Perioperative opioid requirements of patients receiving sublingual buprenorphine-naloxone: a case series.

BACKGROUND: Buprenorphine, a partial opioid agonist, displaces full opioid agonists from receptors and may impede surgical pain management. We report the effects of a sublingual formulation of buprenorphine-naloxone, Suboxone (SL-BUP), on perioperative pain management. METHODS: We identified all adult surgical patients from December 31, 2004, to January 1, 2016, who received SL-BUP within 30 days prior to procedures performed with general, regional, or combined general/regional anesthesia. We recorded opioid use during the procedure, in the post-anesthesia care unit (PACU), and during the 24 h following PACU discharge. We also examined opioid use in those who continued SL-BUP until the day of surgery vs those who preoperatively discontinued SL-BUP. RESULTS: Thirty-two patients were treated preoperatively with SL-BUP. Three patients had regional anesthesia only, and opioid requirements were case dependent. Requirements were minimal for creation of an arteriovenous fistula and high following knee replacement and cesarean section. Twelve patients received combined general/regional anesthesia, and 17 received general anesthesia only. Intraoperative and PACU opioid use in these 2 groups were not significantly different (P = .10 and P = .93, respectively). In both groups opioid use increased after discharge from the PACU, and remained comparable between the general and combined general/regional group through the first 24 h after PACU discharge (P = .78). Although median [interquartile range] 24-h opioid doses were higher among patients who discontinued SL-BUP, the difference was not statistically significant in the general anesthesia-only group (SL-BUP discontinued, 199 [110-411] mg IV-MEq [intravenous morphine equivalent] vs SL-BUP continued, 106 [58-160] mg IV-MEq; P = .15) or in the combined general/regional group (SL-BUP discontinued, 140 [100-157] mg IV-MEq vs SL-BUP continued, 100 [73-203] mg IV-MEq; P = .94). CONCLUSIONS: Regardless of the type of anesthesia used, physicians treating patients with SL-BUP must be prepared to administer large doses of opioids during the early postoperative period. No difference in opioid requirements was noted between patients who perioperatively stopped SL-BUP versus those who continued SL-BUP.

Catecholamine and Metanephrine Levels in Breast Milk Before and After Paraganglioma Resection.

Background: Catecholamine and metanephrine transfer into breast milk in the setting of secreting paraganglioma or pheochromocytoma has not been previously described. Materials and Methods: We present an investigation in which we measured catecholamine and metanephrine levels in the breast milk in a single patient undergoing resection of a paraganglioma at 5 weeks postpartum. Results:As expected, levels were elevated preoperatively and decreased rapidly after resection. Conclusion:This information may be clinically relevant for patient management when pheochromocytoma or paraganglioma resection is delayed with respect to the delivery of the infant or in the postoperative monitoring of the patient's status.

Implications of uninterrupted preoperative transdermal buprenorphine use on postoperative pain management.

BACKGROUND AND OBJECTIVES: Buprenorphine is a partial µ-receptor agonist resistant to displacement from receptors by conventional opioids, which can block the effect of conventional opioids and may interfere with postoperative pain management. We aimed to quantify perioperative opioid use in patients receiving transdermal buprenorphine (TdBUP). METHODS: We identified patients receiving TdBUP who underwent surgery between 2004 and 2016. To compare opioid requirements (intravenous morphine equivalents (IV-MEq)), we constructed a matched study, matching each TdBUP patient with two opioid-naive patients by sex, age, and type of anesthesia and procedure. RESULTS: Nineteen unique patients underwent 22 procedures while receiving TdBUP. Total (IQR) amounts of IV-MEq (intraoperative, recovery room, and 24 hours after recovery-room discharge) were 98 (63, 145) and 46 (30, 65) mg IV-MEq for TdBUP and opioid-naive patients, respectively (p<0.001). Postoperative IV-MEq requirements were 54 (38, 90) and 15 (3, 35) mg for TdBUP and opioid-naive patients, respectively (p<0.001). Among TdBUP patients, higher preoperative doses of TdBUP were associated with greater postoperative opioid requirements (p=0.02). Specifically, patients with a 20 µg/hour TdBUP patch required 133.8 mg IV-MEq more postoperatively than patients with a 5 µg/hour patch (p=0.002). Following discharge from the recovery room, 17 (77%) TdBUP patients and 15 (34%) opioid-naive patients reported severe pain (OR 6.6 (95% CI 2.0 to 21.3); p<0.001; adjusting for baseline pain score, 5.0 (95% CI, 1.4 to 17.8); p=0.01). CONCLUSIONS: Analgesic management for patients receiving TdBUP therapy must account for increased opioid needs, and greater preoperative doses of TdBUP were associated with greater postoperative opioid requirements.

Low minute ventilation episodes during anesthesia recovery following intraperitoneal surgery as detected by a non-invasive respiratory volume monitor.

An electrical impedance-based noninvasive respiratory volume monitor (RVM) accurately reports minute volume, tidal volume and respiratory rate. Here we used the RVM to quantify the occurrence of and evaluate the ability of clinical factors to predict respiratory depression in the post-anesthesia care unit (PACU). RVM generated respiratory data were collected from spontaneously breathing patients following intraperitoneal surgeries under general anesthesia admitted to the PACU. Respiratory depression was defined as low minute ventilation episode (LMVe, < 40% predicted minute ventilation for at least 2 min). We evaluated for associations between clinical variables including minute ventilation prior to opioid administration and LMVe following the first PACU administration of opioid. Also assessed was a low respiratory rate (< 8 breaths per minute) as a proxy for LMVe. Of 107 patients, 38 (36%) had LMVe. Affected patients had greater intraoperative opioid dose, P = 0.05. PACU opioids were administered to 45 (42.1%) subjects, of which 27 (25.2%) had LMVe (P = 0.42) within 30 min following opioid. Pre-opioid minute ventilation < 70% of predicted normal value was associated with LMVe, P < 0.01, (sensitivity = 100%, specificity = 81%).Low respiratory rate was a poor predictor of LMVe (sensitivity = 11.8%). Other clinical variables (e.g., obstructive sleep apnea) were not found to be predictors of LMVe. Using RVM we identified that mild, clinically nondetectable, respiratory depression prior to opioid administration in the PACU was associated with the development of substantial subsequent respiratory depression during the PACU stay.

Perioperative Management of Pheochromocytoma.

Pheochromocytomas are rare neuroendocrine tumors that produce and store catecholamines. Without adequate preparation, the release of excessive amounts of catecholamines, especially during anesthetic induction or during surgical removal, can produce life-threatening cardiovascular complications. This review focuses on the perioperative management of pheochromocytoma/paragangliomas, initially summarizing the clinical aspects of the disease and then highlighting the current evidence available for preoperative, intraoperative, and postoperative anesthetic management.

Sex steroid signaling: implications for lung diseases.

There is increasing recognition that sex hormones (estrogen, progesterone, and testosterone) have biological and pathophysiological actions in peripheral, non-reproductive organs, including the lung. Clinically, sex differences in the incidence, morbidity and mortality of lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, lung cancer and pulmonary hypertension have been noted, although intrinsic sex differences vs. the roles of sex steroids are still not well-understood. Accordingly, it becomes important to ask the following questions: 1) Which sex steroids are involved? 2) How do they affect different components of the lung under normal circumstances? 3) How does sex steroid signaling change in or contribute to lung disease, and in this regard, are sex steroids detrimental or beneficial? As our understanding of sex steroid signaling in the lung improves, it is important to consider whether such information can be used to develop new therapeutic strategies to target lung diseases, perhaps in both sexes or in a sex-specific manner. In this review, we focus on the basics of sex steroid signaling, and the current state of knowledge regarding how they influence structure and function of specific lung components across the life span and in the context of some important lung diseases. We then summarize the potential for sex steroids as useful biomarkers and therapeutic targets in these lung diseases as a basis for future translational research in the area of gender and individualized medicine.

Hyperoxia-induced changes in estradiol metabolism in postnatal airway smooth muscle.

Supplemental oxygen, used to treat hypoxia in preterm and term neonates, increases the risk of neonatal lung diseases, such as bronchopulmonary dysplasia (BPD) and asthma. There is a known sex predilection for BPD, but the underlying mechanisms are not clear. We tested the hypothesis that altered, local estradiol following hyperoxia contributes to pathophysiological changes observed in immature lung. In human fetal airway smooth muscle (fASM) cells exposed to normoxia or hyperoxia, we measured the expression of proteins involved in estrogen metabolism and cell proliferation responses to estradiol. In fASM cells, CYP1a1 expression was increased by hyperoxia, whereas hyperoxia-induced enhancement of cell proliferation was blunted by estradiol. Pharmacological studies indicated that these effects were attributable to upregulation of CYP1a1 and subsequent increased metabolism of estradiol to a downstream intermediate 2-methoxyestradiol. Microarray analysis of mouse lung exposed to 14 days of hyperoxia showed the most significant alteration in CYP1a1 expression, with minimal changes in expression of five other genes related to estrogen receptors, synthesis, and metabolism. Our novel results on estradiol metabolism in fetal and early postnatal lung in the context of hyperoxia indicate CYP1a1 as a potential mechanism for the protective effect of estradiol in hyperoxia-exposed immature lung, which may help explain the sex difference in neonatal lung diseases.

Sex differences in the pulmonary circulation: implications for pulmonary hypertension.

Pulmonary arterial hypertension (PAH), a form of pulmonary hypertension, is a complex disease of multifactorial origin. While new developments regarding pathophysiological features and therapeutic options in PAH are being reported, one important fact has emerged over the years: there is a sex difference in the incidence of this disease such that while there is a higher incidence in females, disease outcomes are much worse in males. Accordingly, recent attention has been focused on understanding the features of sex differences in the pulmonary circulation and the contributory mechanisms, particularly sex hormones and their role in the pathological and pathophysiological features of PAH. However, to date, there is no clear consensus whether sex hormones (particularly female sex steroids) are beneficial or detrimental in PAH. In this review, we highlight some of the most recent evidence regarding the influence of sex hormones (estrogen, testosterone, progesterone, dehydroepiandrosterone) and estrogen metabolites on key pathophysiological features of PAH such as proliferation, vascular remodeling, vasodilation/constriction, and inflammation, thus setting the stage for research avenues to identify novel therapeutic target for PAH as well as potentially other forms of pulmonary hypertension.

Functional genetic polymorphisms in the aromatase gene CYP19 vary the response of breast cancer patients to neoadjuvant therapy with aromatase inhibitors.

Aromatase (CYP19) is a critical enzyme in estrogen biosynthesis and aromatase inhibitors (AI) are employed widely for endocrine therapy in postmenopausal women with breast cancer. We hypothesized that single nucleotide polymorphisms (SNPs) in the CYP19 gene may alter the effectiveness of AI therapy in the neoadjuvant setting. Genomic DNA was obtained for sequencing from 52 women pre-AI and post-AI treatment in this setting. Additionally, genomic DNA obtained from 82 samples of breast cancer and 19 samples of normal breast tissue was subjected to resequencing. No differences in CYP19 sequence were observed between tumor and germ-line DNA in the same patient. A total of 48 SNPs were identified including 4 novel SNPs when compared with previous resequencing data. For genotype-phenotype association studies, we determined the levels of aromatase activity, estrone, estradiol, and tumor size in patients pre-AI and post-AI treatment. We defined two tightly linked SNPs (rs6493497 and rs7176005 in the 5'-flanking region of CYP19 exon 1.1) that were significantly associated with a greater change in aromatase activity after AI treatment. In a follow-up study of 200 women with early-stage breast cancer who were treated with adjuvant anastrozole, these same two SNPs were also associated with higher plasma estradiol levels in patients pre-AI and post-AI treatment. Electrophoretic mobility shift and reporter gene assays confirmed likely functional effects of these two SNPs on transcription of CYP19. Our findings indicate that two common genetic polymorphisms in the aromatase gene CYP19 vary the response of breast cancer patients to aromatase inhibitors.

Human methylenetetrahydrofolate reductase pharmacogenomics: gene resequencing and functional genomics.

5,10-Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme in the folate metabolic pathway. Common genetic polymorphisms in the human MTHFR gene are associated with individual variation in the efficacy and toxicity of chemotherapeutic agents, such as methotrexate and 5-fluorouracil. However, the full range of polymorphisms and intragene haplotypes in the human MTHFR gene remains unclear. Furthermore, cellular mechanisms by which common, naturally occurring nonsynonymous coding single nucleotide polymorphisms (cSNPs) might alter the function of this enzyme have not been defined. The present study focused on the systematic identification and investigation of common polymorphisms and haplotypes in the MTHFR gene using a genotype-to-phenotype strategy, followed by functional genomic studies. Specifically, we resequenced exons, splice junctions and portions of the 5'-flanking region (5'-FR) of the human MTHFR gene using 240 DNA samples from four ethnic groups. A total of 65 polymorphisms were observed, 11 of which were nonsynonymous cSNPs. We then performed functional genomic studies with constructs for wild-type and 15 variant allozymes (some with multiple alterations in amino acid sequence) using a mammalian expression system. Activity for the variant allozymes ranged from 13% to 149% of wild-type activity. Levels of immunoreactive protein for the allozymes ranged from 31% to 120% of wild-type and were significantly correlated with enzyme activity (Rp=0.85, P<0.0001), suggesting that a major mechanism by which nonsynonymous cSNPs influence the function of this gene is by alteration in the quantity of protein. These observations represent steps towards an understanding of molecular genetic mechanisms responsible for variation in MTHFR function that may contribute to individual differences in drug efficacy and toxicity, as well as disease risk.

Human SULT1A3 pharmacogenetics: gene duplication and functional genomic studies.

Sulfotransferase (SULT) 1A3 catalyzes the sulfate conjugation of catecholamines. Inheritance is an important factor responsible for individual variation in SULT1A3 activity, and gene resequencing studies have shown the presence of one functionally significant SULT1A3 nonsynonymous cSNP. However, following completion of the Human Genome Project, it appeared that SULT1A3 might be duplicated. We used specific PCR-based assays and fluorescence in situ hybridization to verify that 2 SULT1A3 genes-SULT1A3 and SULT1A4-were present on chromosome 16 in all human DNA samples studied. Furthermore, reanalysis of previous gene resequencing data confirmed the presence of the SULT1A3 SNPs identified previously, but also revealed 11 novel polymorphisms, including 3 nonsynonymous cSNPs. Functional genomic studies showed that two of those cSNPs, C302T, and C302A, resulted in decreased enzyme activity without striking changes in substrate kinetics but with parallel changes in levels of immunoreactive protein. In addition, RT-PCR revealed that both SULT1A3 and SULT1A4 can be transcriptionally active. The duplication of SULT1A3 will have to be taken into account in future efforts to understand individual variation in SULT1A3 activity or properties.