Hand hygiene compliance in nursing home wards: The effects of feedback with lights on alcohol-based hand rub dispensers.

BACKGROUND: Hand hygiene (HH) among health care workers (HCWs) is crucial in preventing infections in nursing homes. However, HH compliance (HHC) among HCWs remains low. This study aimed to investigate the effect of feedback lights on HCWs' HHC. METHODS: A 5-month interventional study was conducted in 3 wards in a nursing home in Denmark. During the intervention period, a green light with a smiley appeared on the alcohol-based hand rub (ABHR) dispensers when HCWs used the ABHR, acknowledging HCWs for using the ABHR. HHC was monitored using an automatic HH monitoring system (AHHMS). RESULTS: A total of 64 HCWs were enrolled. The AHHMS collected 23,696 HH opportunities in apartments and dirty utility rooms. Overall, HHC in the apartments increased from 50% at baseline (95% CI: 48, 53) to 56% (95% CI: 54, 58) during the intervention. However, the increased HHC level was not sustained during follow-up. CONCLUSIONS: The AHHMS enabled the assessment of the intervention. We found a significant effect of light-guided feedback in the apartments. However, the increased HHC was not sustained after the light was switched off.

Effects of data-driven feedback on nurses' and physicians' hand hygiene in hospitals - a non-resource-intensive intervention in real-life clinical practice.

Background: Hand hygiene (HH) by healthcare workers (HCWs) is one of the most important measures to prevent hospital-acquired infections. However, HCWs struggle to adhere to HH guidelines. We aimed to investigate the effect of a non-resource intensive intervention with group and individual feedback on HCWs HH in a real-life clinical practice during the COVID-19 pandemic. Methods: In 2021, an 11-month prospective, interventional study was conducted in two inpatient departments at a Danish university hospital. An automated hand hygiene monitoring system (Sani Nudge™) was used to collect data. HH opportunities and alcohol-based hand rub events were measured. Data were provided as HH compliance (HHC) rates. We compared HHC across 1) a baseline period, 2) an intervention period with weekly feedback in groups, followed by 3) an intervention period with weekly individual feedback on emails, and 4) a follow-up period. Results: We analyzed data from physicians (N=65) and nurses (N=109). In total, 231,022 hygiene opportunities were analyzed. Overall, we observed no significant effect of feedback, regardless of whether it was provided to the group or individuals. We found a trend toward a higher HHC in staff restrooms than in medication rooms and patient rooms. The lowest HHC was found in patient rooms. Conclusions: The automated hand hygiene monitoring system enabled assessment of the interventions. We found no significant effect of group or individual feedback at the two departments. However, other factors may have influenced the results during the pandemic, such as time constraints, workplace culture, and the degree of leadership support.

Effects of light-guided nudges on health care workers' hand hygiene behavior.

BACKGROUND: Hospital-acquired infections are the most frequent adverse events in health care and can be reduced by improving the hand hygiene compliance (HHC) of health care workers (HCWs). We aimed to investigate the effect of nudging with sensor lights on HCWs' HHC. METHODS: An 11-month intervention study was conducted in 2 inpatient departments at a university hospital. An automated monitoring system (Sani NudgeTM) measured the HHC. Reminder and feedback nudges with lights were displayed on alcohol-based hand rub dispensers. We compared the baseline HHC with HHC during periods of nudging and used the follow-up data to establish if a sustained effect had been achieved. RESULTS: A total of 91 physicians, 135 nurses, and 15 cleaning staff were enrolled in the study. The system registered 274,085 hand hygiene opportunities in patient rooms, staff restrooms, clean rooms, and unclean rooms. Overall, a significant, sustained effect was achieved by nudging with lights in relation to contact with patients and patient-near surroundings for both nurses and physicians. Furthermore, a significant effect was observed on nurses' HHC in restrooms and clean rooms. No significant effect was found for the cleaning staff. CONCLUSIONS: Reminder or feedback nudges with light improved and sustained physicians' and nurses' HHC, and constitute a new way of changing HCWs' hand hygiene behavior.

Clinical evaluation of an electronic hand hygiene monitoring system.

BACKGROUND: We aimed to test the accuracy of an electronic hand hygiene monitoring system (EHHMS) during daily clinical activities in different wards and with varying health care professions. METHODS: The accuracy of an EHHMS (Sani Nudge) was assessed during real clinical conditions by comparing events registered by two observers in parallel with events registered by the EHHMS. The events were categorized as true-positive, false-positive, and false-negative registrations. Sensitivity and positive predictive value (PPV) were calculated. RESULTS: A total of 103 events performed by 25 health care workers (9 doctors, 11 nurses, and 5 cleaning assistants) were included in the analyses. The EHHMS had a sensitivity of 100% and a PPV of 100% when measuring alcohol-based hand rub. When looking at the hand hygiene opportunities of all health care workers combined taking place in the patient rooms and working rooms, the sensitivity was 75% and the PPV 95%. For doctors' and nurses' taking care of patients in their beds the EHHMS had a sensitivity of 100% and a PPV of 94%. CONCLUSIONS: The objective accuracy measures demonstrate that this EHHMS can capture hand hygiene behavior under clinical conditions in different settings with clinical health care workers but show less accuracy with cleaning assistants.

Associations between YKL-40 and markers of disease severity and death in patients with necrotizing soft-tissue infection.

BACKGROUND: Necrotizing soft-tissue infection (NSTI) is a severe and fast-progressing bacterial infection. Prognostic biomarkers may provide valuable information in treatment guidance and decision-making, but none have provided sufficient robustness to have a clinical impact. YKL-40 may reflect the ongoing pathological inflammatory processes more accurately than traditional biomarkers as it is secreted by the activated immune cells, but its prognostic yields in NSTI remains unknown. For this purpose, we investigated the association between plasma YKL-40 and 30-day mortality in patients with NSTI, and assessed its value as a marker of disease severity. METHODS: We determined plasma YKL-40 levels in patients with NSTI (n = 161) and age-sex matched controls (n = 65) upon admission and at day 1, 2 and 3. RESULTS: Baseline plasma YKL-40 was 1191 ng/mL in patients with NSTI compared with 40 ng/mL in controls (p < 0.001). YKL-40 was found to be significantly higher in patients with septic shock (1942 vs. 720 ng/mL, p < 0.001), and in patients receiving renal-replacement therapy (2382 vs. 1041 ng/mL, p < 0.001). YKL-40 correlated with Simplified Acute Physiology Score II (Rho 0.33, p < 0.001). Baseline YKL-40 above 1840 ng/mL was associated with increased risk of 30-day mortality in age-sex-comorbidity adjusted analysis (OR 3.77, 95% CI; 1.59-9.24, p = 0.003), but after further adjustment for Simplified Acute Physiology Score II no association was found between YKL-40 and early mortality. CONCLUSION: High plasma YKL-40 to be associated with disease severity, renal-replacement therapy and risk of death in patients with NSTI. However, YKL-40 is not an independent predictor of 30-day mortality.

Discriminatory plasma biomarkers predict specific clinical phenotypes of necrotizing soft-tissue infections.

BACKGROUNDNecrotizing soft-tissue infections (NSTIs) are rapidly progressing infections frequently complicated by septic shock and associated with high mortality. Early diagnosis is critical for patient outcome, but challenging due to vague initial symptoms. Here, we identified predictive biomarkers for NSTI clinical phenotypes and outcomes using a prospective multicenter NSTI patient cohort.METHODSLuminex multiplex assays were used to assess 36 soluble factors in plasma from NSTI patients with positive microbiological cultures (n = 251 and n = 60 in the discovery and validation cohorts, respectively). Control groups for comparative analyses included surgical controls (n = 20), non-NSTI controls (i.e., suspected NSTI with no necrosis detected upon exploratory surgery, n = 20), and sepsis patients (n = 24).RESULTSThrombomodulin was identified as a unique biomarker for detection of NSTI (AUC, 0.95). A distinct profile discriminating mono- (type II) versus polymicrobial (type I) NSTI types was identified based on differential expression of IL-2, IL-10, IL-22, CXCL10, Fas-ligand, and MMP9 (AUC >0.7). While each NSTI type displayed a distinct array of biomarkers predicting septic shock, granulocyte CSF (G-CSF), S100A8, and IL-6 were shared by both types (AUC >0.78). Finally, differential connectivity analysis revealed distinctive networks associated with specific clinical phenotypes.CONCLUSIONSThis study identifies predictive biomarkers for NSTI clinical phenotypes of potential value for diagnostic, prognostic, and therapeutic approaches in NSTIs.TRIAL REGISTRATIONClinicalTrials.gov NCT01790698.FUNDINGCenter for Innovative Medicine (CIMED); Region Stockholm; Swedish Research Council; European Union; Vinnova; Innovation Fund Denmark; Research Council of Norway; Netherlands Organisation for Health Research and Development; DLR Federal Ministry of Education and Research; and Swedish Children's Cancer Foundation.

Assessing the clinical accuracy of a hand hygiene system: Learnings from a validation study.

There is a need to establish validation standards that allow for comparison of automated hand hygiene systems. To assess the accuracy of an innovative monitoring tool (Sani nudge), 2 test nurses performed clinical standard tasks while being observed by 2 infection preventionists. Data from the direct observations were compared with data obtained from the hand hygiene system (Sani nudge) using an independent-event approach. We identified 54 true-positive events (100% system accuracy) and 4 true-negative events (100% system accuracy). No false-positive or false-negative events were identified. We found this approach to be feasible and clinically useful to validate hand hygiene systems in the future.

Light-guided nudging and data-driven performance feedback improve hand hygiene compliance among nurses and doctors.

BACKGROUND: Evidence-based practices to increase hand hygiene compliance (HHC) among health care workers are warranted. We aimed to investigate the effect of a multimodal strategy on HHC. METHODS: During this 14-month prospective, observational study, an automated monitoring system was implemented in a 29-bed surgical ward. Hand hygiene opportunities and alcohol-based hand rubbing events were measured in patient and working rooms (medication, utility, storerooms, toilets). We compared baseline HHC of health care workers across periods with light-guided nudging from sensors on dispensers and data-driven performance feedback (multimodal strategy) using the Student's t test. RESULTS: The doctors (n = 10) significantly increased their HHC in patient rooms (16% vs 42%, P< .0001) and working rooms (24% vs 78%, P= .0006) when using the multimodal strategy. The nurses (n = 26) also increased their HHC significantly from baseline in both patient rooms (27% vs 43%, P = .0005) and working rooms (39% vs 64%, P< .0001). The nurses (n = 9), who subsequently received individual performance feedback, further increased HHC, compared with the period when they received group performance feedback (patient rooms: 43% vs 55%, P< .0001 and working rooms: 64% vs 80%, P< .0001). CONCLUSIONS: HHC of doctors and nurses can be significantly improved with light-guided nudging and data-driven performance feedback using an automated hand hygiene system.

Risk factors for kidney disorders in patients with type 2 diabetes at high cardiovascular risk: An exploratory analysis (DEVOTE 12).

AIM: To investigate risk factors associated with kidney disorders in patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk. METHODS: In DEVOTE, a cardiovascular outcomes trial, 7637 patients were randomised to insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100), with standard of care. In these exploratory post hoc analyses, serious adverse event reports were searched using Standardised MedDRA® Queries related to chronic kidney disease (CKD) or acute kidney injury (AKI). Baseline predictors of CKD, AKI and change in estimated glomerular filtration rate (eGFR) were identified using stepwise selection and Cox or linear regression. RESULTS: Over 2 years, eGFR (mL/min/1.73 m2) decline was small and similar between treatments (degludec: 2.70; glargine U100: 2.92). Overall, 97 and 208 patients experienced CKD and AKI events, respectively. A history of heart failure was a risk factor for CKD (hazard ratio [HR] 1.97 [95% confidence interval [CI] 1.41; 2.75]) and AKI (HR 2.28 [95% CI 1.64; 3.17]). A history of hepatic impairment was a significant predictor of CKD (HR 3.28 [95% CI 2.12; 5.07]) and change in eGFR (estimate: -8.59 [95% CI -10.20; -7.00]). CONCLUSION: Our findings indicate that traditional, non-modifiable risk factors for kidney disorders apply to insulin-treated patients with T2D at high CV risk. TRIAL REGISTRATION: NCT01959529 (ClinicalTrials.gov).

Complement Activation Is Associated With Mortality in Patients With Necrotizing Soft-Tissue Infections-A Prospective Observational Study.

Aim: We assessed whether different complement factors and complement activation products were associated with poor outcome in patients with necrotizing soft-tissue infection (NSTI). Methods: We conducted a prospective, observational study in an intensive care unit where treatment of NSTI is centralized at a national level. In 135 NSTI patients and 65 control patients, admission levels of MASP-1, MASP-2, MASP-3, C4, C3, complement activation products C4c, C3bc, and terminal complement complex (TCC) were assessed. Results: The 90-day mortality was 23%. In a Cox regression model adjusted for sex, and SAPS II, a higher than median MASP-1 (HR 0.378, CI 95% [0.164-0.872], p = 0.0226) and C4 (HR 0.162, 95% CI [0.060-0.438], p = 0.0003), C4c/C4 ratio (HR 2.290 95% CI [1.078-4.867], p = 0.0312), C3bc (HR 2.664 95% CI [1.195-5.938], p = 0.0166), and C3bc/C3 ratio (HR 4.041 95% CI [1.673-9.758], p = 0.0019) were associated with 90-day mortality, while MASP-2, C4c, C3, and TCC were not. C4 had the highest ROC-AUC (0.748, [95% CI 0.649-0.847]), which was comparable to the AUC for SOFA score (0.753, [95% CI 0.649-0.857]), and SAPS II (0.862 [95% CI 0.795-0.929]). Conclusion: In adjusted analyses, high admission levels of the C4c/C4 ratio, C3bc, and the C3bc/C3 ratio were significantly associated with a higher risk of death after 90 days while high admission levels of MASP-1 and C4 were associated with lower risk. In this cohort, these variables are better predictors of mortality in NSTI than C-reactive protein and Procalcitonin. C4's ability to predict mortality was comparable to the well-established scoring systems SAPS score II and SOFA on day 1.

Clinical experiences with a new system for automated hand hygiene monitoring: A prospective observational study.

BACKGROUND: Hand hygiene compliance (HHC) among health care workers remains suboptimal, and good monitoring systems are lacking. We aimed to evaluate HHC using an automated monitoring system. METHODS: A prospective, observational study was conducted at 2 Danish university hospitals employing a new monitoring system (Sani nudge). Sensors were located on alcohol-based sanitizers, health care worker name tags, and patient beds measuring hand hygiene opportunities and sanitations. RESULTS: In total, 42 nurses were included with an average HHC of 52% and 36% in hospitals A and B, respectively. HHC was lowest in patient rooms (hospital A: 45%; hospital B: 29%) and highest in staff toilets (hospital A: 72%; hospital B: 91%). Nurses sanitized after patient contact more often than before, and sanitizers located closest to room exits and in hallways were used most frequently. There was no association found between HHC level and the number of beds in patient rooms. The HHC level of each nurse was consistent over time, and showed a positive correlation between the number of sanitations and HHC levels (hospital A: r = 0.69; hospital B: r = 0.58). CONCLUSIONS: The Sani nudge system can be used to monitor HHC at individual and group levels, which increases the understanding of compliance behavior.

Glomerular Filtration Rate and Associated Risks of Cardiovascular Events, Mortality, and Severe Hypoglycemia in Patients with Type 2 Diabetes: Secondary Analysis (DEVOTE 11).

INTRODUCTION: The associations of chronic kidney disease (CKD) severity, cardiovascular disease (CVD), and insulin with the risks of major adverse cardiovascular events (MACE), mortality, and severe hypoglycemia in patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk are not known. This secondary, pooled analysis of data from the DEVOTE trial examined whether baseline glomerular filtration rate (GFR) categories were associated with a higher risk of these outcomes. METHODS: DEVOTE was a treat-to-target, double-blind trial involving 7637 patients with T2D at high CV risk who were randomized to once-daily treatment with either insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100). Patients with estimated GFR data at baseline (n = 7522) were analyzed following stratification into four GFR categories. RESULTS: The risks of MACE, CV death, and all-cause mortality increased with worsening baseline GFR category (P < 0.05), with a trend towards higher rates of severe hypoglycemia. Patients with prior CVD, CKD (estimated GFR < 60 mL/min/m2), or both were at higher risk of MACE, CV death, and all-cause mortality. Only CKD was associated with a higher rate of severe hypoglycemia, and the risk of MACE was higher in patients with CVD than in those with CKD (P  = 0.0003). There were no significant interactions between randomized treatment and GFR category. CONCLUSION: The risks of MACE, CV death, and all-cause mortality were higher with lower baseline GFR and with prior CVD, CKD, or both. The relative effects of degludec versus glargine U100 on outcomes were consistent across baseline GFR categories, suggesting that the lower rate of severe hypoglycemia associated with degludec use versus glargine U100 use was independent of baseline GFR category. FUNDING: Novo Nordisk.

Integrated Univariate, Multivariate, and Correlation-Based Network Analyses Reveal Metabolite-Specific Effects on Bacterial Growth and Biofilm Formation in Necrotizing Soft Tissue Infections.

Necrotizing soft-tissue infections (NSTIs) have multiple causes, risk factors, anatomical locations, and pathogenic mechanisms. In patients with NSTI, circulating metabolites may serve as a substrate having impact on bacterial adaptation at the site of infection. Metabolic signatures associated with NSTI may reveal the potential to be useful as diagnostic and prognostic markers and novel targets for therapy. This study used untargeted metabolomics analyses of plasma from NSTI patients (n = 34) and healthy (noninfected) controls (n = 24) to identify the metabolic signatures and connectivity patterns among metabolites associated with NSTI. Metabolite-metabolite association networks were employed to compare the metabolic profiles of NSTI patients and noninfected surgical controls. Out of 97 metabolites detected, the abundance of 33 was significantly altered in NSTI patients. Analysis of metabolite-metabolite association networks showed a more densely connected network: specifically, 20 metabolites differentially connected between NSTI and controls. A selected set of significantly altered metabolites was tested in vitro to investigate potential influence on NSTI group A streptococcal strain growth and biofilm formation. Using chemically defined media supplemented with the selected metabolites, ornithine, ribose, urea, and glucuronic acid, revealed metabolite-specific effects on both bacterial growth and biofilm formation. This study identifies for the first time an NSTI-specific metabolic signature with implications for optimized diagnostics and therapies.

Patient's characteristics and outcomes in necrotising soft-tissue infections: results from a Scandinavian, multicentre, prospective cohort study.

PURPOSE: Necrotising soft-tissue infections (NSTI) are characterised by necrosis, fast progression, and high rates of morbidity and mortality, but our knowledge is primarily derived from small prospective studies and retrospective studies. METHODS: We performed an international, multicentre, prospective cohort study of adults with NSTI describing patient's characteristics and associations between baseline variables and microbiological findings, amputation, and 90-day mortality. RESULTS: We included 409 patients with NSTI; 402 were admitted to the ICU. Cardiovascular disease [169 patients (41%)] and diabetes [98 (24%)] were the most common comorbidities; 122 patients (30%) had no comorbidity. Before surgery, bruising of the skin [210 patients (51%)] and pain requiring opioids [172 (42%)] were common. The sites most commonly affected were the abdomen/ano-genital area [140 patients (34%)] and lower extremities [126 (31%)]. Monomicrobial infection was seen in 179 patients (44%). NSTI of the upper or lower extremities was associated with monomicrobial group A streptococcus (GAS) infection, and NSTI located to the abdomen/ano-genital area was associated with polymicrobial infection. Septic shock [202 patients (50%)] and acute kidney injury [82 (20%)] were common. Amputation occurred in 22% of patients with NSTI of an extremity and was associated with higher lactate level. All-cause 90-day mortality was 18% (95% CI 14-22); age and higher lactate levels were associated with increased mortality and GAS aetiology with decreased mortality. CONCLUSIONS: Patients with NSTI were heterogeneous regarding co-morbidities, initial symptoms, infectious localisation, and microbiological findings. Higher age and lactate levels were associated with increased mortality, and GAS infection with decreased mortality.

Mortality in critical illness: The impact of asymmetric dimethylarginine on survival-A systematic review and meta-analysis.

INTRODUCTION: Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of the nitric oxide system, may be associated with an adverse outcome in critically ill patients. The aim of the present review was to clarify if plasma ADMA and the arginine-to-ADMA ratio (arginine/ADMA) are associated with mortality in critically ill patients. METHODS: We searched PubMed, EMBASE and Web of Science/BIOSIS Previews on 31 July 2017 for studies published after 2000 including critically ill paediatric or adult patients and evaluating any association between all-cause mortality and admission ADMA and/or arginine/ADMA ratio. We pooled data from studies providing sufficient data in random effects meta-analyses. RESULTS: We identified 15 studies including a total of 1300 patients. These studies have a medium to high risk of bias and substantial clinical heterogeneity. After contacting authors for homogenous data, six studies including 705 patients could be included in a formal meta-analysis. This analysis revealed a strong association between high plasma ADMA upon admission and mortality (pooled odds ratio 3.13; 95% confidence interval (CI) 1.78-5.51). A significant association between ADMA/arginine ratio and mortality was found in two studies only (54 patients) out of a total of six studies (564 patients). CONCLUSIONS: A high plasma ADMA level upon admission is strongly associated with mortality in critically ill patients. However, there is no association between the arginine/ADMA ratio and mortality in this group of patients. The pathophysiological role of ADMA in circulatory collapse and its potential as a target for intervention remains to be explored.

Treatment with 24 h-delayed normo- and hyperbaric oxygenation in severe sepsis induced by cecal ligation and puncture in rats.

BACKGROUND: Septic shock remains a leading cause of death worldwide. Hyperbaric oxygen treatment (HBO2) has been shown to alter the inflammatory response during sepsis and to reduce mortality. A therapeutic window of HBO2 treatment has been demonstrated experimentally, but optimal timing remains uncertain. We investigated the effects of 24 h delayed normobaric oxygen (NBO2) and HBO2 treatment on the endogenous production of the inflammatory markers interleukin (IL)-6, tumor necrosis factor (TNF)-α and IL-10, and on mortality in rats with cecal ligation and puncture (CLP) induced sepsis. METHOD: Fifty-five male Sprague-Dawley rats underwent CLP and were randomized to the following groups: 1) HBO2 2.5 bar absolute pressure (pabs); 2) NBO2 1.0 bar pabs; 3) Control (no-treatment), and they were individually monitored for 72 h with intermittent blood sampling. RESULTS: IL-6, TNF-α, and IL-10 were increased 24 h after the procedure, and IL-6 was significantly higher in non-survivors than in survivors. The level of IL-10 was significantly higher at hour 48 in the HBO2 group compared to control (p = 0.01), but this was not the case at other time points. No other significant differences in cytokine levels were found for any group comparisons. Delayed NBO2 and HBO2 treatment failed to change the mortality in the animals. CONCLUSION: High levels of IL-6 in non-surviving animals with sepsis suggest that IL-6 is a potential biomarker. We found a significantly higher concentration of IL-10 in the HBO2 group at hour 48 vs. control animals. However, 24 h-delayed treatment with HBO2 did not change the levels of pro-inflammatory cytokines and survival, suggesting that earlier intervention may be required to obtain an anti-inflammatory effect.

Hyperbaric oxygen therapy may overcome nitric oxide blockage during cyanide intoxication.

PURPOSE: To determine the effects of a blockade of nitric oxide (NO) synthesis on hyperbaric oxygen (HBO2) therapy during cyanide (CN) intoxication. METHODS: 39 anesthetized female Sprague-Dawley rats were exposed to CN intoxication (5.4 mg/kg intra-arterially) with or without previous nitric oxide synthase (NOS) inhibition by L-NG-nitroarginine methyl ester (L-NAME) injection (40 mg/kg intraperitoneally). Subsequently, either HBO2 therapy (284 kPa/90 minutes), normobaric oxygen therapy (100% oxygen/90 minutes) or nothing was administered. Intracerebral microdialysis was used to measure the interstitial brain concentration of lactate, glucose, glycerol and lactate/pyruvate ratios. RESULTS: L-NAME potentiated CN intoxication by higher maximum and prolonged lactate (in mM: 0. 5 ± 0.3 vs. 0.7 ± 0.4, P ⟨ 0.005) concentrations compared with solely CN-intoxicated rats. The same trend was found for mean glucose, glycerol and lactate/pyruvate ratio levels. During HBO2 treatment a sustained reduction occurred in mean lactate levels (in mM: 0.5 ± 0.5 vs. 0.7 ± 0.4, P ⟨ 0.01) regardless of NOS blockade by L-NAME. The same trend was found for mean glucose and glycerol levels. CONCLUSION: The results suggest that blocking NOS using L-NAME can worsen acute CN intoxication. HBO2 treatment can partially overcome this block and continue to ameliorate CN intoxication.

Biomarkers of Necrotising Soft Tissue Infections Aspects of the Innate Immune Response.

Necrotising soft tissue infection (NSTI) is a life-threatening and rapidly progressing bacterial infection involving one or more layers of the soft tissue compartments causing necrosis. The amputation and mortality rates remain high despite increased focus on the patients. Timely treatment, including surgical intervention, reduces the risk of severe disability and death. However, the lack of pathognomonic signs impedes early diagnosis and treatment. Moreover, the rarity of the disease makes it difficult to conduct large prospective studies, thus prospective research is almost non-existent in this group of patients. Instead data regarding biomarkers are extrapolated from the wide and heterogenic group of patients with sepsis, even though the immunological responses are likely to differ because of the large amount of necrotic tissue seen in patients with NSTI.   We performed the largest prospective, observational studies to date of patients with NSTI in Scandinavia sampled over more than two years with up to a 2.7-year follow-up. Blood samples were taken on admission (baseline) and the following three days and subsequently analysed for relevant plasma biomarkers. We elaborated on three aspects of the innate immune response, which included the investigation of acute-phase proteins, pattern recognition molecules of the lectin complement pathway, and inflammatory cytokines. The objective was to investigate aspects of the innate immune response in patients with NSTI, focusing on biomarkers as prognostic markers of disease severity and mortality. The overall hypothesis was that plasma biomarkers, representing the early innate immune response, can be used as prognostic markers of disease severity and mortality assessed by ICU scoring systems (SAPS II and SOFA score), the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score, presence of septic shock, microbial aetiology, renal replacement therapy, and amputation.   In Study 1, we assessed the following acute-phase proteins in 135 patients with NSTI: pentraxin-3 (PTX3), procalcitonin, and C-reactive protein. We found that a high baseline PTX3 level above the median was significantly associated with the presence of septic shock, amputation, and 180-day mortality, albeit PTX3 was not an independent predictor of mortality. PTX3 and procalcitonin performed equally well, whereas C-reactive protein correlated poorly with clinically relevant outcomes.      In Study 2, we assessed the following plasma pattern recognition molecules in the same cohort as in Study 1: mannose-binding lectin, Ficolin-1, Ficolin-2, and Ficolin-3. We found that baseline Ficolin-2 level below the median was associated with short- and long-term mortality and correlated with the SAPS II, whereas low levels of mannose-binding lectin and Ficolin-3 were associated only with short-term mortality.   In Study 3, we assessed the following inflammatory cytokines in 159 patients with NSTI: interleukin-1ß, interleukin-6, interleukin-10, and tumor necrosis factor-α. We found no significant association between the LRINEC score and baseline cytokine levels. In addition, interleukin-6 had the strongest correlation with the disease severity scores (SAPS II and SOFA score), whereas interleukin-1ß and interleukin-10 had the strongest association with 30-day mortality. Moreover, patients with ß-haemolytic streptococcal infection had higher levels of interleukin-6 and tumor necrosis factor-α compared with each subgroup stratified by microbial aetiology.    This thesis provides new knowledge on the aspects of the innate immune response in patients with NSTI. The results prove that NSTI is characterised by a pronounced inflammatory response and that the innate immune response differs according to disease severity, microbial aetiology, and mortality. Through the three studies we have identified relevant biomarkers that are useful in the risk stratification of patients with NSTI, thus perhaps enhancing prognostication and decision making in these critically ill patients.