Feasibility and Analgesic Efficacy of Thoracolumbar Dorsal Ramus Nerve Block Using Multiorifice Pain Catheters for Scoliosis Surgery: A Prospective Cohort Study.

BACKGROUND: Approximately 38,000 scoliosis surgery correction operations are performed annually in the United States; these operations are associated with considerable postoperative pain which can be difficult to manage. This is largely attributed to an incision spanning multiple vertebral segments with paraspinal muscle dissection and retraction to facilitate the implantation of segmental hardware and rods. Frequently utilized analgesic modalities include intravenous patient-controlled analgesia and epidural analgesia, often in combination. We sought to ascertain the feasibility and analgesic efficacy of continuous thoracolumbar dorsal ramus nerve (TDRN) block using surgically placed multiorifice catheters. METHODS: Forty-two patients diagnosed with idiopathic scoliosis who underwent a posterior spinal fusion (PSF) were enrolled after consent was obtained. Patients were managed utilizing a standardized Enhanced Recovery After Surgery) protocol including a perioperative opioid-sparing regimen. Data were collected at specified time intervals during the recovery period. These data points included pain scores using the Numeric Rating Scale. Parenteral or both oral and parenteral opioid consumption doses were also collected every 4 hours. Any significant postoperative adverse events were recorded as well. RESULTS: A total of 42 patients had surgically placed TDRN catheters, and 40 patients were included in this study. The patients all reported low to moderate pain scores with low opioid consumption postoperatively, while the TDRN catheter delivery of local anesthetic analgesics did not result in significant complications. CLINICAL RELEVANCE: A regional technique utilizing TDRN catheters could be a valuable component of the postoperative pain management protocols for PSF surgery, and additional studies are warranted. CONCLUSION: This study evaluated the feasibility and analgesic efficacy of TDRN catheters for postoperative pain control following multilevel PSF for idiopathic scoliosis. Continuous local anesthetic delivery through TDRN catheters is a feasible and safe technique for postoperative pain control in these patients. Selective blockade of the dorsal rami might have benefits over epidural analgesia or other regional techniques.

Veno-Arterial Extracorporeal Membrane Oxygenation Rescue in a Patient With Pulmonary Hypertension Presenting for Revision Total Hip Arthroplasty: A Case Report and Narrative Review.

Patients with pulmonary hypertension (PH) are at an increased risk of perioperative morbidity and mortality when undergoing non-cardiac surgery. We present a case of a 57-year-old patient with severe PH, who developed cardiac arrest as the result of right heart failure, undergoing a revision total hip arthroplasty under combined spinal epidural anesthesia. Emergent veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) was undertaken as rescue therapy during the pulmonary hypertensive crisis and a temporizing measure to provide circulatory support in an intensive care unit (ICU). We present a narrative review on perioperative management for patients with PH undergoing non-cardiac surgery. The review goes through the updated hemodynamic definition, clinical classification of PH, perioperative morbidity, and mortality associated with PH in non-cardiac surgery. Pre-operative assessment evaluates the type of surgery, the severity of PH, and comorbidities. General anesthesia (GA) is discussed in detail for patients with PH regarding the benefits of and unsubstantiated arguments against GA in non-cardiac surgery. The literature on risks and benefits of regional anesthesia (RA) in terms of neuraxial, deep plexus, and peripheral nerve block with or without sedation in patients with PH undergoing non-cardiac surgery is reviewed. The choice of anesthesia technique depends on the type of surgery, right ventricle (RV) function, pulmonary artery (PA) pressure, and comorbidities. Given the differences in pathophysiology and mechanical circulatory support (MCS) between the RV and left ventricle (LV), the indications, goals, and contraindications of VA-ECMO as a rescue in cardiopulmonary arrest and pulmonary hypertensive crisis in patients with PH are discussed. Given the significant morbidity and mortality associated with PH, multidisciplinary teams including anesthesiologists, surgeons, cardiologists, pulmonologists, and psychological and social worker support should provide perioperative management.

A Central Role for Lipocalin-2 in the Adaptation to Short-Bowel Syndrome Through Down-Regulation of IL22 in Mice.

BACKGROUND & AIMS: In short-bowel syndrome (SBS), inadequate intestinal adaptation is responsible for the majority of complications, including sepsis, liver failure, and death. In this study, we sought to further delineate the adaptive response to identify potential therapeutic targets. METHODS: We performed a 75% small-bowel resection (SBR) or sham operation on C57Bl/6J wild-type (WT), lipocalin-2 (LCN2)-/-, and interleukin 22 (IL22)-/- mice. Exogenous IL22 was administered to SBR WT mice. Cecal fecal matter from SBR WT and SBR LCN2-/- mice were transplanted into germ-free mice. Intestinal permeability, inflammation, proliferation, and the microbiome were evaluated 1 week after surgery. CD4+IL22+ laminal propria lymphocytes were sorted by flow cytometry. Naïve T cells were polarized to T-helper cells with or without LCN2. RESULTS: A 75% SBR in a mouse re-creates the increased intestinal permeability, enterocyte proliferation, and intestinal dysbiosis seen in SBS. LCN2 expression increases after 75% SBR, and this increase can be abrogated with broad-spectrum antibiotic treatment. LCN2-/- mice have less intestinal inflammation, increased IL22 expression, and greater adaptation as evidenced by less intestinal permeability, increased carbohydrate enzyme expression, less weight loss, and less dysbiosis after 75% SBR than WT mice. The proinflammatory and anti-adaptive effects of LCN2 can be transferred to germ-free mice via a fecal transplant. Administration of exogenous IL22 improves adaptation and restores the normal microbiome after 75% SBR in WT mice. CONCLUSIONS: LCN2 promotes inflammation and slows intestinal adaptation through changes in the microbiome and IL22 inhibition in a mouse SBS model. Strategies to reduce LCN2 may offer novel therapeutic approaches to enhance adaptation in SBS.

Hypoxia-Inducible Factor 1α Is a Critical Downstream Mediator for Hypoxia-Induced Mitogenic Factor (FIZZ1/RELMα)-Induced Pulmonary Hypertension.

OBJECTIVE: Pulmonary hypertension (PH) is characterized by progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. We have shown that in rodents, hypoxia-induced mitogenic factor (HIMF; also known as FIZZ1 or resistin-like molecule-ß) causes PH by initiating lung vascular inflammation. We hypothesized that hypoxia-inducible factor-1 (HIF-1) is a critical downstream signal mediator of HIMF during PH development. APPROACH AND RESULTS: In this study, we compared the degree of HIMF-induced pulmonary vascular remodeling and PH development in wild-type (HIF-1α(+/+)) and HIF-1α heterozygous null (HIF-1α(+/-)) mice. HIMF-induced PH was significantly diminished in HIF-1α(+/-) mice and was accompanied by a dysregulated vascular endothelial growth factor-A-vascular endothelial growth factor receptor 2 pathway. HIF-1α was critical for bone marrow-derived cell migration and vascular tube formation in response to HIMF. Furthermore, HIMF and its human homolog, resistin-like molecule-ß, significantly increased interleukin (IL)-6 in macrophages and lung resident cells through a mechanism dependent on HIF-1α and, at least to some extent, on nuclear factor κB. CONCLUSIONS: Our results suggest that HIF-1α is a critical downstream transcription factor for HIMF-induced pulmonary vascular remodeling and PH development. Importantly, both HIMF and human resistin-like molecule-ß significantly increased IL-6 in lung resident cells and increased perivascular accumulation of IL-6-expressing macrophages in the lungs of mice. These data suggest that HIMF can induce HIF-1, vascular endothelial growth factor-A, and interleukin-6, which are critical mediators of both hypoxic inflammation and PH pathophysiology.

Intestinal injury following liver transplantation was mediated by TLR4/NF-κB activation-induced cell apoptosis.

Intestinal motility and barriers are often impaired due to intestinal congestion during liver transplantation. Intestinal bacteria and enterogenous endotoxins enter into the blood stream or lymphatic system and translocate to other organs, which can result in postoperative multi-organ dysfunction (MODF) and systemic inflammatory reaction syndrome (SIRS) severely affecting patient survival. However, the mechanisms underlying liver transplantation-induced intestinal injury remain unclear and effective therapies are lacking. Thus, the present study investigated whether these effects were associated with endotoxin-mediated apoptosis. Rat autologous orthotopic liver transplantation (AOLT) models were established to observe dynamic intestinal injuries at different time-points following reperfusion. Changes in the levels of endotoxins and the primary receptor, toll-like receptor 4 (TLR4), as well as its downstream signaling molecule, nuclear factor-κB (NF-κB) were all determined. Finally, immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling assays were conducted to detect caspase-3 expression and intestinal cell apoptosis, respectively. AOLT resulted in significant pathological intestinal injury, with the most serious intestine damage apparent four or eight hours following reperfusion. Furthermore, the levels of endotoxins and inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, peaked during this time period and gradually decreased to the normal level. Notably, TLR4 and downstream NF-κB expression, as well as NF-κB-mediated caspase-3 activation and intestinal cell apoptosis coincided with the intestinal pathological damage. Thus, the possible mechanism of post-liver transplantation intestinal injury was demonstrated to be associated with NF-κB activation-induced cell apoptosis.

Downregulation of Lung Toll-Like Receptor 4 Could Effectively Attenuate Liver Transplantation-Induced Pulmonary Damage at the Early Stage of Reperfusion.

Acute lung injury (ALI) is a severe complication of orthotopic liver transplantation (OLT) with unclear underline mechanism. Toll-like receptor 4 (TLR4) has been identified as a key receptor mediating inflammation. We hypothesized that TLR4-mediated pulmonary inflammation may contribute to development of ALI during OLT. Patients with or without ALI were observed for serum cytokines and expression of TLR4 on peripheral blood polymorphonuclear leukocytes (PMNs). Next, rats which underwent orthotopic autologous liver transplantation (OALT) were divided into sham and model groups. Pulmonary function and the level of TLR4 expression and cytokines were analyzed. Furthermore, the role of TLR4 in OALT-mediated ALI was assessed in rats treated with TLR4-siRNA before OALT. The PMNs TLR4 expression and the serum TNF-α and IL-ß level were higher in patients with ALI than those with non-ALI. Interestingly, lung TLR4 expression was significantly increased after 8 hours of OALT with increased levels of TNF-α and IL-ß, which lead to lung pathological damage and an increase of lung myeloperoxidase content. Moreover, knockdown of TLR4 reduced lung cytokines release and reversed the above pathologic changes after OALT and finally improved rats' survival rate. In conclusion, TLR4 overexpression, potentially by stimulating proinflammatory cytokine overproduction, contributes to the development of ALI after OLT.

Intestinal NF-E2-related factor-2 expression and antioxidant activity changes in rats undergoing orthotopic liver autotransplantation.

Liver transplantation is known to trigger intestinal injuries. Oxidative damage that is induced by reactive oxygen species (ROS) plays a crucial role in ischemia-reperfusion injuries. NF-E2-related factor-2 (Nrf2) and its modulated antioxidant enzymes form the critical endogenous antioxidant system to scavenge ROS. The present study investigated the dynamic changes of intestinal ROS levels, Nrf2 expression and antioxidant enzyme activity following orthotopic liver autotransplantation (OLAT). Sprague-Dawley rats were randomly divided into five groups consisting of one sham group and four groups with rats that underwent OLAT and were evaluated following 4, 8, 16 and 24 h, respectively. The intestinal specimens were collected for histopathological examination and the detection of hydrogen peroxide (H2O2), hydroxyl radical (•OH), malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels and the expression of Nrf2. The present study demonstrated that OLAT resulted in severe intestinal injury, which manifested as a significant change in the intestine pathological scores as early as 4 h and peaking at 8 h post-treatment. Oxidative stress was also revealed by the increase of the H2O2, •OH and MDA levels. Significant decreases were observed in the activity of SOD and CAT and a dramatic decrease occurred in the levels of GSH at 4 and 8 h post-treatment. All the parameters were restored gradually at 16 and 24 h post-treatment. The expression of Nrf2 in the intestinal tissues increased significantly at 4, 16 and 24 h following OLAT. The present study shows that an imbalance between oxidants and antioxidants contributes to intestinal oxidative injury, and that the upregulation of Nrf2 is not sufficient to withstand intestinal oxidative injury following OLAT.

Mast cell stabilization alleviates acute lung injury after orthotopic autologous liver transplantation in rats by downregulating inflammation.

BACKGROUND: Acute lung injury (ALI) is one of the most severe complications after orthotopic liver transplantation. Amplified inflammatory response after transplantation contributes to the process of ALI, but the mechanism underlying inflammation activation is not completely understood. We have demonstrated that mast cell stabilization attenuated inflammation and ALI in a rodent intestine ischemia/reperfusion model. We hypothesized that upregulation of inflammation triggered by mast cell activation may be involve in ALI after liver transplantation. METHODS: Adult male Sprague-Dawley rats received orthotopic autologous liver transplantation (OALT) and were executed 4, 8, 16, and 24 h after OALT. The rats were pretreated with the mast cell stabilizers cromolyn sodium or ketotifen 15 min before OALT and executed 8 h after OALT. Lung tissues and arterial blood were collected to evaluate lung injury. ß-hexosaminidase and mast cell tryptase levels were assessed to determine the activation of mast cells. Tumor necrosis factor α (TNF-α), interleukin (IL)-1ß and IL-6 in serum and lung tissue were analyzed by enzyme-linked immunosorbent assay. Nuclear factor-kappa B (NF-κB) p65 translocation was assessed by Western blot. RESULTS: The rats that underwent OALT exhibited severe pulmonary damage with a high wet-to-dry ratio, low partial pressure of oxygen, and low precursor surfactant protein C levels, which corresponded to the significant elevation of pro-inflammatory cytokines, ß-hexosaminidase, and tryptase levels in serum and lung tissues. The severity of ALI progressed and maximized 8 h after OALT. Mast cell stabilization significantly inhibited the activation of mast cells, downregulated pro-inflammatory cytokine levels and translocation of NF-κB, and attenuated OALT-induced ALI. CONCLUSIONS: Mast cell activation amplified inflammation and played an important role in the process of post-OALT related ALI.

Knockdown of myeloid differentiation protein-2 reduces acute lung injury following orthotopic autologous liver transplantation in a rat model.

BACKGROUND: Acute lung injury (ALI) is a serious complication that commonly occurs during orthotopic liver transplantation (OLT). Toll-like receptor 2/4 (TLR2/4) are the main membrane receptors that respond to inflammatory stimuli and mediate NF-kappa B (NF-κB) signal pathway. We previously showed that TLR2/4 expression on monocytes and serum cytokine levels were increased in patients with ALI induced by OLT. Myeloid differentiation protein-2 (MD-2) expresses the functional domains that combines TLRs and play a key regulatory role in TLRs activation. Therefore, we hypothesized that blocking MD-2 would inhibit the TLR2/4-mediated inflammatory response and lessen ALI induced by liver transplantation. METHOD: Thirty-two Sprague Dawley (SD) rats were randomly divided into four groups. One group received a sham operation (Group S), and the other three groups underwent orthotopic autologous liver transplantation (OALT) 48 h after intratracheal administration of saline (Model group; Group M), non-targeting siRNA (negative siRNA control group; Group NC) or siRNA against MD-2 (intervention group; Group RNAi). Lung pathology, lung water content, PaO2, and expression levels of MD-2, TLR2/4, NF-κB, TNF-α, IL-1ß and IL-6 were assessed 8 h after OALT. RESULTS: In Groups M and NC, OALT produced marked lung pathology with decreased PaO2 levels and increased MD-2, TLR2/4 gene and protein expression levels. Furthermore, the nuclear translocation of the NF-κB P65 subunit, was increased, as were lung concentrations of TNF-α, IL-1ß and IL-6. The pathology of ALI and the severity of the above biochemical changes induced by OALT were significantly reduced in the group treated with MD-2 siRNA. CONCLUSION: MD-2 gene knock-down attenuated the increase in TLR2/4 activation and reduced ALI after OALT.

Lipopolysaccharide effects on the proliferation of NRK52E cells via alternations in gap-junction function.

BACKGROUND: Gap junctions regulate proper kidney function by facilitating intercellular communication, vascular conduction, and tubular purinergic signaling. However, no clear relationship has been described between gap-junction function and acute kidney injury induced by the endotoxin lipopolysaccharide (LPS). METHODS: Normal rat kidney epithelial cells (NRK52E cells) were seeded at high and low densities to promote or impede gap-junction formation, respectively, and establish distinctive levels of intercellular communication in culture. Cells were then challenged with LPS at various concentrations (10-1,000 ng/mL). LPS-induced formation and function of gap junctions were assessed by measuring changes in cell proliferation and colony-forming rates, fluorescent dye transmission to adjacent cells, expression levels of connexin43, and repositioning of confluent cells in response to the gap junction inhibitor oleamide or agonist retinoic acid. RESULTS: The cell proliferation rate and colony-forming rate of high- and low-density NRK52E cells were decreased upon LPS challenge, in a dose-dependent manner. The colony-forming rate of confluent high-density cells was significantly lower than that of low-density cells. Oleamide treatment raised the LPS-induced colony-forming rate of high-density cells, whereas retinoic acid decreased the rate. Neither oleamide nor retinoic acid significantly affected the LPS-induced colony-forming rate of low-density cells. Fluorescence transmission of high-density cells was reduced by LPS challenge, in a dose-dependent manner, but inclusion of retinoic acid increased the LPS-induced transmission of fluorescence. LPS challenge of either high- or low-density NRK52E cells resulted in down-regulated connexin43 expression. CONCLUSION: Gap-junction function plays an important role in concentration-dependent cytotoxic effect of LPS on normal rat kidney cells in vitro.

[Nedaplatin or cisplatin combined with 5-fluorouracil for treatment of stage III-IVa nasopharyngeal carcinoma: a randomized controlled study].

OBJECTIVE: To compare the efficacy and side effects of nedaplatin plus 5-fluorouracil (5-Fu) and cisplatin plus 5-Fu for treatment of stage III-IVa nasopharyngeal carcinoma (NPC). METHODS: A total of 100 patients with NPC proved by histopathology were divided into nedaplatin plus 5-Fu group (NF group) and cisplatin plus 5-Fu group (PF group), 50 cases in each group. NF group: nedaplatin 30 mg/m(2), d1-d3, 5-Fu 500 mg/m(2) d1-d5, repeated every 3 weeks for 2 cycles. PF group: cisplatin 30 mg/m(2) d1-d3, 5-Fu 500 mg/m(2) d1-d5, repeated every 3 weeks for 2 cycles. χ(2) test was used to compare the efficacy and side-effects of the two groups. RESULTS: All the 100 cases were evaluable and their clinical data in the two groups were comparable. Six patients with complete response were observed, 3 cases in NF group and 3 in PF group. The overall response rates were 86.0% in NF group and 84.0% in PF group, with no significant difference (χ(2) = 0.078, P = 0.779). The rates of leukocytopenia, thrombocytopenia, impairment of hepatic and renal function were similar whereas more patients in the PF group than in the NF group suffered from nausea and vomiting (88.0% vs. 56.0%, P = 0.000). CONCLUSIONS: Nedaplatin plus 5-Fu is an effective treatment regimen for NPC. When compared with PF regimen, the response rate is similar. However, NF regimen shows a significant superiority in reducing nausea and vomiting.

[Clinical analysis of xerostomia in patients with nasopharyngeal carcinoma after radiation therapy].

BACKGROUND & OBJECTIVE: There is few report on the xerostomia of the patients with nasopharyngeal carcinoma after conventional radiation therapy. Xerostomia is a serious, permanent, and ubiquitous sequelae in the patients with nasopharyngeal carcinoma after conventional radiation therapy. It has a significant impact on the patient's quality of life. This study was designed to investigate the severity of xerostomia and its impact on the quality of life in patients with nasopharyngeal carcinoma after conventional radiation therapy. METHODS: One hundred and thirty-six patients with nasopharyngeal carcinoma, treated by conventional radiation therapy in Cancer Center, Sun Yat-sen University, were surveyed by interview at the outpatient. A questionnaire and a visual analog scale (VAS) were used in analysis of xerostomia and xerostomia-related problems. RESULTS: Of 136 patents, 73.5% of the patients experienced a moderate to severe degree of xerostomia. 82.4% of the patients had to sip water to facilitate speech; 92.6% of the patients had to sip water to facilitate chewing and swallowing; 91.2% of the patients changed their feeding pattern (can eat only mashed food); 61.3% of the patients had to wake up to drink water because of dry mouth; 75.0% of the patients had teeth deteriorated. CONCLUSION: 73.5% of the patients with nasopharyngeal carcinoma after conventional radiation therapy experienced a moderate to severe degree of xerostomia. Xerostomia has a significant impact on the patient's speech, deglutition, sleep, and increases the morbidity rate of the tooth.

[Significance of cell-free Epstein-Barr virus DNA in monitoring prognosis of nasopharyngeal carcinoma].

BACKGROUND & OBJECTIVE: It has been reported that cell-free Epstein-Barr virus (EBV-DNA) in plasma was useful in diagnosing and monitoring nasopharyngeal carcinoma (NPC). The current study was designed to evaluate the significance of EBV-DNA in monitoring the prognosis of nasopharyngeal carcinoma and to compare with VCA/IgA and EA/IgA. METHODS: EBV-DNA, VCA/IgA, and EA/IgA levels in plasma were detected in different NPC patients after radiotherapy, including 30 distant metastasis patients, 22 locoregional recurrence patients, 24 remission individuals who had been followed up more than 2 years after treatment. EBV-DNA was detected using real-time quantitative PCR system;VCA/IgA and EA/IgA were tested using regular immunofluorescence. In cohort study, the indexes were tested in different radiation periods for the 20 new cases of nasopharyngeal carcinoma. RESULTS: The median plasma EBV-DNA concentration was 135,100 copies/ml (interquartile range: 5,525-1,003,750) in metastasis group, 20,500 copies/ml (interquartile range: 0-58,500) in locoregional recurrence group and 0 copies/ml (interquartile range: 0-0) in continuous remission group (P< 0.05). The levels of VCA/IgA and EA/IgA had no significant difference in different groups. The high level of EBV-DNA concentration in metastasis group was more than that in locoregional recurrence group. At the level of 1,000,000 copies/ml, EBV DNA indicated distant metastasis of NPC with a specificity of 100% and a sensitivity of 27.3%; however, the sensitivity was 0 copies/ml in locoregional recurrence group. For the 20 new patients, EBV DNA concentration gradually decreased in the radiation period, 32,050 copies/ml (interquartile range: 3,880-317,750) before radiation, 0 copies/ml (interquartile range: 0-14,375) when 40 Gy radiation dose and 0 copies/ml (interquartile range: 0-2940) when the radiation finished (P< 0.05). However, the levels of VCA/IgA and EA/IgA had no significant difference. CONCLUSION: The plasma cell-free EBV-DNA is more valuable than VCA/IgA and EA/IgA for monitoring the prognosis of NPC patients.