March 2022

This prospective single-center cohort study found that 5 criteria - CRP level <150 mg/dL, return of bowel function, tolerating a diet, pain <5/10, and lacking a fever - could predict who would be least likely to have an anastomotic leak after laparoscopic colorectal surgery and might be a useful tool to identify patients who are safe for an early discharge.

Summary:
Enhanced Recovery After Surgery (ERAS) pathways have led to reduced postoperative complications, improved surgical outcomes, and shorter hospital lengths of stay for patients undergoing elective colorectal surgery. Data have even shown that discharge as early as postoperative day (POD) 3 is feasible for certain colorectal surgery patients. The most feared and devastating complication associated with early discharge for these patients is a missed anastomotic leak (AL); however, simple, clinically applicable criteria to determine which patients are at highest risk for AL, and thus should not be discharged early in their postoperative course, are not well defined. This single-institution prospective cohort study by Tavernier et al. sought to determine the association between 5 readily assessable clinical criteria (CRP <150mg/dL, diet toleration, return of bowel function, minimal pain, and absent fever throughout the hospital stay) and the development of AL within 30 days of surgery, or the ability for a successful early discharge (discharge by POD3 without development of complications or readmissions within 30 days of surgery), among patients undergoing elective, laparoscopic colorectal surgery.

The study included 287 patients. Notably, patients whose surgery was converted to an open procedure, who underwent creation of a stoma during the same procedure, or who had another major procedure performed simultaneously (eg, liver resection), were excluded. The most common operative indication was diverticulitis (139 of 287 [48.4%]), followed by cancer (83 of 287 [28.9%]), terminal ileitis in patients with Crohn’s disease (34 of 287 [11.8%]), or polyps with dysplasia or the inability to remove them entirely endoscopically (21 of 287 [7.3%]). One hundred and twenty-eight (44.6%) patients fulfilled all 5 clinical criteria, and of these, 76 (59.4%) were discharged by POD3. The most common reasons for delayed discharge were patient or physician preference. Two ALs occurred in patients who had fulfilled all criteria vs. 13 leaks in patients who did not (hazard ratio, 0.15 [95% CI, 0.03-0.69]; P = .01) The negative predictive value of fulfilling the 5 clinical criteria for ruling out ALs was 98.4%, and the positive predictive value of fulfilling the 5 clinical criteria for a successful early discharge was 78.9%. False-negative rates for anastomotic leak were 40% when CRP level alone was considered, 20% when the other 4 criteria alone were considered, and 13.3% when all 5 criteria were considered. Among those discharged on POD 3 or earlier, 9 of 139 (6.5%) required readmission compared with 11 of 148 (7.4%) discharged after POD 3.

A major strength of this study is its ability to take a small number of easily assessable clinical factors and show that they can be utilized to predict ALs. Other models, such as the Dutch Leakage Score, have attempted similar outcomes, but are not as practical for everyday use. This study demonstrates the ability of a simple prognostication model to identify patients at risk for development of an AL or who are safe for early discharge. Furthermore, it demonstrates that, in the correct clinical context, early discharge does not increase rates of readmission. As the authors note, other studies examining enhanced recovery programs have typically reported average length of stays of 5 days. In contrast, the authors find that the majority of patients discharged on either POD#2 or POD#3 within their study cohort who fulfill discharge criteria do not get readmitted. Finally, it demonstrates what one might expect, which is that CRP when considered in solidarity does not function very well as a determinant for AL. Although only patients who underwent laparoscopic colorectal surgery were considered, this has become the standard of care for elective colorectal surgery so is highly applicable to everyday practice. The 5 factors assessed in this study should be evaluated in conjunction with each other when determining a patient’s risk for the development of an AL after laparoscopic colorectal surgery, and thus whether that patient is safe for early discharge. As with any single institution study, this study is limited by selection bias and its generalizability. Any adoption of newly published protocols, procedures, or medications should always include a nuanced examination of the initial study's inclusion and exclusion criteria to best understand how to implement new practices.

This work in Science Translational Medicine combines complex mouse models with liver samples from bariatric surgery patients to suggest that inflammatory transcription factors directly promote metabolic dysfunction in the pathogenesis of insulin resistance, NAFLD, and NASH, rather than the other way around – a finding that speaks to the mechanisms underlying the improvements seen in NASH and insulin sensitivity after bariatric surgery.

Summary:
The incidence of nonalcoholic fatty liver disease (NAFLD) has increased dramatically in parallel with the obesity and diabetes epidemics, so much so that nonalcoholic steatohepatitis (NASH), is now a leading indication for liver transplant. Despite its ubiquity, the mechanisms driving the progression from obesity to NASH remain ill-defined. Obesity-induced inflammation is hypothesized to be central to this process including the upregulation proinflammatory cytokines. TNF and IL-6 are frequently cited as critical mediators of NASH progression and insulin resistance, however, blocking either factor fails to reliably improve insulin sensitivity, steatohepatitis, or obesity in animals or patients. Even today, weight loss, most notably through bariatric surgery, is the only effective means of reversing NASH, highlighting the need to better understand the relationship between obesity and inflammation to reduce the burden of obesity-related comorbidities.

This work from Patel et al including metabolism labs at Harvard, UT Southwestern, and Duke presents a novel axis in the relationship between obesity and inflammation. Work in this space often suggests that inflammatory cytokines and canonical apoptotic pathways are upregulated by steatosis to promote fibrosis, however, these authors suggest that upregulation of inflammatory transcription factors themselves may drive dysfunctional glucose metabolism and steatosis. Here the authors use sophisticated mouse models and targeted DNA sequencing techniques like CUT&RUN to identify that interferon regulatory factor 3 (IRF3) promotes insulin resistance through upregulation of PPP2r1b, a regulatory component of PP2A, a common phosphatase involved in the regulation of insulin signaling, triglyceride transport and hepatic glucose production. Although more work is needed to better define the mechanisms linking PP2A and the improved metabolic phenotype, the authors do show that blocking this axis with antisense oligonucleotides targeted to the IRF3 gene can reverse obesity-associated insulin resistance in mice, suggesting therapeutic potential that warrants further investigation.

While the mechanistic work from Patel et al. was in mice, the translational aspects of their paper demonstrate the power of complementing basic science work with patient samples. Patient cohorts included intraoperative liver biopsies collected during bariatric surgery or other surgical settings to assess liver histology or fibrosis. Bariatric surgery patients also underwent follow-up biopsies via a percutaneous approach at 5-9 months post-surgery. This approach allowed authors to validate the clinical relevance of their findings in humans, namely that the detrimental IRF3 axis was progressively upregulated as patients went from steatosis to NAFLD and NASH and was reversed by bariatric surgery. These elements of their paper not only support the therapeutic potential of the IRF3-PPP2R1B axis, but also suggests a potential mechanism by which bariatric surgery and weight loss improves Type 2 Diabetes and reverse NASH.

Intercostal liposomal bupivacaine injection for the treatment of rib fractures after blunt trauma was not superior to the normal saline injection in terms of reducing pain, hospital length of stay, or complications.

Summary:
This is a prospective, double-blinded, single-center RCT examining the use of liposomal bupivacaine for rib fractures in blunt trauma. There is at least a theoretical reason to think that a liposomal formulation (reported to have effect for 96 hours) injected locally would provide some benefit, with a small amount of evidence in other surgical literature to support that thought, but this population has been inadequately studied.

The authors randomized 100 adults with >=2 rib fractures or a sternal fracture and the inability to achieve 50% of their predicted inspiratory capacity on incentive spirometry, excluding those who were intubated, hemodynamically unstable, had GCS<8, or were being considered for surgical fixation. The treatment group received 3cc of liposomal bupivacaine injected just below each fractured rib in a posterior location, up to a maximum of 18cc over 6 ribs; the placebo group received 1cc of saline injected in the subcutaneous space over each affected rib. The use of ultrasound guidance was left to the discretion of the person performing the procedure and was only used in 5 patients. The injections were performed by trauma surgeons, but not those who were actively caring for the patients. Measured endpoints included morphine milligram equivalents (MME) used, reported pain scales (1-10), and IS volumes over the first 96hrs. A mixed effects model was used to evaluate treatment effect over time, reported as an interaction between treatment and time.

Patients had a mean of 4 +/- 3 rib fractures and study groups were well-balanced with respect to injury severity, demographics, and comorbidities. While both the treatment group and placebo group demonstrated a decrease in MME use over time, there was no difference between groups. Subgroup analyses of patients with <=6, 7-12, or >=13 rib fractures continued to demonstrate no difference. Differences in use of a variety of individual pain medications was also investigated; there was largely no difference except that there was a significant interaction between treatment and time in the oxycodone model, suggesting a trend towards greater oxycodone use over time in the bupivacaine group. There was a similar finding for hydromorphone use. There was no difference in pain scores between groups. The bupivacaine group achieved higher IS volumes and higher respiratory rate (RR) in the first 2 days than the control group, though there was no significant effect on the overall trajectory over the 96-hr study period. There was no difference in hospital or ICU LOS, nor was there a difference in use of epidurals or pneumonia rates, between groups.

Overall, this study is well-done and seems to suggest that there is little role for liposomal bupivacaine in blunt-injured rib fracture patients. The authors note the improvement in IS and RR in the first 48hrs and suggest that this may reflect a modest effect of bupivacaine that lasts for a shorter-than-anticipated time window. However, the downstream outcomes that we think of as related to IS and RR (i.e. LOS, pneumonia rates) were not impacted. It is possible that the success of this procedure is provider-dependent, particularly in the absence of imaging guidance, and that more success might be had with better or more uniform training. Additionally, the authors calculated a goal enrollment of 200 patients for an 80% power for their anticipated change in MME requirement, but stopped at 100 for a variety of logistical reasons. Thus, it is possible that this study was simply underpowered. Nonetheless, based on the data presented in this study, it would seem that there is no role for liposomal bupivacaine in rib fracture patients.