Evidence, not eminence, for surgical management during COVID-19: a multifaceted systematic review and a model for rapid clinical change.

BACKGROUND: Coronavirus (COVID-19) forced surgical evolution worldwide. The extent to which national evidence-based recommendations, produced by the current authors early in 2020, remain valid, is unclear. To inform global surgical management and a model for rapid clinical change, this study aimed to characterize surgical evolution following COVID-19 through a multifaceted systematic review. METHODS: Rapid reviews were conducted targeting intraoperative safety, personal protective equipment and triage, alongside a conventional systematic review identifying evidence-based guidance for surgical management. Targeted searches of PubMed and Embase from 31 December 2019 were repeated weekly until 7 August 2020, and systematic searches repeated monthly until 30 June 2020. Literature was stratified using Evans' hierarchy of evidence. Narrative data were analysed for consistency with earlier recommendations. The systematic review rated quality using the AGREE II and AMSTAR tools, was registered with PROSPERO, CRD42020205845. Meta-analysis was not conducted. RESULTS: From 174 targeted searches and six systematic searches, 1256 studies were identified for the rapid reviews and 21 for the conventional systematic review. Of studies within the rapid reviews, 903 (71.9 per cent) had lower-quality design, with 402 (32.0 per cent) being opinion-based. Quality of studies in the systematic review ranged from low to moderate. Consistency with recommendations made previously by the present authors was observed despite 1017 relevant subsequent publications. CONCLUSION: The evidence-based recommendations produced early in 2020 remained valid despite many subsequent publications. Weaker studies predominated and few guidelines were evidence-based. Extracted clinical solutions were globally implementable. An evidence-based model for rapid clinical change is provided that may benefit surgical management during this pandemic and future times of urgency.

Deaths in Incorrectly Identified Low-Surgical-Risk Patients.

BACKGROUND: The American Society of Anesthesiologists (ASA) physical classification system was developed for assessing anaesthetic risk, but is often also used to estimate surgical death risk. Patients with low ASA grades (ASA 1 or 2) are expected to have better surgical outcomes than patients with higher ASA grades (ASA ≥ 4). This study examined the course to death in patients classified as ASA 1 or 2 was examined, to investigate possible factors in unexpected deaths, in addition to evaluating the use of ASA grades by clinicians. METHODS: Patient data from the national surgical mortality audit of Australian hospitals were examined. The patient group was listed as ASA grade 1 or 2 by surgeons. Patients over 60 or under 20 were excluded in the final analysis, as were cases from New South Wales due to data not being available. A total of 357 cases were examined. Assessor summaries of the cases were examined, and ASA score reassessed to determine accuracy. RESULTS: More than 95% (n = 339) of cases listed as ASA 1 or 2 were found to have an incorrectly low grade, with 17.6% (n = 63) of cases listed as "expected" deaths. CONCLUSION: ASA grades appear to be misunderstood in the reporting of patient surgical risk. Many patient summaries list patients with severe systemic disease or expected deaths as ASA 1 or 2, contrary to the intended use of this classification system. Improved education on the use of the ASA grading system would be beneficial to clinicians.

Processes of care in surgical patients who died with hospital-acquired infections in Australian hospitals.

BACKGROUND: Infection may complicate surgical patients' hospital admission. The effect of hospital-acquired infections (HAIs) on processes of care among surgical patients who died is unknown. AIM: To investigate the effect of HAIs on processes of care in surgical patients who died in hospital. METHODS: Surgeon-recorded infection data extracted from a national Australian surgical mortality audit (2012-2016) were grouped into HAIs and no infection. The audit included all-age surgical patients, who died in hospital. Not all patients had surgery. Excluded from analysis were patients with community-acquired infection and those with missing timing of infection. Multivariate logistic regression was used to determine the adjusted effects of HAIs on the processes of care in these patients. Costs associated with HAIs were estimated. FINDINGS: One-fifth of surgical patients who died did so with an HAI (2242 out of 11,681; 19.2%). HAI patients had increased processes of care compared to those who died without infection: postoperative complications [51.0% vs 30.3%; adjusted odds ratio (aOR): 2.20; 95% confidence interval (CI): 1.98-2.45; P < 0.001]; unplanned reoperations (22.6% vs 10.9%; aOR: 2.38; 95% CI: 2.09-2.71; P < 0.001) and unplanned intensive care unit admission (29.3% vs 14.8%; aOR: 2.18; 95% CI: 1.94-2.45; P < 0.001). HAI patients had longer hospital admissions and greater hospital costs than those without infection. CONCLUSION: HAIs were associated with increased processes of care and costs in surgical patients who died; these outcomes need to be investigated in surgical patients who survive.

Methylation of CpG sites in exon 2 of the bcl-2 gene occurs in colorectal carcinoma.

BACKGROUND: Aberrant bcl-2 expression frequently occurs in colorectal carcinoma. The current study investigated if CpG sites in bcl-2 were methylated in colorectal carcinoma and if methylation correlated with loss of expression of bcl-2 mRNA. METHODS: Methylation was assessed in 23 matched normal mucosae and colonic carcinomas by Southern blotting with methylation-sensitive enzymes. Expression of bcl-2 mRNA was assessed by Northern blotting. RESULTS: A SacII site in exon 2 of the bcl-2 gene was methylated in 5 carcinomas, plus an adjacent HpaII sites in 1 tumour. SacII site in the bcl-2 promoter were not methylated. Elevated levels of bcl-2 mRNA were detected in 3 carcinomas, 5 showed decreased expression and 4 were unchanged. CONCLUSIONS: De novo methylation of CpG sites in exon 2 of the bcl-2 gene occurs during the development of colorectal carcinoma. However, there was no relationship between expression of bc1-2 mRNA and methylation of specific CpG sites.

Lung volume reduction surgery in emphysema: a systematic review.

The aim of this study was to systematically review the literature regarding the safety and efficacy of lung volume reduction surgery (LVRS) in patients with emphysema. Studies on LVRS to August 2000 were identified using MEDLINE, Embase, Current Contents, and the Cochrane Library. Human studies of patients with upper, lower or diffuse distributions of emphysema were included. All types of bullous emphysema were excluded. A surgeon and researcher independently assessed the retrieved articles for their inclusion in the review. When LVRS was compared with medical management, at 2 years LVRS was associated with a higher FEV1 and at least equivalent survival. The use of staple excision of selected areas of lung appeared to be more efficacious than laser ablation. There is insufficient evidence to show preference for median sternotomy or videoscopically assisted thoracotomy, as the more safe and efficacious procedure. In highly selected patients with emphysema LVRS is deemed an acceptable treatment. To fully evaluate the safety and efficacy of LVRS, outcomes beyond 2 years must be included. The results of prospective randomized trials between medical management and LVRS, now in progress, are essential before a final assessment can be made.

Thiol methyltransferase activity in inflammatory bowel disease.

BACKGROUND: Luminal anionic sulphide may contribute to epithelial damage in ulcerative colitis. Thiol methyltransferase (TMT) governs sulphide detoxification by the colonic mucosa and circulating erythrocytes. AIMS: To measure levels of TMT activity in erythrocytes of surgically treated cases of colitis or in rectal biopsies of defined groups of colitis. PATIENTS: Venepuncture blood was obtained from 37 blood donors and 27 subjects who had previously undergone a proctocolectomy for colitis: 18 for ulcerative colitis and nine for Crohn's colitis. Rectal biopsies from 122 cases were obtained: 47 without mucosal disease, 33 post-colon resection for cancer, 14 with moderate to severe ulcerative colitis, 15 with quiescent ulcerative colitis, seven with acute Crohn's colitis, and six with radiation proctitis. METHODS: TMT activity was measured by high performance liquid chromatography with radioactive detection to measure (14)C methylmercaptoethanol formation, the reaction product of cell extracts incubated with mercaptoethanol and (14)C S-adenosylmethionine. RESULTS: Erythrocyte TMT activity of surgically treated cases of colitis was significantly elevated (p<0. 001) compared with control cases. TMT activity of rectal biopsies was significantly decreased (p<0.02) in acute but not quiescent ulcerative colitis, Crohn's colitis, or radiation colitis. CONCLUSIONS: Erythrocyte TMT activity was persistently elevated after proctocolectomy for Crohn's disease and ulcerative colitis. No primary defect of TMT activity was found in any case of unoperated colitis but mucosal activity was diminished with disease progression of ulcerative colitis. Studies of genetic control of TMT activity of erythrocytes in inflammatory bowel disease appear worthwhile.

Nitric oxide effect on colonocyte metabolism: co-action of sulfides and peroxide.

Luminal levels of nitric oxide/nitrite are high in colitis. Whether nitric oxide is injurious or protective to human colonocytes is unknown and the role of nitric oxide in the genesis of colitis unclear. The aims were to establish whether nitric oxide was injurious to oxidation of substrates (n-butyrate and D-glucose) in isolated human and rat colonocytes both alone and in the presence of hydrogen sulfide and hydrogen peroxide, agents implicated in cell damage of colitis. Nitric oxide generation from S-nitrosoglutathione was measured by nitrite appearance. Colonocytes were isolated and incubated with [1-14C] butyrate or [6-14C] glucose and 2.6 microM nitric oxide, 1.5 mM sodium hydrogen sulfide or 2.5 mM hydrogen peroxide. Acyl-CoA esters were measured by high performance liquid chromatography, 14CO2 radiochemically and lactate/ketones by enzymic methods. Results indicate that nitric oxide very significantly (p < .001) reduced acyl-CoA formation but did not impair 14CO2 generation. Peroxide and sulfide with nitric oxide resulted in significant reduction (p < 0.01) of substrate oxidation to CO2. Sulfide significantly stimulated release of nitric oxide from S-nitrosoglutathione. The principal conclusion is that nitric oxide diminishes CoA metabolism in colonocytes. CoA depletion has been observed in chronic human colitis for which a biochemical explanation has been lacking. For acute injurious action in human colonocytes nitric oxide requires co-action of peroxide and sulfide to impair oxidation of substrates in cells. From current observations treatment of colitis should aim to reduce simultaneously nitric oxide, peroxide and sulfide generation in the colon.

Minimally invasive surgery for primary hyperparathyroidism: a systematic review.

BACKGROUND: The aim of the present paper was to systematically review the literature regarding the safety and efficacy of minimally invasive parathyroidectomy techniques in patients with primary hyperparathyroidism. Studies using unilateral or endoscopic exploration following imaging were compared with bilateral open neck exploration. METHODS: Studies on minimally invasive parathyroid surgery were identified using MEDLINE (1984 to August 1998), EMBASE (1974 to August 1998) and Current Contents (1993 to week 34, 1998). The search terms were ((endoscop* or (minimal* and invasive) or unilateral) and parathyroid). The Cochrane Library was searched from 1966 to issue 3 1998, using the search terms 'parathyroidectomy or parathyroid resection'. Human studies of patients with primary hyperparathyroidism using unilateral or endoscopic exploration were included. Animal studies describing minimally invasive technique development were also included. A surgeon and researcher independently assessed the retrieved articles for their inclusion in the review. Studies directly comparing the unilateral method with bilateral open neck exploration were used to analyse outcomes. RESULTS: Analysis of data using odds ratios and 95% confidence intervals (CI) indicated a tendency to favour the unilateral technique. These individual studies generally had large CI, however; therefore preference to the unilateral procedure cannot be espoused with certainty. There is also a selection bias due to the strict enrollment criteria for unilateral surgery. CONCLUSIONS: The proposed role of minimally invasive parathyroid surgery is for patients with primary hyperparathyroidism who have unilateral parathyroid pathology. To assess the safety and efficacy of minimally invasive techniques it is suggested that their introduction be monitored as part of a trial in Australia, from which data should be accrued to a register.

Minimally invasive surgery for primary hyperparathyroidism: systematic review.

HYPOTHESIS: Use of minimally invasive parathyroidectomy techniques, either unilateral or endoscopic, will result in the same or improved safety and efficacy outcomes as those of the bilateral open neck exploration technique in patients with primary hyperparathyroidism. DATA SOURCES: Studies on minimally invasive parathyroid surgery were identified using MEDLINE (January 1984 to August 1998), EMBASE (January 1974 to August 1998), and Current Contents (week 1 of 1993 to week 34 of 1998). The search terms were as follows: ((endoscop* or (minimal* and invasive) or unilateral) and parathyroid). The Cochrane Library was searched from issue 1 of 1966 to issue 3 of 1998, using the search terms "parathyroidectomy or parathyroid resection." STUDY SELECTION: Human studies of patients with primary hyperparathyroidism using unilateral or endoscopic exploration were included. Animal studies describing minimally invasive technique development were also included. A surgeon (R.F.P.) and researcher (W.J.B.) independently assessed the retrieved articles for their inclusion in the review. DATA EXTRACTION: Studies directly comparing the unilateral method with bilateral open neck exploration were used to analyze outcomes. DATA SYNTHESIS: Analysis of data using odds ratios and 95% confidence intervals indicated a tendency to favor the unilateral technique. However, these individual studies generally had large confidence intervals; therefore, preference to the unilateral procedure cannot be espoused with certainty. There is also a selection bias due to the strict enrollment criteria for unilateral surgery. CONCLUSIONS: The proposed role of minimally invasive parathyroid surgery is for patients with primary hyperparathyroidism who have unilateral parathyroid pathological features. To assess the safety and efficacy of minimally invasive techniques, it is suggested that their introduction be monitored as part of a trial in Australia, from which data should be accrued to a register.

Thiolmethyltransferase activity in the human colonic mucosa: implications for ulcerative colitis.

Ulcerative colitis is associated with a selective reduction of n-butyrate oxidation by the colonic epithelial cells although the reason for this has been unclear. Colonic epithelial cell n-butyrate oxidation can be inhibited in vitro by incubation with sulphide but the role of mucosal detoxification of sulphide in the metabolic welfare of the colonic mucosa has not been examined. This study aimed to assess the role mucosal detoxification of sulphide by thiolmethyltransferase (TMT)-mediated methylation may play in protecting the healthy colonic mucosa from the adverse effects of luminal sulphide. Colonic epithelial cell suspensions from healthy human proximal (n = 9) and distal colon (n = 10) were incubated in the presence of 14C-labelled n-butyrate (5 mmol/L) alone, butyrate plus sodium hydrogen sulphide (NaHS) (1.5 mmol/L), or butyrate plus NaHS plus S-adenosyl-methionine 1,4 butane disulphonate (SAMe) (5 mmol/L). Study end points were metabolic performance (14CO2 production) and mucosal TMT activity. Incubation with NaHS induced a significant inhibition of 14CO2 production compared with control incubations (P < 0.001) which was similar for proximal and distal colonic cell suspensions. S-adenosyl-methionine 1,4 butane disulphonate reversed this effect completely in proximal but not in distal cell incubations, suggesting a greater susceptibility of the distal colon to the sulphide effect. Although median whole mucosal TMT values did not differ between proximal and distal colonic mucosa, a non-normal distribution of distal TMT values was observed. However, neither the degree of sulphide inhibition of control 14CO2 production nor the degree to which SAMe reversed this inhibition correlated with whole mucosal TMT activity. The study concluded that regional variation exists in TMT activity in the human colon but whilst methylation appears to protect colonic epithelial cells against sulphide-induced inhibition of n-butyrate oxidation, this cannot be directly correlated with mucosal TMT activity.

Thiol methyltransferase activity in colonocytes and erythrocyte membranes.

AIMS: To verify the improved thiol methyltransferase (TMT) assay and measure activity in isolated colonocytes and erythrocyte membranes of the same subjects. METHODS: High performance liquid chromatography with radioactivity detection was used to measure 14C-methylmercaptoethanol formation, the reaction product of cell extracts incubated with mercaptoethanol and 14C-S-adenosylmethionine. RESULTS: Verification of radiolabelled 14C-methylmercaptoethanol was by exogenous addition of methylmercaptoethanol and simultaneous ultraviolet detection at 214 nm. Using a substrate concentration of 10 mM mercaptoethanol, the Km for S-adenosylmethionine was 25 microM. The sensitivity of the radioactive method was 2 pmol, with coefficients of variation of 7% within assay and 6.4% between assay. TMT activities (mean +/- SE; n = 17) were 471 +/- 64 pmol/hour/mg protein for colonocytes and 73 +/- 7 pmol/hour/mg protein for erythrocyte membranes. CONCLUSIONS: The direct assay of TMT activity is sensitive, specific and eliminates concern over non-enzymatic methylation of thiol compounds. High activities in colonic epithelial cells deserve evaluation in disease states.

Determination of methylmalonic acid by high-performance liquid chromatography.

An isocratic reverse-phase C18 high-performance liquid chromatography (HPLC) technique for methylmalonic acid (MMA) with fluorescence detection is described. MMA is extracted from an acidified sample (plasma, urine, etc.) with ethyl acetate. The extract is dried and derivatized with monodansylcadaverine and dicyclohexylcarbodiimide prior to injection on the HPLC. Ethylmalonic acid is used as an internal standard. Evaluation of the technique was with ovine blood plasma, liver, rumen fluid, and urine. The technique can quantitate as little as 0.2 mumol/liter MMA in samples (based on 10 times the detection limit) and is therefore sufficiently sensitive to measure levels in normal blood plasma. The method is rapid, with up to 60 samples per day throughput, and so is suitable as a routine diagnostic test for the detection of vitamin B12 deficiency.