Efficacy of perioperative pharmacological and regional pain interventions in adult spine surgery: a network meta-analysis and systematic review of randomised controlled trials.

BACKGROUND: Development of a widely accepted standardised analgesic pathway for adult spine surgery has been hampered by the lack of quantitative analysis. We conducted a systematic review and network meta-analysis (NMA) to compare, rank, and grade all pharmacological and regional interventions used in adult spine surgery. METHODS: A systematic search was performed in January 2021. We performed double study screening, selection, and data extraction. The co-primary outcomes were cumulative morphine consumption (mg) and visual analogue pain score (range 0-10) at postoperative 24 h. An NMA was performed using the Bayesian approach (random effects model). We also ranked and graded all analgesic interventions using the Grading of Recommendations Assessment, Development and Evaluation approach for NMA. RESULTS: We screened 5908 studies and included 86 randomised controlled studies, which comprised 6284 participants. Of 20 pharmacological and 10 regional interventions, the most effective intervention was triple-drug therapy, consisting of paracetamol, nonsteroidal anti-inflammatory drugs, and adjunct. The pooled mean reduction in morphine consumption and pain score at postoperative 24 h were -26 (95% credible interval [CrI]: -39 to -12) mg and -2.3 (95% CrI: -3.1 to -1.4), respectively. Double-drug therapy was less effective, but showed moderate morphine reduction in a range of -15 to -17 mg and pain score reduction in a range of -1 to -1.6. Single-agent interventions were largely ineffective. CONCLUSIONS: Triple-drug therapy is the most effective pain intervention in adult spine surgery with moderate-to-high certainty of evidence. We have also identified a graded analgesic effect, in which analgesic efficacy increased with the number of multimodal drugs used. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (CRD42020171326).

Mapping and functional characterization of murine kidney injury molecule-1 proteolytic cleavage site.

Kidney injury molecule-1 (KIM-1), also known as T cell immunoglobulin and mucin domain 1 (TIM-1), is a transmembrane glycoprotein expressed on proximal tubule epithelia during acute kidney injury (AKI). Extracellular domain of KIM-1 undergoes spontaneous and activated ectodomain shedding into urine and blood via metalloproteases. Soluble KIM-1 (blood and urinary) is a reliable clinical biomarker of proximal tubular injury, but the biological significance of shedding remains unknown. The aim of this study was to identify the specific shedding enzyme and the proteolytic cleavage site of murine KIM-1, followed by the characterization of its functional relevance. In this regard, isoleucine (I) I202 was identified as the potential cleavage site. Mutation of isoleucine I202 to glutamine (I202Q) or alanine (I202A) significantly reduced both constitutive and induced KIM-1 shedding and ultimately efferocytosis. It was also uncovered that ADAM10 is the major sheddase that mediates the proteolytic cleavage of murine KIM-1. In addition, ADAM10-induced KIM-1 shedding was required for efficient phagocytic clearance of apoptotic cells. Importantly, the findings that the addition of exogenous shed KIM-1 rescued the phagocytic impairment suggest that shed KIM-1 is capable of modulating efferocytosis of apoptotic bodies and could represent a potential functional role of the soluble ectodomain KIM-1 during AKI.