Infections
Hospital-acquired infections with antibiotic-resistant bacteria are an important problem among critically ill patients. Control of these organisms has largely focused within individual hospitals. Karkada et al. [
27] examined the extent to which transfers of critically ill patients could be a vector for the spread of such bacteria and compared the efficiency of different infection control measures in a simulation study of an American hospital network system. Hospitals varied substantially in the importance placed on limiting potential spread, and targeting resources to a small subset of hospitals on the basis of their position in the transfer network was 16 times more efficient than distributing infection control resources uniformly.
Changes in the consumption of MRSA-active antibiotics and in the burden of MRSA between 2001 and 2009 were analyzed in a network of 55 German ICUs [
28]. “Old MRSA-active antibiotics” included vancomycin, teicoplanin, and fosfomycin and “new MRSA-active antibiotics” included quinupristin/dalfopristin, linezolid, and daptomycin. Both the burden of MRSA and the pooled mean MRSA resistance proportion did not change significantly over time. In contrast, MRSA-active antibiotics more than doubled from 44 defined daily doses per 1,000 patient-days in 2001 to 92 in 2009. This was due to the significant increase of new MRSA-active antibiotics (from 1 to 40), whereas old MRSA antibiotics stayed stable (43 in 2001 and 52 in 2009).
Crandon and co-workers [
29] developed a meropenem population pharmacokinetic model in critically ill patients with particular focus on optimizing dosing regimens based on renal function. Initial modeling was performed on 21 patients (55 samples) and validation was conducted with 12 samples from 5 patients. The model was capable of accurately estimating meropenem concentrations in critically ill patients over a range of creatinine clearance values. Compared with 0.5-h infusions, regimens employing prolonged infusions improved target attainment across all creatinine clearance ranges.
Selective decontamination of the digestive tract (SDD) has received continued interest for the prevention of infections. In a randomized trial in a Dutch ICU, SDD and probiotics were compared [
30]. The probiotics contained
Lactobacillus 299/299v plus fiber, administered two times daily. The trial was prematurely stopped after a study reporting increased mortality in critically ill pancreatitis patients receiving probiotics [
31]. There were no significant differences in infection rates [31% in the probiotic group and 24% in the SDD group (OR 1.68, 95% CI 0.91–3.08,
p = 0.10)].
Although SDD can significantly decrease infection rates (and possibly mortality) in ICU patients, it has not been widely accepted and adopted possibly because of fear of encouraging bacterial resistance to the antimicrobials used. To evaluate the long-term incidence of carriage of antibiotic-resistant bacteria, its clinical impact on developing infections, and to explore risk factors for acquiring resistance, Ochoa-Ardila and colleagues conducted a 5-year cohort study in 1,588 patients given SDD [
32]. Interestingly, long-term use of SDD in that study was not associated with an increased resistance against the antimicrobials used as part of the SDD, or with an increase in the rate in infections caused by resistant strains; in fact, a reduction in the incidence of
P. aeruginosa resistant to aminoglycosides was observed. These findings are in line with those reported by de Smet et al. [
33], showing that the use of SDD was associated with a reduction in acquired bacteremia and respiratory tract colonization caused by highly resistant microorganisms compared with standard care.
H1N1
Early use of corticosteroids in patients affected by pandemic (H1N1)v influenza A infection, although relatively common, remains highly debated. In order to assess the potential usefulness of such a treatment, Martin-Loeches and colleagues [
34] analyzed the chart records of 220 patients admitted to ICU with a confirmed H1N1 infection, prospectively included in the European Society of Intensive Care Medicine H1N1 registry. Among these patients, 126 (57.3%) received corticosteroid therapy on admission to ICU. They were significantly older and were more likely to have coexisting asthma, chronic obstructive pulmonary disease, and chronic steroid use. Cox regression analysis adjusted for severity and potential confounding factors identified that early use of corticosteroids was not significantly associated with mortality (HR 1.3, 95% CI 0.7–2.4,
p = 0.4) but was still associated with an increased rate of hospital-acquired pneumonia (OR 2.2, 95% CI 1.0–4.8,
p < 0.05). Very similar findings were observed in two other large cohort studies, the first one by Kim et al. [
35], and the second one by Brun-Buisson et al. [
36], confirming that early use of corticosteroids in patients affected by pandemic (H1N1)v influenza A infection did not result in better outcomes and was associated with increased risk of superinfections.
Because some uncertainty about the severity of the A(H1N1) pandemia persists, particularly regarding its impact on the healthcare system, Bertolini and colleagues [
37] conducted a prospective observational study in 155 Italian ICUs contributing to the GiViTI national database during the epidemic phase of the disease. At the epidemic’s peak (October–December 2009) the ICU occupancy rate did not significantly differ from the same period of the previous year, and was significantly lower than the 2009 seasonal influenza outbreak (January–March 2009). Compared with community-acquired pneumonia (CAP) of other origin (3,678 patients), A(H1N1) pneumonia was associated with the same risk of death when potential confounders were taken into account (OR 0.88, 95% CI 0.59–1.31,
p = 0.52). Thus, on the basis of these data, it seems that the pandemic did not increase ICU workload compared with other periods, at least in Italy. However, it is still true that the pandemic affected many young people, and the burden in terms of young lives lost cannot be overlooked.
In a retrospective observational study in 23 French ICUs, Cuquemelle and co-workers [
38] investigated whether procalcitonin (PCT) levels could discriminate isolated viral from mixed (bacterial and viral) pneumonia during the A/H1N1v2009 influenza pandemic. Of 103 patients with confirmed A/H1N1 infection and not having received prior antibiotics, 48 had a documented bacterial co-infection (mostly caused by
Streptococcus pneumoniae or
Staphylococcus aureus). Median values of PCT were significantly higher in patients with bacterial co-infection: 29.5 (3.9–45.3) versus 0.5 (0.12–2) μg/L (
p < 0.01). For a cutoff of 0.8 μg/L or more, the sensitivity and specificity of PCT for distinguishing isolated viral from mixed pneumonia were 91 and 68%, respectively.
MRSA pneumonia
Although vancomycin has been the mainstay for treatment of MRSA infections, the drug may not be adequate for patients with MRSA pneumonia, particularly when the infection is caused by a strain with a relatively high vancomycin minimal inhibitory concentration (MIC) (≥1.5 μg/mL). To assess the distribution of vancomycin MICs in MRSA isolates and evaluate the efficacy of vancomycin relative to vancomycin MICs in adult patients with MRSA nosocomial pneumonia, Choi and colleagues [
39] analyzed the clinical outcomes of 70 adults with MRSA nosocomial pneumonia treated with vancomycin. Thirty-four (48.6%) isolates had high (≥1.5 μg/mL) vancomycin MICs, and 36 (51.4%) had low (≤ 1 μg/mL) MICs, as determined by
E test. Patients infected with high-MIC strains showed slower clinical response and higher relapse rate (29.6 vs. 6.9%,
p = 0.038) than patients infected with low-MIC vancomycin isolates. Infection caused by high-MIC strains was also an independent predictor of early clinical response failure when tested on multivariate analysis. These results are in accordance with those obtained by other investigators in patients with MRSA bloodstream infections [
40].
Emergency and ICU physicians often face the routine challenge of predicting short- to mid-term adverse outcomes for patients with CAP. As biomarkers have significantly improved practices in emergency medicine, it was suggested that they could help management of CAP, particularly when using endothelium-associated peptides, such as precursor peptides of endothelin-1 (proET-1) that correlate closely with endothelial activation. Indeed, emerging evidence points to a critical role of the endothelium in patients with systemic infections [
44]. In this context, Schuetz and colleagues [
45] evaluated the prognostic information derived from repeated measurements of proET-1 for monitoring patients during the course of disease in a well-defined cohort of 925 CAP patients. They found that both admission proET-1 levels and relative changes between baseline and day 3 provided significant prognostic information in regard to mortality and the need for ICU admission and improved classification of the pneumonia severity index (PSI) score. The results also showed that relative changes in the marker level provided more information compared with absolute marker levels during the follow-up. If verified in intervention studies, monitoring of proET-1 may be helpful for endothelium targeting therapies and for risk stratification complementary to other prohormones.
Two reviews addressed important issues in the field of CAP. The first analyzed the four different validated rules to help in the decision regarding ICU admission in patients with CAP. Ewig and colleagues [
46] critically reviewed these rules: the modified American Thoracic Society (ATS) rule, Infectious Diseases Society of America (IDSA)/ATS rule, España rule, and SMART-COP (systolic blood pressure, multilobar extension of infiltrates, albumin, respiratory rate, tachycardia, confusion, oxygen, and arterial pH). Their performance varies, with sensitivity of around 70% and specificity of around 80–90%. Only negative predictive values are consistently high. Critical methodological issues include the appropriate reference for derivation, the populations studied, the variables included, and the time course of pneumonia. Pneumonia-related complications and decompensated comorbidities may be additional or independent reasons for a severe course. The authors advocate an approach that refers to the evaluation of the need for intensified treatment rather than ICU, based on a set of minor criteria but sensitive to the dynamic nature of pneumonia.
The second review pertained to the assessment of severity to guide ICU admission [
47]. Universally accepted criteria for ICU care in patients with CAP are mechanical ventilation and/or vasopressor support. Chalmers and collaborators aimed to determine if severity assessment tools could be used to guide decisions regarding ICU admission of patients with CAP. To that end, a meta-analysis of 28 studies and five scoring systems was performed. These scoring systems were the PSI, the CURB65 (confusion, urea, respiratory rate, blood pressure, and age >65) score, the CRB65 score, the ATS 2001 criteria, and the IDSA/ATS 2007 criteria. The PSI, CURB65, and CRB65 performed similarly in terms of sensitivity and specificity. Patients in CURB65 group zero were at lowest risk of ICU admission (negative likelihood ratio 0.14), whereas the ATS 2001 criteria had the highest positive likelihood ratio (7.05). However, a marked heterogeneity between studies was detected. The authors concluded that scoring systems designed to predict 30-day mortality perform less well in predicting ICU admission.
Sepsis and septic shock
Severe sepsis is associated with high mortality, and the Surviving Sepsis Campaign (SSC) protocol was developed as an international initiative to reduce mortality. Cost-effectiveness of the SSC protocol for the treatment of severe sepsis was determined in 59 Spanish ICUs in an observational prospective before-and-after study after the implementation of an educational program compared with the conventional care of severe sepsis [
48]. Patients in the SSC protocol care cohort (
n = 1,465) had a lower risk of hospital mortality (44.0 vs. 39.7%,
p = 0.04), but mean costs per patient were 1,736 euros higher, largely as a result of increased length of stay. The adjusted incremental cost-effectiveness ratio (ICER) of the SSC protocol was 4,435 euros per life years gained.
An option still debated is the use of steroids for severe sepsis and septic shock. Three recent meta-analyses on the effects of low-dose corticosteroids on mortality reduction in patients with severe sepsis and septic shock gave contradictory results: two showed potential mortality benefit and one showed no mortality benefit. In the March issue Kalil and Sun [
49] assessed the efficacy and safety of low-dose steroids for severe sepsis and septic shock by Bayesian methodology. Relative risk reductions (RRR) for 28-day mortality and relative risk increases (RRI) for shock reversal and side effects were estimated. The authors found that in septic shock trials only (Marik meta-analysis), the probability that low-dose steroids decrease mortality by more than 15% (i.e., RRR > 15%) was 0.41 (0.24 for RRR > 20% and 0.14 for RRR > 25%). For severe sepsis and septic shock trials combined, the results were as follows: (1) for the Annane meta-analysis, the probabilities were 0.57 (RRR > 15%), 0.32 (RRR > 20%), and 0.13 (RRR > 25%); (2) for the Minneci meta-analysis, the probability was 0.57 to achieve mortality RRR > 15%, 0.32 (RRR > 20%), and 0.14 (RRR > 25%). The probability of achieving shock reversal ranged from 65 to 92%. The probability of developing steroid-induced side effects was as follows: for gastrointestinal bleeding (
n = 924), there was a 0.73 probability of steroids causing an RRI > 1%, 0.70 for RRI > 2%, and 0.67 for RRI > 5%; for superinfections (
n = 964), probabilities were 0.81 (RRI > 1%), 0.76 (RRI > 2%), and 0.70 (RRI > 5%); and for hyperglycemia (
n = 540), 0.99 (RRI > 1%), 0.97 (RRI > 2%), and 0.94 (RRI > 5%). It was concluded that the findings strongly suggest that survival benefit is unlikely to be achieved with low-dose steroids for patients with severe sepsis and/or septic shock. In addition, the probabilities of developing serious drug-induced side effects such as superinfections, bleeding, and hyperglycemia are too high to justify shock reversal as the sole indication for the use of low-dose steroids.
The time course of organ failure in patients with septic shock treated with hydrocortisone was analyzed in a study that was an addendum of the Corticus trial [
50]. The authors hypothesized that patients treated with hydrocortisone when compared to placebo would have a faster resolution of organ dysfunction/failure. The authors analyzed the patients who had been enrolled in the Corticus trial: a prospective, randomized, double-blind, placebo-controlled study of 28-day mortality in patients with septic shock for less than 72 h who underwent a short high-dose ACTH test and patients received 11-day treatment with hydrocortisone or placebo. A total of 499 patients were enrolled (hydrocortisone 251, placebo 248). There was no difference in 28-day mortality between the two treatment groups (hydrocortisone 34.3 vs. placebo 31.5%). There was a decrease in the SOFA score of hydrocortisone-treated patients from day 0 to day 7 compared with the placebo-treated patients (
p = 0.0027), driven by an improvement in cardiovascular organ dysfunction/failure (
p = 0.0005) and in liver failure (
p < 0.0001) in the hydrocortisone-treated patients. It was concluded that patients treated with hydrocortisone demonstrated a faster decrease in total organ dysfunction/failure, without being accompanied by a decreased mortality.
It is well known that sepsis is also an important cause of morbidity and mortality for neonates, but a rapid and accurate diagnostic is difficult. A group of authors coordinated by Falagas [
51] aimed at assessing the value of PCT for the diagnosis of neonatal sepsis by performing a diagnostic test accuracy meta-analysis of relevant studies. Twenty-nine articles were analyzed. The authors found a sensitivity and specificity of 81% (95% CI 74–87%) and 79% (95% CI 69–87%), respectively. The area under the receiver operating characteristic curve (AUC-ROC) was 0.87. However, high statistical heterogeneity was observed for all analyses. It was concluded that although serum PCT at presentation has very good diagnostic accuracy for the diagnosis of neonatal sepsis; the marked heterogeneity along with the lack of a uniform definition for neonatal sepsis, means that the interpretation of the findings is to be done cautiously.
Polymerase chain reaction (PCR)-based techniques allow more rapid and sensitive detection of pathogens compared with conventional blood culture. The current opinion is that PCR can supplement but not replace blood culture in septic patients. A review article published in the July issue [
52] deals with these problems. Numerous studies showed that the combined detection rate of both methods (PCR and blood culture) was significantly higher compared with PCR or blood culture alone. An inherent limitation of PCR is that determination of antibiotic resistance can currently be performed only by blood culture. PCR techniques are also costly and involve a significant workload. Except for diagnosis of patients in whom unusual, not cultivable, or fastidious pathogens are of concern, such as immunosuppressed patients with suspected parasitic infection, it might even not be necessary to further increase the spectrum of detectable species. In the authors’ opinion, a narrower assay is more cost effective, may achieve higher accuracy owing to reduced intratest interference, and would better address current and emerging clinical needs.
Phosphorylation pathways may be altered during severe sepsis and septic shock. These pathways play a central role in the development and progression of many other disease states, because they control central biological mechanisms in nearly all cellular functions. In a review published at the beginning of 2011, Martin and Ranieri [
53] summarized the function and activity of various phosphorylation mechanisms. The authors discussed the phosphorylation mechanisms in the pathogenesis, diagnosis, and treatment of heart failure, myocardial infarction, stroke, respiratory failure, ventilation-induced lung injury, traumatic brain injury, acute organ failure, systemic sepsis, and shock. It was concluded that a proper understanding of these mechanisms will provide new avenues of treatment by targeting this biological function.
Gastrointestinal dysfunction in critically ill septic patients is common, and probably underestimated. A validated definition of acute intestinal failure is lacking, in the absence of a marker to measure it. A review on gastrointestinal dysfunction in critically ill patients [
54] proposed a definition of acute intestinal failure. Small bowel ischemia is related to acute reduction of enterocyte mass and loss of gut barrier. Systemic inflammatory response syndrome and sepsis could be linked to an acute dysfunction of enterocytes without enterocyte reduction. Citrulline is an amino acid mainly synthesized by small bowel enterocytes. Patients with shock have an acute reduction of enterocyte mass and reduced gut citrulline synthesis, leading to a low plasma citrulline concentration. The authors proposed that acute intestinal failure could be defined as an acute reduction of enterocyte mass and/or acute dysfunction of enterocytes, associated or not with loss of gut barrier function. The authors also stated that the value of plasmatic citrulline as an indicator of acute intestinal failure in critically ill patients must be further evaluated.