Enhanced recovery protocols for major upper gastrointestinal, liver and pancreatic surgery

BACKGROUND: 'Fast-track surgery' or 'enhanced recovery protocol' or 'fast-track rehabilitation', incorporating one or more elements of preoperative education, pain relief, early mobilisation, enteral nutrition and growth factors, may improve health-related quality of life and reduce length of hospital stay and costs. The role of enhanced recovery protocols in major upper gastrointestinal, liver and pancreatic surgery is unclear. OBJECTIVES: To assess the benefits and harms of enhanced recovery protocols compared with standard care (or usual practice) in major upper gastrointestinal, liver and pancreatic surgery. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Cochrane Library; 2015, Issue 3), MEDLINE, EMBASE and Science Citation Index Expanded until March 2015 to identify randomised trials. We also searched the references of included trials to identify further trials. SELECTION CRITERIA: We considered only randomised controlled trials (RCTs) performed in people undergoing major upper gastrointestinal, liver and pancreatic surgery, irrespective of language, blinding or publication status for inclusion in the review. DATA COLLECTION AND ANALYSIS: Two review authors independently identified trials and independently extracted data. We calculated the risk ratio (RR), mean difference (MD), or standardised mean difference (SMD) with 95% confidence intervals (CIs) using both fixed-effect and random-effects models using Review Manager 5, based on available case analysis. MAIN RESULTS: Ten studies met the inclusion criteria for the review, and nine studies provided information on one or more outcomes for the review. A total of 1014 participants were randomly assigned to the enhanced recovery protocol (499 participants) or standard care (515 participants) in the nine RCTs. Most of the trials included low anaesthetic risk participants with high performance status undergoing different upper gastrointestinal, liver and pancreatic surgeries. Eight trials incorporated more than one element of the enhanced recovery protocol. All of the trials were at high risk of bias. The overall quality of evidence was low or very low.None of the trials reported long-term mortality, medium-term health-related quality of life(three months to one year), time to return to normal activity, or time to return to work. The difference between the enhanced recovery protocol and standard care were imprecise for short-term mortality (enhanced recovery protocol: 4/425 (adjusted proportion = 0.6%); standard care: 1/443 (0.2%); seven trials; 868 participants; RR 2.79; 95% CI 0.44 to 17.73; very low quality evidence), proportion of people with serious adverse events (enhanced recovery protocol: 4/157 (adjusted proportion = 0.6%); standard care: 0/184 (0.0%); two trials; 341 participants; RR 5.57; 95% CI 0.68 to 45.89; very low quality evidence), number of serious adverse events (enhanced recovery protocol: 34/421 (8 per 100 participants); standard care: 46/438 (11 per 100 participants); seven trials; 859 participants; rate ratio 0.72; 95% CI 0.45 to 1.13; very low quality evidence), health-related quality of life (four trials; 373 participants; SMD 0.29; 95% CI -0.04 to 0.62; very low quality evidence) and hospital readmissions (enhanced recovery protocol: 14/355 (adjusted proportion = 3.3%); standard care: 9/378 (2.4%); seven trials; 733 participants; RR 1.4; 95% CI 0.69 to 2.87; very low quality evidence). The enhanced recovery protocol group had a lower proportion of people with mild adverse events (enhanced recovery protocol: 31/254 (adjusted proportion = 10.9%); standard care: 51/271 (18.8%); four trials; 525 participants; RR 0.58; 95% CI 0.39 to 0.85; low quality evidence), fewer number of mild adverse events (enhanced recovery protocol: 69/499 (13 per 100 participants); standard care: 128/515 (25 per 100 participants); nine trials; 1014 participants; rate ratio 0.52; 95% CI 0.39 to 0.70; low quality evidence), shorter length of hospital stay (nine trials; 1014 participants; MD -2.19 days; 95% CI -2.53 to -1.85; low quality evidence) and lower costs (four trials; 282 participants; MD USD -6300; 95% CI -8400 to -4200; low quality evidence) than standard care group. AUTHORS' CONCLUSIONS: Based on low quality evidence, enhanced recovery protocols may reduce length of hospital stay and costs (primarily because of reduction in hospital stay) in people undergoing major upper gastrointestinal, liver and pancreatic surgeries. However, the validity of the results is uncertain because of the risk of bias in the trials and the way the outcomes were measured. Future RCTs should be conducted with low risk of bias, and measure clinically important outcomes for including the three months to one year period

Interventions for necrotising pancreatitis

BACKGROUND: Acute necrotising pancreatitis carries significant mortality, morbidity, and resource use. There is considerable uncertainty as to how people with necrotising pancreatitis should be treated. OBJECTIVES: To assess the benefits and harms of different interventions in people with acute necrotising pancreatitis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2015, Issue 4), MEDLINE, EMBASE, Science Citation Index Expanded, and trials registers to April 2015 to identify randomised controlled trials (RCT). We also searched the references of included trials to identify further trials. SELECTION CRITERIA: We considered only RCTs performed in people with necrotising pancreatitis, irrespective of aetiology, presence of infection, language, blinding, or publication status for inclusion in the review. DATA COLLECTION AND ANALYSIS: Two review authors independently identified trials and extracted data. We calculated the odds ratio (OR) and mean difference with 95% confidence intervals (CI) using Review Manager 5 based on an available-case analysis using fixed-effect and random-effects models. We planned a network meta-analysis using Bayesian methods, but due to sparse data and uncertainty about the transitivity assumption, performed only indirect comparisons and used Frequentist methods. MAIN RESULTS: We included eight RCTs with 311 participants in this review. After exclusion of five participants, we included 306 participants in one or more outcomes. Five trials (240 participants) investigated the three main treatments: open necrosectomy (121 participants), minimally invasive step-up approach (80 participants), and peritoneal lavage (39 participants) and were included in the network meta-analysis. Three trials (66 participants) investigated the variations in the main treatments: early open necrosectomy (25 participants), delayed open necrosectomy (11 participants), video-assisted minimally invasive step-up approach (12 participants), endoscopic minimally invasive step-up approach (10 participants), minimally invasive step-up approach (planned surgery) (four participants), and minimally invasive step-up approach (continued percutaneous drainage) (four participants). The trials included infected or sterile necrotising pancreatitis of varied aetiology.All the trials were at unclear or high risk of bias and the overall quality of evidence was low or very low for all the outcomes. Overall, short-term mortality was 30% and serious adverse events rate was 139 serious adverse events per 100 participants. The differences in short-term mortality and proportion of people with serious adverse events were imprecise in all the comparisons. The number of serious adverse events and adverse events were fewer in the minimally invasive step-up approach compared to open necrosectomy (serious adverse events: rate ratio 0.41, 95% CI 0.25 to 0.68; 88 participants; 1 study; adverse events: rate ratio 0.41, 95% CI 0.25 to 0.68; 88 participants; 1 study). The proportion of people with organ failure and the mean costs were lower in the minimally invasive step-up approach compared to open necrosectomy (organ failure: OR 0.20, 95% CI 0.07 to 0.60; 88 participants; 1 study; mean difference in costs: USD -11,922; P value < 0.05; 88 participants; 1 studies). There were more adverse events with video-assisted minimally invasive step-up approach group compared to endoscopic-assisted minimally invasive step-up approach group (rate ratio 11.70, 95% CI 1.52 to 89.87; 22 participants; 1 study), but the number of interventions per participant was less with video-assisted minimally invasive step-up approach group compared to endoscopic minimally invasive step-up approach group (difference in medians: 2 procedures; P value < 0.05; 20 participants; 1 study). The differences in any of the other comparisons for number of serious adverse events, proportion of people with organ failure, number of adverse events, length of hospital stay, and intensive therapy unit stay were either imprecise or were not consistent. None of the trials reported long-term mortality, infected pancreatic necrosis (trials that included participants with sterile necrosis), health-related quality of life at any time frame, proportion of people with adverse events, requirement for additional invasive intervention, time to return to normal activity, and time to return to work. AUTHORS' CONCLUSIONS: Low to very low quality evidence suggested that the minimally invasive step-up approach resulted in fewer adverse events, serious adverse events, less organ failure, and lower costs compared to open necrosectomy. Very low quality evidence suggested that the endoscopic minimally invasive step-up approach resulted in fewer adverse events than the video-assisted minimally invasive step-up approach but increased the number of procedures required for treatment. There is currently no evidence to suggest that early open necrosectomy is superior or inferior to peritoneal lavage or delayed open necrosectomy. However, the CIs were wide and significant benefits or harms of different treatments cannot be ruled out. The TENSION trial currently underway in Netherlands is assessing the optimal way to perform the minimally invasive step-up approach (endoscopic drainage followed by endoscopic necrosectomy if necessary versus percutaneous drainage followed by video-assisted necrosectomy if necessary) and is assessing important clinical outcomes of interest for this review. Implications for further research on this topic will be determined after the results of this RCT are available

Pharmacological interventions for acute pancreatitis

Background: In people with acute pancreatitis, it is unclear what the role should be for medical treatment as an addition to supportive care such as fluid and electrolyte balance and organ support in people with organ failure. Objectives: To assess the effects of different pharmacological interventions in people with acute pancreatitis. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2016, Issue 9), MEDLINE, Embase, Science Citation Index Expanded, and trial registers to October 2016 to identify randomised controlled trials (RCTs). We also searched the references of included trials to identify further trials. Selection criteria We considered only RCTs performed in people with acute pancreatitis, irrespective of aetiology, severity, presence of infection, language, blinding, or publication status for inclusion in the review. Data collection and analysis: Two review authors independently identified trials and extracted data. We did not perform a network meta-analysis as planned because of the lack of information on potential effect modifiers and differences of type of participants included in the different comparisons, when information was available. We calculated the odds ratio (OR) with 95% confidence intervals (CIs) for the binary outcomes and rate ratios with 95% CIs for count outcomes using a fixed-effect model and random-effects model. Main results: We included 84 RCTs with 8234 participants in this review. Six trials (N = 658) did not report any of the outcomes of interest for this review. The remaining 78 trials excluded 210 participants after randomisation. Thus, a total of 7366 participants in 78 trials contributed to one or more outcomes for this review. The treatments assessed in these 78 trials included antibiotics, antioxidants, aprotinin, atropine, calcitonin, cimetidine, EDTA (ethylenediaminetetraacetic acid), gabexate, glucagon, iniprol, lexipafant, NSAIDs (non-steroidal anti-inflammatory drugs), octreotide, oxyphenonium, probiotics, activated protein C, somatostatin, somatostatin plus omeprazole, somatostatin plus ulinastatin, thymosin, ulinastatin, and inactive control. Apart from the comparison of antibiotics versus control, which included a large proportion of participants with necrotising pancreatitis, the remaining comparisons had only a small proportion of patients with this condition. Most trials included either only participants with severe acute pancreatitis or included a mixture of participants with mild acute pancreatitis and severe acute pancreatitis (75 trials). Overall, the risk of bias in trials was unclear or high for all but one of the trials. Source of funding: seven trials were not funded or funded by agencies without vested interest in results. Pharmaceutical companies partially or fully funded 21 trials. The source of funding was not available from the remaining trials. Since we considered short-term mortality as the most important outcome, we presented only these results in detail in the abstract. Sixty-seven studies including 6638 participants reported short-term mortality. There was no evidence of any differences in short-term mortality in any of the comparisons (very low-quality evidence). With regards to other primary outcomes, serious adverse events (number) were lower than control in participants taking lexipafant (rate ratio 0.67, 95% CI 0.46 to 0.96; N = 290; 1 study; very low-quality evidence), octreotide (rate ratio 0.74, 95% CI 0.60 to 0.89; N = 770; 5 studies; very low-quality evidence), somatostatin plus omeprazole (rate ratio 0.36, 95% CI 0.19 to 0.70; N = 140; 1 study; low-quality evidence), and somatostatin plus ulinastatin (rate ratio 0.30, 95% CI 0.15 to 0.60; N = 122; 1 study; low-quality evidence). The proportion of people with organ failure was lower in octreotide than control (OR 0.51, 95% CI 0.27 to 0.97; N = 430; 3 studies; very low-quality evidence). The proportion of people with sepsis was lower in lexipafant than control (OR 0.26, 95% CI 0.08 to 0.83; N = 290; 1 study; very low-quality evidence). There was no evidence of differences in any of the remaining comparisons in these outcomes or for any of the remaining primary outcomes (the proportion of participants experiencing at least one serious adverse event and the occurrence of infected pancreatic necrosis). None of the trials reported heath-related quality of life. Authors' conclusions: Very low-quality evidence suggests that none of the pharmacological treatments studied decrease short-term mortality in people with acute pancreatitis. However, the confidence intervals were wide and consistent with an increase or decrease in short-term mortality due to the interventions. We did not find consistent clinical benefits with any intervention. Because of the limitations in the prognostic scoring systems and because damage to organs may occur in acute pancreatitis before they are clinically manifest, future trials should consider including pancreatitis of all severity but power the study to measure the differences in the subgroup of people with severe acute pancreatitis. It may be difficult to power the studies based on mortality. Future trials in participants with acute pancreatitis should consider other outcomes such as complications or health-related quality of life as primary outcomes. Such trials should include health-related quality of life, costs, and return to work as outcomes and should follow patients for at least three months (preferably for at least one year)

Progressive systemic sclerosis in childhood: A report of three cases

Systemic sclerosis is unusual in childhood. We describe three children who presented with diffuse hidebound skin associated with gastrointestinal and pulmonary abnormalities. Cardiac and renal dysfunctions, which are often encountered in these patients, were notably absent in our cases

Single lesion multibacillary leprosy, a treatment enigma: a case report

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Circulating levels of insulin-like growth factor-I (IGF-I) correlate with disease status in leprosy

<p>Abstract</p> <p>Background</p> <p>Caused by <it>Mycobacterium leprae </it>(ML), leprosy presents a strong immune-inflammatory component, whose status dictates both the clinical form of the disease and the occurrence of reactional episodes. Evidence has shown that, during the immune-inflammatory response to infection, the growth hormone/insulin-like growth factor-I (GH/IGF-I) plays a prominent regulatory role. However, in leprosy, little, if anything, is known about the interaction between the immune and neuroendocrine systems.</p> <p>Methods</p> <p>In the present retrospective study, we measured the serum levels of IGF-I and IGBP-3, its major binding protein. These measurements were taken at diagnosis in nonreactional borderline tuberculoid (NR BT), borderline lepromatous (NR BL), and lepromatous (NR LL) leprosy patients in addition to healthy controls (HC). LL and BL patients who developed reaction during the course of the disease were also included in the study. The serum levels of IGF-I, IGFBP-3 and tumor necrosis factor-alpha (TNF-α) were evaluated at diagnosis and during development of reversal (RR) or erythema nodosum leprosum (ENL) reaction by the solid phase, enzyme-labeled, chemiluminescent-immunometric method.</p> <p>Results</p> <p>The circulating IGF-I/IGFBP-3 levels showed significant differences according to disease status and occurrence of reactional episodes. At the time of leprosy diagnosis, significantly lower levels of circulating IGF-I/IGFBP-3 were found in NR BL and NR LL patients in contrast to NR BT patients and HCs. However, after treatment, serum IGF-I levels in BL/LL patients returned to normal. Notably, the levels of circulating IGF-I at diagnosis were low in 75% of patients who did not undergo ENL during treatment (NR LL patients) in opposition to the normal levels observed in those who suffered ENL during treatment (R LL patients). Nonetheless, during ENL episodes, the levels observed in RLL sera tended to decrease, attaining similar levels to those found in NR LL patients. Interestingly, IGF-I behaved contrary to what was observed during RR episodes in R BL patients.</p> <p>Conclusions</p> <p>Our data revealed important alterations in the IGF system in relation to the status of the host immune-inflammatory response to ML while at the same time pointing to the circulating IGF-I/IGFBP-3 levels as possible predictive biomarkers for ENL in LL patients at diagnosis.</p

Use of a T cell interferon gamma release assay in the investigation for suspected active tuberculosis in a low prevalence area

<p>Abstract</p> <p>Background</p> <p>In settings with low background prevalence of tuberculosis (TB) infection, interferon-γ release assays (IGRA) could be useful for diagnosing active TB. This study aims to evaluate the performance of QuantiFERON^®-TB Gold (QFT-G) in the investigation for suspected active TB, with particular attention to patients originating in high-incidence countries. Furthermore, factors associated with QFT-G results in patients with active TB were assessed.</p> <p>Methods</p> <p>From patients investigated for clinically suspected active TB, blood was obtained for QFT-G testing, in addition to routine investigations. Positive (PPV) and negative (NPV) predictive values for QFT-G were calculated, comparing patients with confirmed TB and those with other final diagnoses. QFT-G results in TB patients originating from countries with intermediate or high TB incidence were compared with QFT-G results from a control group of recently arrived asymptomatic immigrants from high-incidence countries. Factors associated with QFT-G outcome in patients with confirmed TB were assessed.</p> <p>Results</p> <p>Among 141 patients, 41/70 (58.6%) with confirmed TB had a positive QFT-G test, compared to 16/71 (22.6%) patients with other final diagnoses, resulting in overall PPV of 71.9% and NPV of 67.6%. For patients with pulmonary disease, PPV and NPV were 61.1% and 67.7%, respectively, and 90.5% and 66.7% for subjects with extrapulmonary manifestations. Comparing patients from high-incidence countries with controls yielded a PPV for active TB of 76.7%, and a NPV of 82.7%. Patients with confirmed TB and positive QFT-G results were characterized by a lower median peripheral white blood cell count (5.9 × 10⁹/L vs. 8.8 × 10⁹/L; <it>P </it>< 0.001) and a higher median body mass index (22.7 vs. 20.7; <it>P </it>= 0.043) as compared to QFT-G-negative TB patients.</p> <p>Conclusion</p> <p>The overall PPV and NPV of QFT-G for identifying active TB were unsatisfactory, especially for pulmonary disease. Thus, the usefulness of QFT-G for this purpose is questionable. However, a high PPV was observed for extrapulmonary TB and QFT-G might be considered in the diagnostic process in this situation. The PPV and NPV for identifying active TB among persons originating from regions with high-and intermediate TB incidence was similar to that observed in subjects originating in the low-incidence region.</p

Potential plasma markers of type 1 and type 2 leprosy reactions: a preliminary report

<p>Abstract</p> <p>Background</p> <p>The clinical management of leprosy Type 1 (T1R) and Type 2 (T2R) reactions pose challenges mainly because they can cause severe nerve injury and disability. No laboratory test or marker is available for the diagnosis or prognosis of leprosy reactions. This study simultaneously screened plasma factors to identify circulating biomarkers associated with leprosy T1R and T2R among patients recruited in Goiania, Central Brazil.</p> <p>Methods</p> <p>A nested case-control study evaluated T1R (n = 10) and TR2 (n = 10) compared to leprosy patients without reactions (n = 29), matched by sex and age-group (+/- 5 years) and histopathological classification. Multiplex bead based technique provided profiles of 27 plasma factors including 16 pro inflammatory cytokines: tumor necrosis factor-α (TNF-α), Interferon-γ (IFN-γ), interleukin (IL)- IL12p70, IL2, IL17, IL1 β, IL6, IL15, IL5, IL8, macrophage inflammatory protein (MIP)-1 alpha (MIP1α), 1 beta (MIP1β), regulated upon activation normal T-cell expressed and secreted (RANTES), monocyte chemoattractrant protein 1 (MCP1), CC-chemokine 11 (CCL11/Eotaxin), CXC-chemokine 10 (CXCL10/IP10); 4 anti inflammatory interleukins: IL4, IL10, IL13, IL1Rα and 7 growth factors: IL7, IL9, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), platelet-derived growth factor BB (PDGF BB), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF).</p> <p>Results</p> <p>Elevations of plasma CXCL10 (P = 0.004) and IL6 (p = 0.013) were observed in T1R patients compared to controls without reaction. IL6 (p = 0.05), IL7 (p = 0.039), and PDGF-BB (p = 0.041) were elevated in T2R. RANTES and GMCSF were excluded due to values above and below detection limit respectively in all samples.</p> <p>Conclusion</p> <p>Potential biomarkers of T1R identified were CXCL10 and IL6 whereas IL7, PDGF-BB and IL6, may be laboratory markers of TR2. Additional studies on these biomarkers may help understand the immunopathologic mechanisms of leprosy reactions and indicate their usefulness for the diagnosis and for the clinical management of these events.</p

SARS-CoV-2 infection in acute pancreatitis increases disease severity and 30-day mortality: COVID PAN collaborative study

Objective: There is emerging evidence that the pancreas may be a target organ of SARS-CoV-2 infection. This aim of this study was to investigate the outcome of patients with acute pancreatitis (AP) and coexistent SARS-CoV-2 infection. Design: A prospective international multicentre cohort study including consecutive patients admitted with AP during the current pandemic was undertaken. Primary outcome measure was severity of AP. Secondary outcome measures were aetiology of AP, intensive care unit (ICU) admission, length of hospital stay, local complications, acute respiratory distress syndrome (ARDS), persistent organ failure and 30-day mortality. Multilevel logistic regression was used to compare the two groups. Results: 1777 patients with AP were included during the study period from 1 March to 23 July 2020. 149 patients (8.3%) had concomitant SARS-CoV-2 infection. Overall, SARS-CoV-2-positive patients were older male patients and more likely to develop severe AP and ARDS (p&lt;0.001). Unadjusted analysis showed that SARS-CoV-2-positive patients with AP were more likely to require ICU admission (OR 5.21, p&lt;0.001), local complications (OR 2.91, p&lt;0.001), persistent organ failure (OR 7.32, p&lt;0.001), prolonged hospital stay (OR 1.89, p&lt;0.001) and a higher 30-day mortality (OR 6.56, p&lt;0.001). Adjusted analysis showed length of stay (OR 1.32, p&lt;0.001), persistent organ failure (OR 2.77, p&lt;0.003) and 30-day mortality (OR 2.41, p&lt;0.04) were significantly higher in SARS-CoV-2 co-infection. Conclusion: Patients with AP and coexistent SARS-CoV-2 infection are at increased risk of severe AP, worse clinical outcomes, prolonged length of hospital stay and high 30-day mortality

Medium-term mortality after hip fractures and COVID-19: A prospective multi-centre UK study

Purpose The COVID-19 pandemic has caused 1.4 million deaths globally and is associated with a 3–4 times increase in 30-day mortality after a fragility hip fracture with concurrent COVID-19 infection. Typically, death from COVID-19 infection occurs between 15 and 22 days after the onset of symptoms, but this period can extend up to 8 weeks. This study aimed to assess the impact of concurrent COVID-19 infection on 120-day mortality after a fragility hip fracture. Methods A multi-centre prospective study across 10 hospitals treating 8% of the annual burden of hip fractures in England between 1st March and 30th April, 2020 was performed. Patients whose surgical treatment was payable through the National Health Service Best Practice Tariff mechanism for “fragility hip fractures” were included in the study. Patients’ 120-day mortality was assessed relative to their peri-operative COVID-19 status. Statistical analysis was performed using SPSS version 27. Results A total of 746 patients were included in this study, of which 87 (11.7%) were COVID-19 positive. Mortality rates at 30- and 120-day were significantly higher for COVID-19 positive patients relative to COVID-19 negative patients (p < 0.001). However, mortality rates between 31 and 120-day were not significantly different (p = 0.107), 16.1% and 9.4% respectively for COVID-19 positive and negative patients, odds ratio 1.855 (95% CI 0.865–3.978). Conclusion Hip fracture patients with concurrent COVID-19 infection, provided that they are alive at day-31 after injury, have no significant difference in 120-day mortality. Despite the growing awareness and concern of “long-COVID” and its widespread prevalence, this does not appear to increase medium-term mortality rates after a hip fracture