Novel application of acetazolamide to reduce cerebrospinal fluid production in patients undergoing thoracoabdominal aortic surgery.

OBJECTIVES: Paraplegia is a rare but devastating complication, which may follow thoracoabdominal aortic surgery. Many adjuncts have been developed to reduce this risk including cerebrospinal fluid (CSF) drainage. Acetazolamide (carbonic anhydrase inhibitor) is a drug used to counteract mountain sickness and one of its effects is to reduce CSF production. Here, we report its first postoperative application in thoracoabdominal surgery with the aim of reducing cerebrospinal cord perfusion pressure and reducing risk of paraplegia. METHODS: We retrospectively reviewed 6 patients who have been treated with this drug between 2011 and 2012 who were undergoing thoracoabdominal aortic surgery. Our indications were decided to include: (i) patients in whom a spinal drain could not be positioned; (ii) patients with blood-stained CSF; (iii) patients in whom the volume of CSF drained was outside guidelines; (iv) patients in whom CSF pressure was elevated; (v) patients with excessive vasopressor usage and (vi) patients with postoperative neurological dysfunction as measured by motor-evoked potentials or clinical examination. All were given 500 mg intravenous acetazolamide, not more than eight hourly, for a duration dependent on response. RESULTS: In the 6 patients, 2 received a single dose of the drug and responded by an immediate drop in intracranial pressure (ICP) pressure. Of the 4 who received multiple doses of the drug, 1 had an immediate decline in ICP after each of the first six doses, while 3 had no discernable response. CONCLUSIONS: This is the first report of the efficacy of acetazolamide in reducing CSF production and lowering ICP during thoracoabdominal aortic surgery. We believe that its use will be beneficial in the 6 patient groups described. Our experience suggests there are 'responders' and 'non-responders', the characteristics of whom are yet to be defined. Its efficacy in reducing not just CSF volume and ICP but also clinically relevant morbidity such as paraplegia, is the subject of a planned randomized controlled trial. This report serves to raise awareness of the possible efficacy of this drug when normal management strategies are limited or exhausted.

Activation of retinoid receptor-mediated signaling ameliorates diabetes-induced cardiac dysfunction in Zucker diabetic rats.

Diabetic cardiomyopathy (DCM) is a significant contributor to the morbidity and mortality associated with diabetes and metabolic syndrome. Retinoids, through activation of retinoic acid receptor (RAR) and retinoid x receptor (RXR), have been linked to control glucose and lipid homeostasis, with effects on obesity and diabetes. However, the functional role of RAR and RXR in the development of DCM remains unclear. Zucker diabetic fatty (ZDF) and lean rats were treated with Am580 (RARα agonist) or LGD1069 (RXR agonist) for 16 weeks, and cardiac function and metabolic alterations were determined. Hyperglycemia, hyperlipidemia and insulin resistance were observed in ZDF rats. Diabetic cardiomyopathy was characterized in ZDF rats by increased oxidative stress, apoptosis, fibrosis, inflammation, activation of MAP kinases and NF-κB signaling and diminished Akt phosphorylation, along with decreased glucose transport and increased cardiac lipid accumulation, and ultimately diastolic dysfunction. Am580 and LGD1069 attenuated diabetes-induced cardiac dysfunction and the pathological alterations, by improving glucose tolerance and insulin resistance; facilitating Akt activation and glucose utilization, and attenuating oxidative stress and interrelated MAP kinase and NF-κB signaling pathways. Am580 inhibited body weight gain, attenuated the increased cardiac fatty acid uptake, ß-oxidation and lipid accumulation in the hearts of ZDF rats. However, LGD1069 promoted body weight gain, hyperlipidemia and cardiac lipid accumulation. In conclusion, our data suggest that activation of RAR and RXR may have therapeutic potential in the treatment of diabetic cardiomyopathy. However, further studies are necessary to clarify the role of RAR and RXR in the regulation of lipid metabolism and homeostasis.

Retinoic acid protects cardiomyocytes from high glucose-induced apoptosis through inhibition of NF-κB signaling pathway.

We have previously shown that retinoic acid (RA) has protective effects on high glucose (HG)-induced cardiomyocyte apoptosis. To further elucidate the molecular mechanisms of RA effects, we determined the interaction between nuclear factor (NF)-κB and RA signaling. HG induced a sustained phosphorylation of IKK/IκBα and transcriptional activation of NF-κB in cardiomyocytes. Activated NF-κB signaling has an important role in HG-induced cardiomyocyte apoptosis and gene expression of interleukin-6 (IL-6), tumor necrosis factor (TNF)-α, and monocyte chemoattractant protein-1 (MCP-1). All-trans RA (ATRA) and LGD1069, through activation of RAR/RXR-mediated signaling, inhibited the HG-mediated effects in cardiomyocytes. The inhibitory effect of RA on NF-κB activation was mediated through inhibition of IKK/IκBα phosphorylation. ATRA and LGD1069 treatment promoted protein phosphatase 2A (PP2A) activity, which was significantly suppressed by HG stimulation. The RA effects on IKK and IκBα were blocked by okadaic acid or silencing the expression of PP2Ac-subunit, indicating that the inhibitory effect of RA on NF-κB is regulated through activation of PP2A and subsequent dephosphorylation of IKK/IκBα. Moreover, ATRA and LGD1069 reversed the decreased PP2A activity and inhibited the activation of IKK/IκBα and gene expression of MCP-1, IL-6, and TNF-α in the hearts of Zucker diabetic fatty rats. In summary, our findings suggest that the suppressed activation of PP2A contributed to sustained activation of NF-κB in HG-stimulated cardiomyocytes; and that the protective effect of RA on hyperglycemia-induced cardiomyocyte apoptosis and inflammatory responses is partially regulated through activation of PP2A and suppression of NF-κB-mediated signaling and downstream targets.

The safe use of spinal drains in thoracic aortic surgery.

Paraplegia is a devastating complication which may occur following surgery on the thoracic aorta. The use of a cerebrospinal fluid drain (CSFD) has helped reduce the incidence of neurological deficit; however, the management of patients with a CSFD postsurgery requires nurses and doctors to have expertise and awareness of the associated complications. The National Patient Safety Agency (UK) has highlighted a number of cases involving inadvertent spinal injections throughout the UK National Health Service (NHS). To this end we have introduced a protocol or 'care bundle' for safe CSFD care as well as drain management. The protocol was developed by medical and nursing staff at our institution based on clinical experience and literature reviews over a two-year period (2008-2010). Interventions undertaken during the development of the protocol included discussion with the UK National Patient Safety Agency (NPSA). Content of the protocol was reviewed by internal regulatory bodies within the hospital prior to ratification and general dissemination. Clear guidance is given within the policy on the standards expected when caring for the line and managing drainage according to agreed parameters of spinal cord perfusion pressure. The protocol constitutes five documents which guide staff in the care of CSFD, its routine management, documentation and interventions necessary once neurological deficit is detected. Document 1 which is a checklist, communication tool and aide-memoire was developed to ensure effective management, when the patient arrives in intensive care unit (ICU) from theatre. Document 2 ensures that early detection of a neurological deficit is noted and with Document 3 is acted upon immediately to reverse the injury. Document 4 provides information on the safe administration of analgesia via the spinal drain and has reference to the Glasgow Coma Scale. Document 5 is a bespoke observation chart for documenting CSFD pressure and cerebrospinal fluid drainage. In conclusion, the protocol acts as a guide for safe management of the CSFD and directs staff in reacting to detection of neurological deficit.

Adenoviral sensors for high-content cellular analysis.

To maximize the potential of high-content cellular analysis for investigating complex cellular signaling pathways and processes, we have generated a library of adenoviral encoded cellular sensors based on protein translocation and reporter gene activation that enable a diverse set of assays to be applied to lead compound profiling in drug discovery and development. Adenoviral vector transduction is an efficient and technically simple system for expression of cellular sensors in diverse cell types, including primary cells. Adenoviral vector-mediated transient expression of cellular sensors, either as fluorescent protein fusions or live cell gene reporters, allows rapid assay development for profiling the activities of candidate drugs across multiple cellular systems selected for biological and physiological relevance to the target disease state.

Gastroesophageal reflux and tracheal aspiration in the thoracotomy position: should ranitidine premedication be routine?

UNLABELLED: Aspiration of gastric contents may contribute to pulmonary complications after thoracotomy. The incidence of gastroesophageal reflux (GER) and tracheal acid aspiration in patients undergoing thoracotomy in the lateral position is unknown. Ranitidine premedication reduces gastric volume, increases gastric pH, and may reduce GER. We used continuous intraluminal esophageal and tracheal pH monitoring probes to investigate the effect of ranitidine on the incidence of GER and tracheal aspiration in 80 adult patients undergoing thoracotomy. The study was placebo-controlled, randomized, and double-blinded. Patients at high risk of GER were excluded from the study. The incidence of acid GER in the placebo and ranitidine groups was 28.2% and 2.5%, respectively (P = 0.006). Multiple episodes of GER occurred in some patients in the placebo group only. The total number of episodes of GER in the placebo and ranitidine groups was 16 and 1, respectively (P = 0.002). The incidence of tracheal acid aspiration in the placebo and ranitidine groups was 7.7% and 2.5%, respectively (not significant). Patients undergoing thoracotomy are therefore at high risk of acid GER, which may lead to tracheal acid aspiration in an appreciable proportion. Premedication with ranitidine significantly reduces, but does not eliminate, the incidence of this potentially life-threatening complication. IMPLICATIONS: Gastroesophageal reflux (GER) and tracheal aspiration of acid may increase morbidity and mortality in patients undergoing thoracotomy. This randomized, double-blinded, placebo-controlled study demonstrates frequent incidences of both acid GER and tracheal acid aspiration during surgery that are significantly reduced by premedication with ranitidine.