These physiologic alterations suggest the continued presence of adaptive autonomic regulatory mechanisms and may explain why the at‐risk period after major surgery appears to be about 1 week or more.