Research Publications Spotlight

Hopkins TJ, Raghunathan K, Barbeito A, Cooter M, Stafford-Smith M, Schroeder R, Grichnik K, Gilbert R, Aronson S. Associations Between ASA Physical Status and Postoperative Mortality at 48 H: A Contemporary Dataset Analysis Compared to a Historical Cohort. Perioper Med (Lond). 2016 Oct 20;5:29. eCollection 2016.


BACKGROUND: In this study, we examined the association between American Society of Anesthesiologists Physical Status (ASA PS) designation and 48-h mortality for both elective and emergent procedures in a large contemporary dataset (patient encounters between 2009 and 2014) and compared this association with data from a landmark study published by Vacanti et al. in 1970.

METHODS: Patient history, hospital characteristics, anesthetic approach, surgical procedure, efficiency and quality indicators, and patient outcomes were prospectively collected for 732,704 consecutive patient encounters between January 1, 2009, and December 31, 2014, at 233 anesthetizing locations across 19 facilities in two US states and stored in the Quantum™ Clinical Navigation System (QCNS) database. The outcome (death within 48 h of procedure) was tabulated against ASA PS designations separately for patients with and without “E” status labels. To maintain consistency with the historical cohort from the landmark study performed by Vacanti et al. on adult men at US naval hospitals in 1970, we then created a comparison cohort in the contemporary dataset that consisted of 242,103 adult male patients (with/without E designations) undergoing elective and emergent procedures. Differences in the relationship between ASA PS and 48-h mortality in the historical and contemporary cohorts were assessed for patients undergoing elective and emergent procedures.

RESULTS: As reported nearly five decades ago, we found a significant trend toward increased mortality with increasing ASA PS for patients undergoing both elective and emergent procedures in a large contemporary cohort (p < 0.0001). Additionally, the overall mortality rate at 48 h was significantly higher among patients undergoing emergent compared to elective procedures in the large contemporary cohort (1.27 versus 0.03 %, p < 0.0001). In the comparative analysis with the historical cohort that focused on adult males, we found the overall 48-h mortality rate was significantly lower among patients undergoing elective procedures in the contemporary cohort (0.05 % now versus 0.24 % in 1970, p < 0.0001) but not significantly lower among those undergoing emergent procedures (1.88 % now versus 1.22 % in 1970, p < 0.0001).

CONCLUSIONS: The association between increasing ASA PS designation (1-5) and mortality within 48 h of surgery is significant for patients undergoing both elective and emergent procedures in a contemporary dataset consisting of over 700,000 patient encounters. Emergency surgery was associated with a higher risk of patient death within 48 h of surgery in this contemporary dataset. These data trends are similar to those observed nearly five decades ago in a landmark study evaluating the association between ASA PS and 48-h surgical mortality on adult men at US naval hospitals. When a comparison cohort was created from the contemporary dataset and compared to this landmark historical cohort, the absolute 48-h mortality rate was significantly lower in the contemporary cohort for elective procedures but not significantly lower for emergency procedures. The underlying implications of these findings remain to be determined.

Sisignano M, Angioni C, Park CK, Meyer Dos Santos S, Jordan H, Kuzikov M, Liu D, Zinn S, Hohman SW, Schreiber Y, Zimmer B, Schmidt M, Lu R, Suo J, Zhang DD, Schäfer SM, Hofmann M, Yekkirala AS, de Bruin N, Parnham MJ, Woolf CJ, Ji RR, Scholich K, Geisslinger G. Targeting CYP2J to Reduce Paclitaxel-Induced Peripheral Neuropathic Pain. Proc Natl Acad Sci U S A. 2016 Oct 17. pii: 201613246. [Epub ahead of print]


Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a severe dose- and therapy-limiting side effect of widely used cytostatics that is particularly difficult to treat. Here, we report increased expression of the cytochrome-P450-epoxygenase CYP2J6 and increased concentrations of its linoleic acid metabolite 9,10-EpOME (9,10-epoxy-12Z-octadecenoic acid) in dorsal root ganglia (DRGs) of paclitaxel-treated mice as a model of CIPNP. The lipid sensitizes TRPV1 ion channels in primary sensory neurons and causes increased frequency of spontaneous excitatory postsynaptic currents in spinal cord nociceptive neurons, increased CGRP release from sciatic nerves and DRGs, and a reduction in mechanical and thermal pain hypersensitivity. In a drug repurposing screen targeting CYP2J2, the human ortholog of murine CYP2J6, we identified telmisartan, a widely used angiotensin II receptor antagonist, as a potent inhibitor. In a translational approach, administration of telmisartan reduces EpOME concentrations in DRGs and in plasma and reverses mechanical hypersensitivity in paclitaxel-treated mice. We therefore suggest inhibition of CYP2J isoforms with telmisartan as a treatment option for paclitaxel-induced neuropathic pain.

Zhang MD, Barde S, Yang T, Lei B, Eriksson LI, Mathew JP, Andreska T, Akassoglou K, Harkany T, Hökfelt TG, Terrando N. Orthopedic Surgery Modulates Neuropeptides and BDNF Expression at the Spinal and Hippocampal Levels. Proc Natl Acad Sci U S A. 2016 Oct 25;113(43):E6686-E6695. Epub 2016 Oct 10.


Pain is a critical component hindering recovery and regaining of function after surgery, particularly in the elderly. Understanding the role of pain signaling after surgery may lead to novel interventions for common complications such as delirium and postoperative cognitive dysfunction. Using a model of tibial fracture with intramedullary pinning in male mice, associated with cognitive deficits, we characterized the effects on the primary somatosensory system. Here we show that tibial fracture with pinning triggers cold allodynia and up-regulates nerve injury and inflammatory markers in dorsal root ganglia (DRGs) and spinal cord up to 2 wk after intervention. At 72 h after surgery, there is an increase in activating transcription factor 3 (ATF3), the neuropeptides galanin and neuropeptide Y (NPY), brain-derived neurotrophic factor (BDNF), as well as neuroinflammatory markers including ionized calcium-binding adaptor molecule 1 (Iba1), glial fibrillary acidic protein (GFAP), and the fractalkine receptor CX3CR1 in DRGs. Using an established model of complete transection of the sciatic nerve for comparison, we observed similar but more pronounced changes in these markers. However, protein levels of BDNF remained elevated for a longer period after fracture. In the hippocampus, BDNF protein levels were increased, yet there were no changes in Bdnf mRNA in the parent granule cell bodies. Further, c-Fos was down-regulated in the hippocampus, together with a reduction in neurogenesis in the subgranular zone. Taken together, our results suggest that attenuated BDNF release and signaling in the dentate gyrus may account for cognitive and mental deficits sometimes observed after surgery.