Paradoxical ventilator associated pneumonia incidences among selective digestive decontamination studies versus other studies of mechanically ventilated patients: benchmarking the evidence base

Introduction  

Selective digestive decontamination (SDD) appears to have a more compelling evidence base than non-antimicrobial methods for the prevention of ventilator associated pneumonia (VAP). However, the striking variability in ventilator associated pneumonia-incidence proportion (VAP-IP) among the SDD studies remains unexplained and a postulated contextual effect remains untested for.     

Hypothermia does not increase the risk of infection: a case control study

Introduction  

Hypothermia may improve outcome in patients after traumatic brain injury, especially when hypothermia is maintained for more than 48 hours. In the acute phase, patients with severe brain injury are more vulnerable to infections. Prolonged hypothermic treatment may further enhance the risk of infection. Selective decontamination of the digestive tract (SDD) reduces the risk of respiratory tract infections. The aim of this study was to investigate the incidence of infections in patients treated with hypothermia and normothermia while receiving SDD.     

<Emphasis Type="Italic">IL17A</Emphasis> genetic variation is associated with altered susceptibility to Gram-positive infection and mortality of severe sepsis

Introduction  

Interleukin 17A (IL17A) plays a key role in host defense against microbial infection including Gram-positive bacteria. Genetic factors contribute to the host defense, but the role of IL17A single nucleotide polymorphisms (SNPs) has not yet been investigated in severe sepsis. Therefore, we hypothesized that SNPs in the IL17A gene alter susceptibility to infection and clinical outcome of severe sepsis.     

Physicians' and nurses' opinions on selective decontamination of the digestive tract and selective oropharyngeal decontamination: a survey

Introduction

Use of selective decontamination of the digestive tract (SDD) and selective oropharyngeal decontamination (SOD) in intensive care patients has been controversial for years. Through regular questionnaires we determined expectations concerning SDD (effectiveness) and experience with SDD and SOD (workload and patient friendliness), as perceived by nurses and physicians.

Methods

A survey was embedded in a group-randomized, controlled, cross-over multicenter study in the Netherlands in which, during three 6-month periods, SDD, SOD or standard care was used in random order. At the end of each study period, all nurses and physicians from participating intensive care units received study questionnaires.

Results

In all, 1024 (71%) of 1450 questionnaires were returned by nurses and 253 (82%) of 307 by physicians. Expectations that SDD improved patient outcome increased from 71% and 77% of respondents after the first two study periods to 82% at the end of the study (P = 0.004), with comparable trends among nurses and physicians. Nurses considered SDD to impose a higher workload (median 5.0, on a scale from 1 (low) to 10 (high)) than SOD (median 4.0) and standard care (median 2.0). Both SDD and SOD were considered less patient friendly than standard care (medians 4.0, 4.0 and 6.0, respectively). According to physicians, SDD had a higher workload (median 5.5) than SOD (median 5.0), which in turn was higher than standard care (median 2.5). Furthermore, physicians graded patient friendliness of standard care (median 8.0) higher than that of SDD and SOD (both median 6.0).

Conclusions

Although perceived effectiveness of SDD increased as the trial proceeded, both among physicians and nurses, SOD and SDD were, as compared to standard care, considered to increase workload and to reduce patient friendliness. Therefore, education about the importance of oral care and on the effects of SDD and SOD on patient outcomes will be important when implementing these strategies.

Trial registration

ISRCTN35176830.     

The use of exenatide in severely burned pediatric patients

Introduction

Use of selective decontamination of the digestive tract (SDD) and selective oropharyngeal decontamination (SOD) in intensive care patients has been controversial for years. Through regular questionnaires we determined expectations concerning SDD (effectiveness) and experience with SDD and SOD (workload and patient friendliness), as perceived by nurses and physicians.

Methods

A survey was embedded in a group-randomized, controlled, cross-over multicenter study in the Netherlands in which, during three 6-month periods, SDD, SOD or standard care was used in random order. At the end of each study period, all nurses and physicians from participating intensive care units received study questionnaires.

Results

In all, 1024 (71%) of 1450 questionnaires were returned by nurses and 253 (82%) of 307 by physicians. Expectations that SDD improved patient outcome increased from 71% and 77% of respondents after the first two study periods to 82% at the end of the study (P = 0.004), with comparable trends among nurses and physicians. Nurses considered SDD to impose a higher workload (median 5.0, on a scale from 1 (low) to 10 (high)) than SOD (median 4.0) and standard care (median 2.0). Both SDD and SOD were considered less patient friendly than standard care (medians 4.0, 4.0 and 6.0, respectively). According to physicians, SDD had a higher workload (median 5.5) than SOD (median 5.0), which in turn was higher than standard care (median 2.5). Furthermore, physicians graded patient friendliness of standard care (median 8.0) higher than that of SDD and SOD (both median 6.0).

Conclusions

Although perceived effectiveness of SDD increased as the trial proceeded, both among physicians and nurses, SOD and SDD were, as compared to standard care, considered to increase workload and to reduce patient friendliness. Therefore, education about the importance of oral care and on the effects of SDD and SOD on patient outcomes will be important when implementing these strategies.

Trial registration

ISRCTN35176830.     

Selective decontamination of the digestive tract: the mechanism of action is control of gut overgrowth

Purpose

Gut overgrowth is the pathophysiological event in the critically ill requiring intensive care. In relation to the risk of developing a clinically important outcome, gut overgrowth is defined as?≥10⁵ potential pathogens including ‘abnormal’ aerobic Gram-negative bacilli (AGNB), ‘normal’ bacteria and yeasts, per mL of digestive tract secretion. Surveillance samples of throat and gut are the only samples to detect overgrowth. Gut overgrowth is the crucial event which precedes both primary and secondary endogenous infection, and a risk factor for the development of de novo resistance. Selective decontamination of the digestive tract (SDD) is an antimicrobial prophylaxis designed to control overgrowth.

Methods

There have been 65 randomised controlled trials of SDD in 15,000 patients over 25?years and 11 meta-analyses, which are reviewed.

Results and conclusions

These trials demonstrate that the full SDD regimen using parenteral and enteral antimicrobials reduces lower airway infection by 72?%, blood stream infection by 37?%, and mortality by 29?%. Resistance is also controlled. Parenteral cefotaxime which reaches high salivary and biliary concentrations eradicates overgrowth of ‘normal’ bacteria such as Staphylococcus aureus in the throat. Enteral polyenes control ‘normal’ Candida species. Enteral polymyxin and tobramycin, eradicate, or prevent gut overgrowth of ‘abnormal’ AGNB. Enteral vancomycin controls overgrowth of ‘abnormal’ methicillin-resistant S. aureus. SDD controls overgrowth by achieving high antimicrobial concentrations effective against ‘normal’ and ‘abnormal’ potential pathogens rather than by selectivity.     

Use of the probiotic <Emphasis Type="Italic">Lactobacillus plantarum</Emphasis> 299 to reduce pathogenic bacteria in the oropharynx of intubated patients: a randomised controlled open pilot study

Introduction  

Ventilator-associated pneumonia (VAP) is usually caused by aspiration of pathogenic bacteria from the oropharynx. Oral decontamination with antiseptics, such as chlorhexidine (CHX) or antibiotics, has been used as prophylaxis against this complication. We hypothesised that the probiotic bacteria Lactobacillus plantarum 299 (Lp299) would be as efficient as CHX in reducing the pathogenic bacterial load in the oropharynx of tracheally intubated, mechanically ventilated, critically ill patients.     

Adhesion of the probiotic bacterium <Emphasis Type="Italic">Lactobacillus plantarum</Emphasis> 299v onto the gut mucosa in critically ill patients: a randomised open trial

Introduction  

To achieve any possible positive effect on the intestinal mucosa cells it is important that probiotics adhere tightly onto the intestinal mucosa. It has been shown in healthy volunteers that Lactobacillus plantarum 299v (Lp 299v) (DSM 9843), a probiotic bacterium, given orally in a fermented oatmeal formula adheres onto the intestinal mucosa, but whether this also occurs in critically ill patients is unknown.     

Impact of digestive and oropharyngeal decontamination on the intestinal microbiota in ICU patients

Purpose

Selective digestive microbial decontamination (SDD) is hypothesized to benefit patients in intensive care (ICU) by suppressing Gram-negative potential pathogens from the colon without affecting the anaerobic intestinal microbiota. The purpose of this study was to provide more insight to the effects of digestive tract and oropharyngeal decontamination on the intestinal microbiota by means of a prospective clinical trial in which faecal samples were collected from ICU patients for intestinal microbiota analysis.

Methods

The faecal samples were collected from ICU patients enrolled in a multicentre trial to study the outcome of SDD and selective oral decontamination (SOD) in comparison with standard care (SC). Fluorescent in situ hybridization (FISH) was used to analyze the faecal microbiota. The numbers of bacteria from different bacterial groups were compared between the three regimens.

Results

The total counts of bacteria per gram faeces did not differ between regimens. The F. prausnitzii group of bacteria, representing an important group among intestinal microbiota, was significantly reduced in the SDD regimen compared to the SC and SOD. The Enterobacteriaceae were significantly suppressed during SDD compared to both SOD and SC; enterococci increased in SDD compared to both other regimens.

Conclusions

The composition of the intestinal microbiota is importantly affected by SDD. The F. prausnitzii group was significantly suppressed during SDD. This group of microbiota is a predominant producer of butyrate, the main energy source for colonocytes. Reduction of this microbiota is an important trade-off while reducing gram-negative bacteria by SDD.     

Clinical stakeholders’ opinions on the use of selective decontamination of the digestive tract in critically ill patients in intensive care units: an international Delphi study

Introduction

Selective decontamination of the digestive tract (SDD) is a prophylactic antibiotic regimen that is not widely used in practice. We aimed to describe the opinions of key ‘stakeholders’ about the validity of the existing evidence base, likely consequences of implementation, relative importance of their opinions in influencing overall practice, likely barriers to implementation and perceptions of the requirement for further research to inform the decision about whether to embark on a further large randomised controlled trial.

Methods

This was a Delphi study informed by comprehensive framework of possible determinants of health professionals’ behaviour to study Critical Care practice in four countries. There were four key stakeholder participant groups including ICU physicians, pharmacists, clinical leads, and clinical microbiologists/ infectious disease physicians. Round one comprised participant interviews and Rounds two and three were online questionnaires using Delphi method.

Results

In this study, 141 participants were recruited of whom 82% were retained. Participants rated themselves as knowledgeable about SDD. Antibiotic resistance was identified as the most important issue. SDD was seen as a low clinical priority but few participants reported strong opposition. There was moderate agreement that research to date has not adequately addressed concerns about antibiotic resistance and lacks generalizability. Participants indicated equipoise with regard to benefits and harms of SDD, and indicated strong support for a further randomised trial.

Conclusions

Clinicians have clinical equipoise about the effectiveness of SDD. Future research requires longer follow up to assess antibiotic resistance as well as greater validity/generalizability to provide definitive answers on the effectiveness of decontamination and effects on antibiotic resistance. SDD was regarded as not being a high clinical priority, which may limit future trial participation. These results have identified that further large randomised controlled trial of SDD in critical care is both warranted and appropriate.     

Cost effectiveness of antimicrobial catheters in the intensive care unit: addressing uncertainty in the decision

Introduction  

Some types of antimicrobial-coated central venous catheters (A-CVC) have been shown to be cost effective in preventing catheter-related bloodstream infection (CR-BSI). However, not all types have been evaluated, and there are concerns over the quality and usefulness of these earlier studies. There is uncertainty amongst clinicians over which, if any, A-CVCs to use. We re-evaluated the cost effectiveness of all commercially available A-CVCs for prevention of CR-BSI in adult intensive care unit (ICU) patients.     

Colistin resistance in gram-negative bacteria during prophylactic topical colistin use in intensive care units

Purpose

Topical use of colistin as part of selective digestive decontamination (SDD) and selective oropharyngeal decontamination (SOD) has been associated with improved patient outcome in intensive care units (ICU), yet little is known about the risks of colistin resistance. We quantified effects of selective decontamination on acquisition of colistin-resistant gram-negative bacteria (GNB) using data from a cluster-randomized study and a single-centre cohort.

Methods

Acquisition of colistin-resistant GNB and conversion from susceptible to resistance in GNB was determined in respiratory samples [from patients receiving SDD (n = 455), SOD (n = 476), or standard care (SC) (n = 315)], and in rectal swabs from 1,840 SDD-patients. Genotyping of converting isolates was performed where possible.

Results

The respiratory tract acquisition rates of colistin-resistant GNB were comparable during SDD, SOD, and SC and ranged from 0.7 to 1.1/1,000 patient-days at risk. Rectal acquisition rates during SDD were <3.3/1,000 days at risk. In patients with respiratory tract GNB carriage, conversion rates were 3.6 and 1.1/1,000 patient-days at risk during SDD and SC, respectively, (p > 0.05). In patients with rectal GNB carriage conversion rates during SDD were 5.4 and 3.2/1,000 days at risk and 15.5 and 12.6/1,000 days at risk when colonized with tobramycin-resistant GNB.

Conclusions

Acquisition rates with colistin-resistant GNB in the respiratory tract were low and comparable with and without topical use of colistin. Rates of acquisition of colistin-resistant GNB during SDD were—in ICUs with low endemicity of antibiotic resistance—<2.5/1,000 days at risk, but were fivefold higher during persistent GNB colonization and 15-fold higher during carriage with tobramycin-resistant GNB.     

Effects of the enteral administration of Bifidobacterium breve on patients undergoing chemotherapy for pediatric malignancies

Purpose  

Probiotics are expected to be effective in prophylaxis of infection in cancer patient, since infections in neutropenics are mainly caused by endogenous flora through the intestinal mucosa. However, the experience with the use of probiotics in immunocompromised patients is limited, and precise fecal bacteria analysis has not been reported. The aim of the study was to evaluate the effects of the enteral administration of the probiotic, Bifidobacterium breve strain Yakult, on its ability to prevent infection, fecal micro flora, and intestinal environments in cancer patients on chemotherapy.     

Decontamination of the digestive tract and oropharynx: hospital acquired infections after discharge from the intensive care unit

Objective  To determine the incidence rates of hospital acquired infections (HAI) during the first 14 days after ICU discharge after treatment during ICU-stay with Selective Decontamination of the Digestive tract (SDD), Selective Oropharyngeal Decontamination (SOD) or Standard Care (SC). Design  Prospective observational study. Setting  ICUs in two tertiary care hospitals. Patients  Patients discharged from the ICU to the ward. Interventions  None. Measurements and results  Post-ICU incidences of HAI per 1,000 days at risk were 11.2, 12.9 and 8.3 for patients that had received SDD (n = 296), SOD (n = 286) or SC (n = 289) respectively in ICU, yielding relative risks, as compared to SC, of 1.49 (CI₉₅ 0.9–2.47) for SOD and 1.44 (CI₉₅ 0.87–2.39) for SDD. Incidences of surgical site infections (per 100 surgical procedures) were 4 after SC and 11.8 and 8 after SOD and SDD (p = 0.04). Among patients that succumbed in the hospital after ICU-stay (n = 58) eight (14%) had developed HAI after ICU discharge; 3 of 21 after SDD, 3 of 15 after SOD and 2 of 22 after SC. Conclusions  Incidences of HAI in general wards tended to be higher in patients that had received either SDD or SOD during ICU-stay, but it seems unlikely that these infections have an effect on hospital mortality rates.     

Nebulised amphotericin B to eradicate Candida colonisation from the respiratory tract in critically ill patients receiving selective digestive decontamination: a cohort study

Introduction

Colonisation of the lower respiratory tract with Candida species occurs in 25% of mechanically ventilated critically ill patients, and is associated with increased morbidity. Nebulised amphotericin B has been used to eradicate Candida as part of selective decontamination of the digestive tract (SDD) protocols, but its effectiveness is unknown. We aimed to determine the effectiveness of nebulised amphotericin B in eradicating Candida respiratory tract colonisation in patients receiving SDD.

Methods

We included consecutive mechanically ventilated patients during a four-year period. Microbiological screening was performed upon admission and twice weekly thereafter according to a standardised protocol. A colonisation episode was defined as the presence of Candida species in two consecutive sputum samples taken at least one day apart. To correct for time-varying bias and possible confounding, we used a multistate approach and performed time-varying Cox regression with adjustment for age, disease severity, Candida load at baseline and concurrent corticosteroid use.

Results

Among 1,819 patients, colonisation with Candida occurred 401 times in 363 patients; 333 of these events were included for analysis. Decolonisation occurred in 51 of 59 episodes (86%) and in 170 of 274 episodes (62%) in patients receiving and not receiving nebulised amphotericin B, respectively. Nebulised amphotericin B was associated with an increased rate of Candida eradication (crude HR 2.0; 95% CI 1.4 to 2.7, adjusted HR 2.2; 95% CI 1.6 to 3.0). Median times to decolonisation were six and nine days, respectively. The incidence rate of ventilator-associated pneumonia, length of stay and mortality did not differ between both groups.

Conclusions

Nebulised amphotericin B reduces the duration of Candida colonisation in the lower respiratory tracts of mechanically ventilated critically ill patients receiving SDD, but data remain lacking that this is associated with a meaningful improvement in clinical outcomes. Until more evidence becomes available, nebulised amphotericin B should not be used routinely as part of the SDD protocol.     

Long-term use of selective decontamination of the digestive tract does not increase antibiotic resistance: a 5-year prospective cohort study

Purpose  

Despite the evidence, the use of selective decontamination of the digestive tract (SDD) remains controversial, largely because of concerns that it may promote the emergence of antibiotic-resistant strains. The purpose of this study was to evaluate the long-term incidence of carriage of antibiotic-resistant bacteria (ARB), its clinical impact on developing infections and to explore risk factors of acquiring resistance.     

Remote electrical neuromodulation for migraine prevention: A double-blind,randomized, placebo-controlled clinical trial

Objective

To assess the clinical efficacy of remote electrical neuromodulation (REN), used every other day, for the prevention of migraine.

Background

Preventive treatment is key to managing migraine, but it is often underutilized. REN, a non-pharmacological acute treatment for migraine, was evaluated as a method of migraine prevention in patients with episodic and chronic migraine.

Methods

We conducted a prospective, randomized, double-blind, placebo-controlled, multi-center trial, with 1:1 ratio. The study consisted of a 4-week baseline observation phase, and an 8-week double-blind intervention phase in which participants used either REN or a placebo stimulation every other day. Throughout the study, participants reported their symptoms daily, via an electronic diary.

Results

Two hundred forty-eight participants were randomized (128 active, 120 placebo), of which 179 qualified for the modified intention-to-treat (mITT) analysis (95 active; 84 placebo). REN was superior to placebo in the primary endpoint, change in mean number of migraine days per month from baseline, with mean reduction of 4.0 ± SD of 4.0 days (1.3 ± 4.0 in placebo, therapeutic gain = 2.7 [confidence interval −3.9 to −1.5], p < 0.001). The significance was maintained when analyzing the episodic (−3.2 ± 3.4 vs. −1.0 ± 3.6, p = 0.003) and chronic (−4.7 ± 4.4 vs. −1.6 ± 4.4, p = 0.001) migraine subgroups separately. REN was also superior to placebo in reduction of moderate/severe headache days (3.8 ± 3.9 vs. 2.2 ± 3.6, p = 0.005), reduction of headache days of all severities (4.5 ± 4.1 vs. 1.8 ± 4.6, p < 0.001), percentage of patients achieving 50% reduction in moderate/severe headache days (51.6% [49/95] vs. 35.7% [30/84], p = 0.033), and reduction in days of acute medication intake (3.5 ± 4.1 vs. 1.4 ± 4.3, p = 0.001). Similar results were obtained in the ITT analysis. No serious device-related adverse events were reported in any group.

Conclusion

Applied every other day, REN is effective and safe for the prevention of migraine.     

Migraine,inflammatory bowel disease and celiac disease: A Mendelian randomization study

Objective

To assess whether migraine may be genetically and/or causally associated with inflammatory bowel disease (IBD) or celiac disease.

Background

Migraine has been linked to IBD and celiac disease in observational studies, but whether this link may be explained by a shared genetic basis or could be causal has not been established. The presence of a causal association could be clinically relevant, as treating one of these medical conditions might mitigate the symptoms of a causally linked condition.

Methods

Linkage disequilibrium score regression and two-sample bidirectional Mendelian randomization analyses were performed using summary statistics from cohort-based genome-wide association studies of migraine (59,674 cases; 316,078 controls), IBD (25,042 cases; 34,915 controls) and celiac disease (11,812 or 4533 cases; 11,837 or 10,750 controls). Migraine with and without aura were analyzed separately, as were the two IBD subtypes Crohn's disease and ulcerative colitis. Positive control analyses and conventional Mendelian randomization sensitivity analyses were performed.

Results

Migraine was not genetically correlated with IBD or celiac disease. No evidence was observed for IBD (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.99–1.02, p = 0.703) or celiac disease (OR 1.00, 95% CI 0.99–1.02, p = 0.912) causing migraine or migraine causing either IBD (OR 1.08, 95% CI 0.96–1.22, p = 0.181) or celiac disease (OR 1.08, 95% CI 0.79–1.48, p = 0.614) when all participants with migraine were analyzed jointly. There was some indication of a causal association between celiac disease and migraine with aura (OR 1.04, 95% CI 1.00–1.08, p = 0.045), between celiac disease and migraine without aura (OR 0.95, 95% CI 0.92–0.99, p = 0.006), as well as between migraine without aura and ulcerative colitis (OR 1.15, 95% CI 1.02–1.29, p = 0.025). However, the results were not significant after multiple testing correction.

Conclusions

We found no evidence of a shared genetic basis or of a causal association between migraine and either IBD or celiac disease, although we obtained some indications of causal associations with migraine subtypes.     

Leptin and leptin receptor polymorphisms are associated with poor outcome (death) in patients with non-appendicular secondary peritonitis

Introduction  

Leptin (LEP) and its receptor (LEPR) participate in the immunological response during infection. LEP serum levels rise during sepsis. In patients with peritonitis, an insufficient elevation in serum LEP is associated with an increased risk of death. As gene variants of LEP and LEPR have been associated with diverse pathologic conditions, we explored the association of genetic polymorphisms of LEP or LEPR with death in patients with secondary peritonitis.