Interleukin-8 as a therapeutic target for chronic low back pain: Upregulation in human cerebrospinal fluid and pre-clinical validation with chronic reparixin in the SPARC-null mouse model.

BACKGROUND: Low back pain (LBP) is the leading global cause of disability and is associated with intervertebral disc degeneration (DD) in some individuals. However, many adults have DD without LBP. Understanding why DD is painful in some and not others may unmask novel therapies for chronic LBP. The objectives of this study were to a) identify factors in human cerebrospinal fluid (CSF) associated with chronic LBP and b) examine their therapeutic utility in a proof-of-concept pre-clinical study. METHODS: Pain-free human subjects without DD, pain-free human subjects with DD, and patients with chronic LBP linked to DD were recruited and lumbar MRIs, pain and disability levels were obtained. CSF was collected and analyzed by multiplex cytokine assay. Interleukin-8 (IL-8) expression was confirmed by ELISA in CSF and in intervertebral discs. The SPARC-null mouse model of progressive, age-dependent DD and chronic LBP was used for pre-clinical validation. Male SPARC-null and control mice received systemic Reparixin, a CXCR1/2 (receptors for IL-8 and murine analogues) inhibitor, for 8 weeks. Behavioral signs of axial discomfort and radiating pain were assessed. Following completion of the study, discs were excised and cultured, and conditioned media was evaluated with a protein array. FINDINGS: IL-8 was elevated in CSF of chronic LBP patients with DD compared to pain-free subjects with or without DD. Chronic inhibition with reparixin alleviated low back pain behaviors and attenuated disc inflammation in SPARC-null mice. INTERPRETATION: These studies suggest that the IL-8 signaling pathway is a viable therapy for chronic LBP. FUND: Supported by NIH, MMF, CIHR and FRQS.

Evidence for a Role of Nerve Injury in Painful Intervertebral Disc Degeneration: A Cross-Sectional Proteomic Analysis of Human Cerebrospinal Fluid.

Intervertebral disc degeneration (DD) is a cause of low back pain (LBP) in some individuals. However, although >30% of adults have DD, LBP only develops in a subset of individuals. To gain insight into the mechanisms underlying nonpainful versus painful DD, human cerebrospinal fluid (CSF) was examined using differential expression shotgun proteomic techniques comparing healthy control participants, subjects with nonpainful DD, and patients with painful DD scheduled for spinal fusion surgery. Eighty-eight proteins were detected, 27 of which were differentially expressed. Proteins associated with DD tended to be related to inflammation (eg, cystatin C) regardless of pain status. In contrast, most differentially expressed proteins in DD-associated chronic LBP patients were linked to nerve injury (eg, hemopexin). Cystatin C and hemopexin were selected for further examination using enzyme-linked immunosorbent assay in a larger cohort. While cystatin C correlated with DD severity but not pain or disability, hemopexin correlated with pain intensity, physical disability, and DD severity. This study shows that CSF can be used to study mechanisms underlying painful DD in humans, and suggests that while painful DD is associated with nerve injury, inflammation itself is not sufficient to develop LBP. PERSPECTIVE: CSF was examined for differential protein expression in healthy control participants, pain-free adults with asymptomatic intervertebral DD, and LBP patients with painful intervertebral DD. While DD was related to inflammation regardless of pain status, painful degeneration was associated with markers linked to nerve injury.

Anesthetic care and perioperative complications in children with Sanfilipo Syndrome Type A.

BACKGROUND: Patients with mucopolysaccharidoses (MPS) are generally considered high risk for anesthesia care, owing to disease-related factors. Sanfilippo syndrome type A (MPS IIIA) is the most frequently occurring MPS. Anesthesia-specific information for MPS IIIA is not readily available in the literature. OBJECTIVES: To report post hoc analyses on anesthesia care and outcomes from a 2-year study of the natural history of patients with untreated MPS IIIA (NCT01047306). METHODS: Subjects were ≥1 year of age, developmental age ≥1 year, and without significant central nervous system impairment (other than that due to MPS IIIA) or issues that would preclude study procedures. Procedures requiring general anesthesia included brain/abdominal magnetic resonance imaging, lumbar puncture, and echocardiography. Sedation, intubation, and extubation procedures as well as postoperative airway problems were recorded at baseline and 6, 12, and 24 months of age. RESULTS: Twenty-five patients (baseline age, 13-220 months) received a total of 94 general anesthetics. Patients successfully received oral sedation prior to 76 of 94 anesthetics. No patients required airway intervention or oxygen supplementation during sedation. All anesthesia providers described facemask ventilation and endotracheal intubations as 'easy'. All subjects were successfully extubated after completion of the procedures. No patients required reintubation. Six (24%) patients had episodes of postoperative airway problems: wheezing (7/94, 7.4%), croup (6/94, 6.4%), and laryngospasm (2/94, 2.1%). CONCLUSION: We found no change in the modified Cormack-Lehane intubation grades in 25 Sanfilippo syndrome type A children over the 2-year study period.

Sodium nitroprusside in 2014: A clinical concepts review.

Sodium nitroprusside has been used in clinical practice as an arterial and venous vasodilator for 40 years. This prodrug reacts with physiologic sulfhydryl groups to release nitric oxide, causing rapid vasodilation, and acutely lowering blood pressure. It is used clinically in cardiac surgery, hypertensive crises, heart failure, vascular surgery, pediatric surgery, and other acute hemodynamic applications. In some practices, newer agents have replaced nitroprusside, either because they are more effective or because they have a more favorable side-effect profile. However, valid and adequately-powered efficacy studies are sparse and do not identify a superior agent for all indications. The cyanide anion release concurrent with nitroprusside administration is associated with potential cyanide accumulation and severe toxicity. Agents to ameliorate the untoward effects of cyanide are limited by various problems in their practicality and effectiveness. A new orally bioavailable antidote is sodium sulfanegen, which shows promise in reversing this toxicity. The unique effectiveness of nitroprusside as a titratable agent capable of rapid blood pressure control will likely maintain its utilization in clinical practice for the foreseeable future. Additional research will refine and perhaps expand indications for nitroprusside, while parallel investigation continues to develop effective antidotes for cyanide poisoning.

Cyanide toxicity in juvenile pigs and its reversal by a new prodrug, sulfanegen sodium.

BACKGROUND: Cyanide (CN) toxicity is a serious clinical problem and can occur with sodium nitroprusside (SNP) administration, accidental smoke inhalation, industrial mishaps, and bio-terrorism. In this study, we induced severe CN toxicity independently with SNP or sodium cyanide (NaCN) in a juvenile pig model to demonstrate reversal of severe CN toxicity with a new antidote, sulfanegen sodium, a prodrug of 3-mercaptopyruvate. METHODS: SNP study: A pilot study in 11 anesthetized, mechanically ventilated juvenile pigs allowed us to determine the dose of SNP to induce CN toxicity. Blood CN, serum lactates, and blood gases were monitored. CN toxicity was defined as the occurrence of severe lactic acidosis accompanied by significant elevation in blood CN levels. Based on this pilot study, 8 anesthetized pigs received a high-dose i.v. infusion of SNP (100 mg/h) for 2 hours to induce CN toxicity. They were then randomized to receive either sulfanegen sodium or placebo. Four pigs received 3 doses of sulfanegen sodium (2.5 g i.v.) every hour after induction of severe CN toxicity, and 4 pigs received placebo. NaCN study: A pilot study was conducted in 4 spontaneously ventilating pigs sedated with propofol plus ketamine to demonstrate hemodynamic and metabolic stability for several hours. After this, 6 pigs were similarly sedated and given NaCN in bolus aliquots to produce CN toxicity ultimately resulting in death. Hemodynamics and metabolic variables were followed to define peak CN toxicity. In another group of 6 pigs, severe CN toxicity was induced by this method, and at peak toxicity, the animals were given sulfanegen sodium (2.5 g i.v.) followed by a repeat dose 60 minutes later in surviving animals. RESULTS: SNP study: The pilot study demonstrated the occurrence of a significant increase in blood CN levels (P < 0.05) accompanied by severe lactic acidemia (P < 0.05) in all pigs receiving a high dose of SNP. Administration of the sulfanegen antidote resulted in progressive significant reduction in blood lactate and CN levels with 100% survival (P < 0.05), whereas the placebo-treated pigs deteriorated and did not survive (P < 0.05). NaCN study: NaCN injection resulted in CN toxicity accompanied by severe lactic acidosis and mortality in all the pigs. Sulfanegen sodium reversed this toxicity and prevented mortality in all the pigs treated with this antidote. CONCLUSIONS: CN toxicity can be successfully induced in a juvenile pig model with SNP or NaCN. The prodrug, sulfanegen sodium, is effective in reversing CN toxicity induced by SNP or NaCN.

The effect of insufflation pressure on CO(2) pneumoperitoneum and embolism in piglets.

UNLABELLED: We conducted this study to investigate the effect of insufflation pressure on the pathophysiology of CO(2) pneumoperitoneum and embolism in an infant model. Twenty anesthetized piglets had stepwise intraperitoneal insufflation with CO(2) for 15 min at pressures ranging from 5 to 20 mm Hg. The piglets were ventilated to baseline normocarbia (ETCO(2) = 30 mm Hg, PaCO(2) = 38 mm Hg) before beginning each insufflation. CO(2) was then insufflated IV in 15 of these piglets at the same pressures. There was no reduction of blood pressure or cardiac output with intraperitoneal insufflation, but the stroke volume declined significantly (*P < 0.05) from (mean +/- SE) 10.6 +/- 1.3 mL to 8.5 +/- 1.3* mL and from 10.0 +/- 1.4 mL to 7.2 +/- 1.2* mL at 15 and 20 mm Hg insufflation pressure, respectively. Abdominal insufflation at 5, 10, 15, and 20 mm Hg caused an increase in ETCO(2) to 31.7 +/- 0.8 mm Hg, 35.6 +/- 1.2* mm Hg, 37.5 +/- 1.5* mm Hg, and 40.1 +/- 1.8* mm Hg and in PaCO(2) to 41.1 +/- 1.3* mm Hg, 44.2 +/- 1.4* mm Hg, 49.9 +/- 1.8* mm Hg, and 53.0 +/- 2.1* mm Hg, respectively. In contrast, the ETCO(2)decreased to 19.4 +/- 1.5* mm Hg, 20.4 +/- 1.4 mm Hg, 15.2 +/- 2.1* mm Hg, and 10.6 +/- 2.0* mm Hg with IV insufflation using the same pressures. IV insufflation caused marked hypotension and mortality. As the insufflation pressure increased, the mortality increased (0 in 15, 1 in 15, 1 in 14, and 6 in 13* at 5, 10, 15, and 20 mm Hg; *P < 0.05 vs 0 in 15, 1 in 15, and 1 in 14). This study suggests that although intraperitoneal insufflation up to 20 mm Hg may be tolerated hemodynamically, the lowest possible pressure should be used to reduce hypercarbia. A low insufflation pressure may also prevent mortality from CO(2) embolism. IMPLICATIONS: The lowest pressure possible should be used when inflating the abdomen with CO(2) to perform a laparoscopy in babies. A low pressure allows better ventilation and may prevent mortality if CO(2) is accidentally injected into a vein.

Anaesthetic management of patients with congenital heart disease presenting for non-cardiac surgery.

The incidence of congenital heart disease is about one percent of all live births in the United States. Treatment is being performed at a younger age and these children are showing improved survival. It is not unusual for children with congenital heart disease to present for non-cardiac surgery. Their management depends on their age, type of lesion, extent of corrective procedure, the presence of complications and other congenital anomalies. Each patient needs a detailed pre-operative evaluation to understand the abnormal anatomy and physiology, and related anaesthetic implications. No anaesthetic agent is an absolute contraindication, although drugs beneficial for one lesion may be detrimental for another. Regional anaesthesia has also been safely used in children with congenital heart disease. However the anaesthesiologist must have a detailed understanding of the pathophysiology of the lesion and the pharmacology of drugs being used to be able to provide safe anaesthesia for children with congenital heart disease.