Jan J. De Waele

Micafungin versus Caspofungin for Treatment of Candidemia and Other Forms of Invasive Candidiasis

BACKGROUND Invasive candidiasis is an important cause of morbidity and mortality among patients with health care-associated infection. The echinocandins have potent fungicidal activity against most Candida species, but there are few data comparing the safety and efficacy of echinocandins in the treatment of invasive candidiasis. METHODS This was an international, randomized, double-blind trial comparing micafungin (100 mg daily) and micafungin (150 mg daily) with a standard dosage of caspofungin (70 mg followed by 50 mg daily) in adults with candidemia and other forms of invasive candidiasis. The primary end point was treatment success, defined as clinical and mycological success at the end of blinded intravenous therapy. RESULTS A total of 595 patients were randomized to one the treatment groups and received at least 1 dose of study drug. In the modified intent-to-treat population, 191 patients were assigned to the micafungin 100 mg group, 199 to the micafungin 150 mg group, and 188 to the caspofungin group. Demographic characteristics and underlying disorders were comparable across the groups. Approximately 85% of patients had candidemia; the remainder had noncandidemic invasive candidiasis. At the end of blinded intravenous therapy, treatment was considered successful for 76.4% of patients in the micafungin 100 mg group, 71.4% in the micafungin 150 mg group, and 72.3% in the caspofungin group. The median time to culture negativity was 2 days in the micafungin 100 mg group and the caspofungin group, compared with 3 days in the micafungin 150 mg groups. There were no significant differences in mortality, relapsing and emergent infections, or adverse events between the study arms. CONCLUSIONS Dosages of micafungin 100 mg daily and 150 mg daily were noninferior to a standard dosage of caspofungin for the treatment of candidemia and other forms of invasive candidiasis.

Intra-abdominal hypertension and the abdominal compartment syndrome: updated consensus definitions and clinical practice guidelines from the World Society of the Abdominal Compartment Syndrome

PurposeTo update the World Society of the Abdominal Compartment Syndrome (WSACS) consensus definitions and management statements relating to intra-abdominal hypertension (IAH) and the abdominal compartment syndrome (ACS).MethodsWe conducted systematic or structured reviews to identify relevant studies relating to IAH or ACS. Updated consensus definitions and management statements were then derived using a modified Delphi method and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) guidelines, respectively. Quality of evidence was graded from high (A) to very low (D) and management statements from strong RECOMMENDATIONS (desirable effects clearly outweigh potential undesirable ones) to weaker SUGGESTIONS (potential risks and benefits of the intervention are less clear).ResultsIn addition to reviewing the consensus definitions proposed in 2006, the WSACS defined the open abdomen, lateralization of the abdominal musculature, polycompartment syndrome, and abdominal compliance, and proposed an open abdomen classification system. RECOMMENDATIONS included intra-abdominal pressure (IAP) measurement, avoidance of sustained IAH, protocolized IAP monitoring and management, decompressive laparotomy for overt ACS, and negative pressure wound therapy and efforts to achieve same-hospital-stay fascial closure among patients with an open abdomen. SUGGESTIONS included use of medical therapies and percutaneous catheter drainage for treatment of IAH/ACS, considering the association between body position and IAP, attempts to avoid a positive fluid balance after initial patient resuscitation, use of enhanced ratios of plasma to red blood cells and prophylactic open abdominal strategies, and avoidance of routine early biologic mesh use among patients with open abdominal wounds. NO RECOMMENDATIONS were possible regarding monitoring of abdominal perfusion pressure or the use of diuretics, renal replacement therapies, albumin, or acute component-parts separation.ConclusionAlthough IAH and ACS are common and frequently associated with poor outcomes, the overall quality of evidence available to guide development of RECOMMENDATIONS was generally low. Appropriately designed intervention trials are urgently needed for patients with IAH and ACS.

Clinical and Economic Outcomes in Critically Ill Patients with Nosocomial Catheter-Related Bloodstream Infections

BACKGROUND Central venous catheters are universally used during the treatment of critically ill patients. Their use, however, is associated with a substantial infection risk, potentially leading to increased mortality and costs. We evaluate clinical and economic outcomes associated with nosocomial central venous catheter-related bloodstream infection (CR-BSI) in intensive care unit (ICU) patients. METHODS A retrospective (1992-2002), pairwise-matched (ratio of case patients to control subjects, 1:2 or 1:1), risk-adjusted cohort study was performed at a 54-bed general ICU at a university hospital. ICU patients with microbiologically documented CR-BSI (n = 176) were matched with control subjects (n = 315) on the basis of disease severity, diagnostic category, and length of ICU stay (equivalent or longer) before the onset of CR-BSI in the index case patient. Clinical outcome was principally evaluated by in-hospital mortality. Economic outcome was evaluated on the basis of duration of mechanical ventilation, length of ICU and hospital stays, and total hospital costs, as derived from the patients hospital invoices. RESULTS The attributable mortality rate for CR-BSI was estimated to be 1.8% (95% confidence interval, -6.4% to 10.0%); in-hospital mortality rates for patients with CR-BSI and matched control subjects were 27.8% and 26.0%, respectively. CR-BSI was associated with significant excesses in duration of mechanical ventilation, duration of ICU and hospital stays, and a significant increase in total hospital cost. Linear regression analysis with adjustment for duration of hospitalization and clinical covariates, revealed that CR-BSI is independently associated with higher costs. CONCLUSIONS In ICU patients, CR-BSI does not result in increased mortality. It is, however, associated with a significant economic burden, emphasizing the importance of continuous efforts in prevention.

Decompressive laparotomy for abdominal compartment syndrome – a critical analysis

IntroductionAbdominal compartment syndrome (ACS) is increasingly recognized in critically ill patients, and the deleterious effects of increased intraabdominal pressure (IAP) are well documented. Surgical decompression through a midline laparotomy or decompressive laparotomy remains the sole definite therapy for ACS, but the effect of decompressive laparotomy has not been studied in large patient series.MethodsWe reviewed English literature from 1972 to 2004 for studies reporting the effects of decompressive laparotomy in patients with ACS. The effect of decompressive laparotomy on IAP, patient outcome and physiology were analysed.ResultsEighteen studies including 250 patients who underwent decompressive laparotomy could be included in the analysis. IAP was significantly lower after decompression (15.5 mmHg versus 34.6 mmHg before, p < 0.001), but intraabdominal hypertension persisted in the majority of the patients. Mortality in the whole group was 49.2% (123/250). The effect of decompressive laparotomy on organ function was not uniform, and in some studies no effect on organ function was found. Increased PaO2/FIO2 ratio (PaO2 = partial pressure of oxygen in arterial blood, FiO2 = fraction of inspired oxygen) and urinary output were the most pronounced effects of decompressive laparotomy.ConclusionThe effects of decompressive laparotomy have been poorly investigated, and only a small number of studies report its effect on parameters of organ function. Although IAP is consistently lower after decompression, mortality remains considerable. Recuperation of organ dysfunction after decompressive laparotomy for ACS is variable.

Intra-abdominal Hypertension and Abdominal Compartment Syndrome.

Increased intra-abdominal pressure (IAP), also referred to as intra-abdominal hypertension (IAH), affects organ function in critically ill patients and may lead to abdominal compartment syndrome (ACS). Although initially described in surgical patients, IAH and ACS also occur in medical patients without abdominal conditions. IAP can be measured easily and reliably in patients through the bladder using simple tools. The effects of increased IAP are multiple, but the kidney is especially vulnerable to increased IAP because of its anatomic position. Although the means by which kidney function is impaired in patients with ACS is incompletely elucidated, available evidence suggests that the most important factor involves alterations in renal blood flow. IAH should be considered as a potential cause of acute kidney injury in critically ill patients; its role in other conditions, such as hepatorenal syndrome, remains to be elucidated. Because several treatment options (both medical and surgical) are available, IAH and ACS should no longer be considered irrelevant epiphenomena of severe illness or critical care. An integrated approach targeting IAH may improve outcomes and decrease hospital costs, and IAP monitoring is a first step toward dedicated IAH management. IAH prevention, most importantly during abdominal surgery but also during fluid resuscitation, may avoid ACS altogether. However, when ACS occurs and medical treatment fails, decompressive laparotomy is the only option.

Fungal Infections in Patients with Severe Acute Pancreatitis and the Use of Prophylactic Therapy

Data from an 8-year period for 46 patients with severe acute pancreatitis and infected pancreatic necrosis were analyzed to determine the incidence of fungal infection, to identify risk factors for the development of fungal infection, and to assess the use of early fluconazole treatment. Intraabdominal fungal infection was found in 17 (37%) of 46 patients. Candida albicans was isolated most frequently (15 patients); Candida tropicalis and Candida krusei were found in 1 patient each. Characteristics of patients with fungal infection were not different from patients without fungal infection. The difference in mortality was not statistically significant between patients with fungal infection and patients without fungal infection. Early antifungal therapy (prophylactic or preemptive antifungal therapy) was administered to 18 patients, and only 3 of them developed fungal infection. In this cohort of critically ill patients, no risk factors for fungal infection could be demonstrated, and mortality among patients who received early antifungal therapy was not different. Early treatment with fluconazole seems to prevent fungal infection in these high-risk patients.

Intra-abdominal hypertension in patients with severe acute pancreatitis

IntroductionAbdominal compartment syndrome has been described in patients with severe acute pancreatitis, but its clinical impact remains unclear. We therefore studied patient factors associated with the development of intra-abdominal hypertension (IAH), the incidence of organ failure associated with IAH, and the effect on outcome in patients with severe acute pancreatitis (SAP).MethodsWe studied all patients admitted to the intensive care unit (ICU) because of SAP in a 4 year period. The incidence of IAH (defined as intra-abdominal pressure ≥ 15 mmHg) was recorded. The occurrence of organ dysfunction during ICU stay was recorded, as was the length of stay in the ICU and outcome.ResultsThe analysis included 44 patients, and IAP measurements were obtained from 27 patients. IAH was found in 21 patients (78%). The maximum IAP in these patients averaged 27 mmHg. APACHE II and Ranson scores on admission were higher in patients who developed IAH. The incidence of organ dysfunction was high in patients with IAH: respiratory failure 95%, cardiovascular failure 91%, and renal failure 86%. Mortality in the patients with IAH was not significantly higher compared to patients without IAH (38% versus 16%, p = 0.63), but patients with IAH stayed significantly longer in the ICU and in the hospital. Four patients underwent abdominal decompression because of abdominal compartment syndrome, three of whom died in the early postoperative course.ConclusionIAH is a frequent finding in patients admitted to the ICU because of SAP, and is associated with a high occurrence rate of organ dysfunction. Mortality is high in patients with IAH, and because the direct causal relationship between IAH and organ dysfunction is not proven in patients with SAP, surgical decompression should not routinely be performed.

Critical issues in the clinical management of complicated intra-abdominal infections.

Intra-abdominal infections differ from other infections through the broad variety in causes and severity of the infection, the aetiology of which is often polymicrobial, the microbiological results that are difficult to interpret and the essential role of surgical intervention. From a clinical viewpoint, two major types of intra-abdominal infections can be distinguished: uncomplicated and complicated. In uncomplicated intra-abdominal infection, the infectious process only involves a single organ and no anatomical disruption is present. Generally, patients with such infections can be managed with surgical resection alone and no antimicrobial therapy besides perioperative prophylaxis is necessary. In complicated intra-abdominal infections, the infectious process proceeds beyond the organ that is the source of the infection, and causes either localised peritonitis, also referred to as abdominal abscess, or diffuse peritonitis, depending on the ability of the host to contain the process within a part of the abdominal cavity. In particular, complicated intra-abdominal infections are an important cause of morbidity and are more frequently associated with a poor prognosis. However, an early clinical diagnosis, followed by adequate source control to stop ongoing contamination and restore anatomical structures and physiological function, as well as prompt initiation of appropriate empirical therapy, can limit the associated mortality.The biggest challenge with complicated intra-abdominal infections is early recognition of the problem. Antimicrobial management is generally standardised and many regimens, either with monotherapy or combination therapy, have proven their efficacy. Routine coverage against enterococci is not recommended, but can be useful in particular clinical conditions such as the presence of septic shock in patients previously receiving prolonged treatment with cephalosporins, immunosuppressed patients at risk for bacteraemia, the presence of prosthetic heart valves and recurrent intra-abdominal infection accompanied by severe sepsis. In patients with prolonged hospital stay and antibacterial therapy, the likelihood of involvement of antibacterial-resistant pathogens must be taken into account. Antimicrobial coverage of Candida spp. is recommended when there is evidence of candidal involvement or in patients with specific risk factors for invasive candidiasis such as immunodeficiency and prolonged antibacterial exposure. In general, antimicrobial therapy should be continued for 5–7 days. If sepsis is still present after 1 week, a diagnostic work up should be performed, and if necessary a surgical reintervention should be considered.

High-Protein Enteral Nutrition Enriched With Immune-Modulating Nutrients vs Standard High-Protein Enteral Nutrition and Nosocomial Infections in the ICU: A Randomized Clinical Trial

IMPORTANCE Enteral administration of immune-modulating nutrients (eg, glutamine, omega-3 fatty acids, selenium, and antioxidants) has been suggested to reduce infections and improve recovery from critical illness. However, controversy exists on the use of immune-modulating enteral nutrition, reflected by lack of consensus in guidelines. OBJECTIVE To determine whether high-protein enteral nutrition enriched with immune-modulating nutrients (IMHP) reduces the incidence of infections compared with standard high-protein enteral nutrition (HP) in mechanically ventilated critically ill patients. DESIGN, SETTING, AND PARTICIPANTS The MetaPlus study, a randomized, double-blind, multicenter trial, was conducted from February 2010 through April 2012 including a 6-month follow-up period in 14 intensive care units (ICUs) in the Netherlands, Germany, France, and Belgium. A total of 301 adult patients who were expected to be ventilated for more than 72 hours and to require enteral nutrition for more than 72 hours were randomized to the IMHP (n = 152) or HP (n = 149) group and included in an intention-to-treat analysis, performed for the total population as well as predefined medical, surgical, and trauma subpopulations. INTERVENTIONS High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition, initiated within 48 hours of ICU admission and continued during the ICU stay for a maximum of 28 days. MAIN OUTCOMES AND MEASURES The primary outcome measure was incidence of new infections according to the Centers for Disease Control and Prevention (CDC) definitions. Secondary end points included mortality, Sequential Organ Failure Assessment (SOFA) scores, mechanical ventilation duration, ICU and hospital lengths of stay, and subtypes of infections according CDC definitions. RESULTS There were no statistically significant differences in incidence of new infections between the groups: 53% (95% CI, 44%-61%) in the IMHP group vs 52% (95% CI, 44%-61%) in the HP group (P = .96). No statistically significant differences were observed in other end points, except for a higher 6-month mortality rate in the medical subgroup: 54% (95% CI, 40%-67%) in the IMHP group vs 35% (95% CI, 22%-49%) in the HP group (P = .04), with a hazard ratio of 1.57 (95% CI, 1.03-2.39; P = .04) for 6-month mortality adjusted for age and Acute Physiology and Chronic Health Evaluation II score comparing the groups. CONCLUSIONS AND RELEVANCE Among adult patients breathing with the aid of mechanical ventilation in the ICU, IMHP compared with HP did not improve infectious complications or other clinical end points and may be harmful as suggested by increased adjusted mortality at 6 months. These findings do not support the use of IMHP nutrients in these patients. TRIAL REGISTRATION trialregister.nl Identifier: NTR2181.

Sodium bicarbonate for prevention of contrast-induced acute kidney injury: a systematic review and meta-analysis

BACKGROUND There have been conflicting reports on the use of intravenous administration of sodium bicarbonate for prevention of contrast-induced acute kidney injury (CI-AKI). The aim of this study was to evaluate the use of sodium bicarbonate for prevention of CI-AKI. METHODS This is a symptomatic review and meta-analysis of prospectively randomized studies, abstracts and manuscripts, published from 1950 to 20 February 2009. RESULTS Of 192 identified publications, 18 studies (n = 3055) were included. Nine studies were only published as an abstract. CI-AKI occurred in 11.6%. Six prospective studies demonstrated that intervention with sodium bicarbonate resulted in a decreased risk of CI-AKI. The aggregate result of the prospective trials also demonstrated a benefit favouring sodium bicarbonate (RR = 0.66, 95% CI = 0.45-0.95). This effect was most prominent in coronary procedures and in patients with chronic kidney disease. There was no effect on need for renal replacement therapy (RRT) and mortality. Published manuscripts demonstrated a beneficial effect, while abstracts could not. Also, funnel plot analysis suggested a publication bias. In addition, we found significant clinical and statistical heterogeneity between studies. Finally, the quality of the individual studies was limited. CONCLUSIONS The incidence of CI-AKI was higher than recently reported, and varied among study cohorts. We found a preventive effect of the use of sodium bicarbonate on the risk for CI-AKI, however, with borderline statistical significance. There was no effect on need for RRT or mortality. The relative low quality of the individual studies, heterogeneity and possible publication bias means that only a limited recommendation can be made in favour of the use of sodium bicarbonate.