Ventilator-associated pneumonia
Whether azithromycin, a drug that could block the quorum-sensing (QS) system, could prevent ventilator-associated pneumonia (VAP) in patients colonized by rhamnolipid-producing isolates is unknown. To test this hypothesis, Van Delden and colleagues [
3] randomized 92 patients proven to be colonized by
Pseudomonas aeruginosa, to receive either placebo or 300 mg/day iv azithromycin in a double-blind fashion for a maximum of 20 days. Considering only the subgroup of patients at very high risk of developing VAP because they were colonized by isolates producing intermediate or high levels of rhamnolipids (
n = 41), the incidence of VAP was reduced fivefold in azithromycin versus placebo patients (1/5 vs. 5/5 VAP,
p = 0.048). These data stress the need for a large phase IIb clinical trial restricted to patients colonized by QS-proficient isolates to further establish safety and efficacy of QS inhibition by azithromycin to prevent
P. aeruginosa VAP.
Fungal airway colonization is a frequent finding in patients submitted to mechanical ventilation (MV) and could promote VAP development, especially if caused by
P. aeruginosa, a bacterium likely to become resistant to antimicrobial agents. Indeed, a growing body of evidence supports the strong interplay between
Candida albicans and
P. aeruginosa when coexisting within a biofilm environment such as the endotracheal tube or the airway [
4,
5]. In a prospective study of 323 consecutive cases of suspected VAP, Hamet et al. [
6] were able to demonstrate that mortality rate was greater in patients with fungal airway colonization than in those without (44 vs. 31 %,
p = 0.02). Moreover,
Candida spp. airway colonization was an independent risk factor for multidrug-resistant bacteria isolation, such as
P. aeruginosa and Enterobacteriaceae [odds ratio (OR) 1.79, 95 % confidence interval (CI) 1.05–3.05;
p = 0.03], in addition to the time elapsed between ICU admission and VAP suspicion. Whether or not
Candida spp. airway colonization should be considered when selecting an empiric antibiotic treatment for VAP will require additional studies, as well as for defining the clinical utility of antifungal drugs in such patients [
7].
Etomidate has a favorable hemodynamic profile and is frequently used as a single bolus for rapid sequence intubation in trauma patients, as well as ICU patients. However, its use can induce transient corticosteroid insufficiency and thus increases susceptibility to nosocomial infection [
8]. To investigate the impact of etomidate on the rate of hospital-acquired pneumonia (HAP) in trauma patients and the effects of hydrocortisone in etomidate-treated patients, Asehnoune and colleagues [
9,
10] did a post hoc analysis of the HYPOLYTE double-blind, placebo-controlled trial of hydrocortisone in trauma patients. The administration of etomidate did not alter basal cortisolemia, but it did decrease the delta of cortisolemia at 60 min, leading to corticosteroid insufficiency in 83 % of the patients (
p = 0.007). Forty-nine (52 %) patients with etomidate and 16 (30 %) patients without etomidate developed pneumonia by day 28, respectively (
p = 0.009). Among etomidate-exposed patients, hydrocortisone was found to significantly decrease the rate of HAP and the duration of MV. These data should alert physicians to limit the use of etomidate for the intubation of severe trauma patients unless they use hydrocortisone to counteract the deleterious effects of the drug.
Treatment of VAP is increasingly hampered by antibiotic resistance and an innovative approach is to augment antibiotic delivery at the site of infection.
Nebulized colistimethate sodium (CMS)/colistin is frequently used as an adjunctive therapy for the treatment of VAP in patients infected by very difficult-to-treat pathogens, such as carbapenemase-producing
Klebsiella pneumoniae or multiresistant strains of
P. aeruginosa or
Acinetobacter baumannii. However, very little information is available regarding the pharmacokinetics of the drug when used by aerosolization in ventilated patients. To fill this gap, Athanassa and colleagues [
11] determined colistin concentrations in bronchoalveolar lavage fluid and serum of 20 patients mechanically ventilated, who had symptoms and signs suggestive of ventilator-associated tracheobronchitis caused by gram-negative bacilli only susceptible to polymyxin and who were treated by colistin inhalation at a dose of 1 MU (80 mg CMS) every 8 h via a vibrating-mesh nebulizer. Results demonstrated relatively high colistin concentrations in the epithelial lining fluid at 1 and 4 h and substantially lower concentrations at 8 h after inhalation, underlining that a dose of 80 mg of inhaled CMS every 8 h may not be adequate for the treatment of patients with VAP due to multidrug-resistant gram-negative bacteria (GNB). Additional studies are required to determine whether larger doses of nebulized CMS may result in higher and sustained colistin concentrations at the target site in pulmonary infections.
A newly designed device for nebulizing amikacin (BAY41-6551) was used to treat 69 patients with VAP in a randomized, placebo-controlled, double-blind phase II study. Treatment was well tolerated and associated with good clinical cure rates that warrant further clinical evaluation [
12].
Gram-negative bacteria predominate in HAP, and among them,
Escherichia coli is the main Enterobacteriaceae involved in VAP. Phylogenetic analysis shows that
E. coli population can be divided into four major groups (A, B1, B2, and D). Strains belonging to groups A and B1 are known to carry few genes encoding virulence factors (VF), with weak extraintestinal pathogenicity, and are commonly multidrug-resistant. On the other hand, group B2 and D strains typically express numerous VF mediating bacterial adhesion, cell host invasion, and toxicity, and usually exert high extraintestinal pathogenicity [
13]. To provide a detailed analysis of
E. coli strains colonizing and infecting ICU patients, Messika and colleagues [
14] screened 132 consecutive ICU patients ventilated for longer than 3 days for simultaneous presence of
E. coli in rectal, oropharyngeal, and respiratory samples (colonization or VAP). If present,
E. coli isolates were characterized by antimicrobial susceptibility, phylogenetic grouping, and VF gene content. The authors found that multisite colonization with
E. coli was frequent, observed in 19 % of the patients. The majority of isolates belonged to phylogenetic group B2, characterized by high VF gene content and low antimicrobial resistance. Among screened VF genes, iron uptake genes such as
iroN and
sfa appeared important for lung infection. Targeting the associated proteins by way of vaccines or monoclonal antibodies may help establish novel therapeutic strategies in that setting.
H1N1
Pulmonary complications in the course of systemic infection might be clinically relevant. Although some isolated case reports of H1N1-associated rhabdomyolysis have been published, uncertainty still remains regarding the clinical implications of elevated creatine kinase (CK) levels in this setting [
15]. To assess if increased CK was related to worse global, renal, and respiratory outcomes in critically ill patients with H1N1 infection, and if it could serve as a biomarker of severity, Borgatta and colleagues [
16] retrospectively analyzed data gathered from 505 patients with confirmed H1N1 severe infection in Spain. They found that slight elevations were associated with increased pulmonary and kidney complications as well as increased length of stay (both ICU and hospital). Furthermore, starting from CK greater than 500 UI/l, a breakpoint close to normal upper values, significant associations with worse renal outcomes were documented. These included higher occurrence of acute kidney injury (AKI), as well as more frequent need for renal replacement therapy, which progressively increased with rising CK values. Greater pulmonary injury was observed from CK greater than 1,000 UI/l, with 50 % more involvement in chest radiograph in addition to more prolonged MV.
Early use of corticosteroids in patients affected by pandemic H1N1 influenza A infection, although relatively common, remains highly debated and might lead to opportunistic infections by
Aspergillus fungi. Of 40 critically ill patients with confirmed H1N1 infection, 9 (23 %) developed invasive pulmonary aspergillosis (IPA) 3 days after ICU admission [
17]. On multivariate analysis, use of corticosteroids before ICU admission was independently associated with IPA (OR 14.4,
p = 0.007), confirming that early use of corticosteroids in patients affected by pandemic H1N1 influenza A infection did not result in better outcomes and was associated with an increased risk of superinfection.
Since there are no guidelines for the design and conduct of randomized trials in pandemic critical illness, Annane et al. [
18] presented their recommendations based on the experience they acquired during a multicenter randomized trial performed in ICU patients with 2009 H1N1 influenza pandemia. The authors report how they carried out a multicenter, randomized, placebo-controlled, double-blind trial of corticosteroids in ICU patients with 2009 H1N1 influenza pneumonia requiring MV. The feasibility of and hurdles in designing and initiating a phase III trial in a short-lived pandemic crisis were analyzed. The peak of the wave was missed by 2–3 weeks and only 26 patients were randomized. The two main reasons for non-inclusion were patients’ admission before the beginning of the trial and ICU personnel overwhelmed by clinical duties. Parallel rather than sequential regulatory and ethics approval, and preparation and masking of study drugs by local pharmacists would have allowed the study to start 1 month earlier. A dedicated research team in each participating center would have increased the ratio of screened to randomized patients. It was concluded that future pandemic research should consider an adaptive design.
Other infections and sepsis
The spread of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, notably
E. coli and
K. pneumoniae, to the community, and the need for prudent use of carbapenems require updated studies to identify current risk factors for colonization with ESBL-producing isolates in patients admitted to the ICU. To do that, Razazi and colleagues [
19] conducted an 8-month prospective study in the medical ICU of an 850-bed general and university-affiliated hospital in France. ESBL-producing Enterobacteriaceae caused 3 % of the infections diagnosed on admission. By multivariable analysis, transfer from another ICU, hospital admission in another country, surgery within the past year, prior neurologic disease, and prior administration of third-generation cephalosporin (within 3–12 months before ICU admission) were independent predictive factors of colonization by ESBL-producing isolates upon ICU admission. In carriers, ESBL-strains caused 10 and 27 % of first and second episodes of ICU-acquired infections, respectively. These data may be useful for identifying which ICU patients really warrant empiric therapy with carbapenems for targeting ESBL-producing Enterobacteriaceae, and thus they may contribute to more efficient antibiotic stewardship programs to help control these organisms.
The recent increase in drug-resistant microorganisms complicates the management of hospital-acquired bloodstream infections (HA-BSIs). To investigate the epidemiology of HA-BSI and evaluate the impact of drug resistance on outcomes of ICU patients, controlling for patient characteristics and infection management, Tabah and colleagues [
20] conducted a large, prospective, multicenter cohort study in 162 ICUs in 24 countries, enrolling a total of 1,156 patients who had developed such an infection. Overall, 48 % of isolates were multidrug-resistant, including 20.5 % extensively resistant, and 0.4 % pan-drug-resistant. The 28-day all-cause fatality rate was 36 %. Inadequate antibiotic treatment and failure to control the source of infection were both associated with 28-day mortality, independently from age, chronic co-morbidities, severity of acute illness, shock, and organ dysfunctions. Antimicrobial resistance was associated with a significantly longer time to adequate antimicrobial treatment and with a higher risk of death, even after controlling for adequacy of antimicrobial treatment. Intensified efforts to prevent HA-BSIs and to optimize their management through adequate source control and antibiotic therapy are clearly needed to improve outcomes.
Catheter-related infections (CRI) are an important source of HA-BSIs and represent relevant complications in ICU patients, although considerable achievements in infection prevention have been realized. In 51 French ICUs the overall CRI rate was 2.2 per 1,000 central venous catheter days in 7,188 patients and identified risk factors for CRI amenable for improvement were the preference of the subclavian route and the use of an antiseptic solution containing alcohol [
21]. In a randomized study of 78 ICU patients with acute renal failure requiring hemodialysis, sodium citrate catheter locks were, as compared to saline locks, associated with less catheter complications, longer catheter life span, but comparable incidence of infections [
22]. Another important infectious complication of treatment in ICU is the invasive candidiasis (IC). In a prospective study of 176 non-neutropenic patients with severe abdominal conditions at ICU admission and expected to stay at least 7 days, the value of (1→3)-β-
d-glucan (BDG),
C. albicans germ tube antibody (CAGTA), C-reactive protein (CRP), and procalcitonin (PCT) levels were assessed for the diagnosis of IC and for differentiating
Candida spp. colonization from infection. BDG with a positive test for CAGTA accurately differentiated
Candida colonization from IC with an area under the curve of 0.78 (95 % CI 0.76–0.81). CRP and PCT were less discriminatory [
23].
Duration of the antibiotic treatment still remains a controversial problem. The European Society of Intensive Care Medicine (ESICM) working group performed a systematic review and meta-analysis of randomized clinical trials (RCTs) to determine whether plasma PCT determination can be used as a guide in order to shorten and optimize the duration of antibiotic therapy strategies for critically ill adult patients [
24]. Seven evaluable RCTs were identified and analyzed. Primary outcomes included the duration of antibiotic therapy for the first episode of infection and 28-day mortality. Secondary outcomes included length of ICU stay, length of hospitalization, antibiotic-free days within the first 28 days of hospitalization, recurrences, and superinfections. The authors found that the duration of antibiotic therapy for the first episode of infection was reduced in favor of PCT-guided treatment [pooled weighted mean difference (WMD) = −3.15 days, random effects model, 95 % CI −4.36 to −1.95,
p < 0.001]. There was no difference in 28-day mortality between the compared arms [fixed effect model (FEM), OR 0.96, 95 % CI 0.79–1.15,
p = 0.63). Antibiotic-free days were increased within the first 28 days of hospitalization in favor of the PCT-guided treatment arm (pooled WMD = 3.08 days, FEM, 95 % CI 2.06–4.10,
p < 0.001). No difference was found regarding the remaining outcomes. It was concluded that PCT-guided antibiotic therapy algorithms could help in reducing the duration of antimicrobial administration without having a negative impact on survival.
The increased number of infections caused by antimicrobial-resistant bacteria (AMRB) is increasing worldwide. Chlorhexidine body washing (CHG-BW) has been proposed as a measure to limit the spread of AMRB. Cross-transmission of AMRB is extremely important and temporarily contaminated hands of health-care workers are considered the most important vectors for spread. Derde et al. [
25] systematically assessed the evidence on the effectiveness of CHG-BW in reducing colonization and infection with AMRB in adult ICU patients. Data from 16 studies were extracted; 9 were excluded because of assessed high risk of bias or inadequate analyses. The remaining studies differed markedly in interventions/co-interventions and case mix which precluded pooling of data in a formal meta-analysis, but overall the quality of the studies was good. It was found that the incidences of methicillin-resistant
Staphylococcus aureus (MRSA) acquisition were reduced significantly in three studies in which this was the primary endpoint. A significant reduction in MRSA infection rates was observed in only one of five studies. The carriage and bacteremia rates of vancomycin-resistant enterococcus (VRE) were assessed in one study, and both significantly declined. Finally, there were hardly any data on the effects of CHG-BW on antibiotic-resistant gram-negative bacteria (ARGNB). It was concluded that CHG-BW may be effective in preventing carriage, and possibly BSIs, with MRSA and VRE in different ICU settings. As CHG-BW protocols, co-interventions, and case mix varied widely, the attribution of these effects to CHG-BW alone should be done with care. Evidence that CHG-BW reduces carriage of or infections with ARGNB is lacking.
Gut overgrowth happens in the critically ill requiring intensive care. Gut overgrowth is the crucial event which precedes both primary and secondary endogenous infection and is 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. In a review article Silvestri et al. [
26] revised the mechanisms of action of SDD. Data assessed by the authors show that the full SDD regimen using parenteral and enteral antimicrobials reduces lower airway infection by 72 %, bloodstream 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
S. aureus in the throat. Enteral polyenes control ‘normal’
Candida species. Enteral polymyxin and tobramycin eradicate or prevent gut overgrowth of ‘abnormal’ ARGNB. Enteral vancomycin controls overgrowth of ‘abnormal’ MSRA. SDD controls overgrowth by achieving high antimicrobial concentrations effective against ‘normal’ and ‘abnormal’ potential pathogens rather than by selectivity.
Early identification of infection and sepsis is crucial. Systemic levels of soluble urokinase-type plasminogen activator receptor (suPAR) positively correlate with the activation level of the immune system. Backes et al. [
27] reviewed the usefulness of systemic levels of suPAR in the care of critically ill patients with sepsis, SIRS, and bacteremia, focusing on its diagnostic and prognostic value. Ten papers on original studies of critically ill patients were identified that report on suPAR in sepsis, SIRS, or bacteremia. Systematic levels of suPAR have little diagnostic value in critically ill patients with sepsis, SIRS, or bacteremia. Systemic levels of suPAR, however, have superior prognostic power over other commonly used biological markers in these patients. Mortality prediction by other biological markers or severity-of-disease classification system scores improves when combining them with suPAR. Systemic levels of suPAR correlate positively with markers of organ dysfunction and severity-of-disease classification system scores. Notably, the type of assay used to measure suPAR, the age of the patients, and underlying disease affect systemic levels of suPAR. The authors concluded that the diagnostic value of suPAR is low in patients with sepsis and infections and that the studies are limited to the predictive potential to estimate the mortality risk in observational designs.
The largest part of the sepsis burden occurs in middle- and low-income countries, and guidelines developed in high-income countries cannot be implemented in most middle- and low-income countries because lack of resources. Dunser et al. [
28], representing a working group of the ESICM, provide a set of affordable recommendations for clinicians practicing in resource-limited settings in order to improve the management of pediatric and adult septic patients. Recommendations are grouped into acute and post-acute interventions. Acute interventions include liberal fluid resuscitation to achieve adequate tissue perfusion, use of epinephrine or dopamine for inadequate tissue perfusion despite fluid resuscitation, measurement of arterial blood pressure in hemodynamically unstable patients, administration of hydrocortisone or prednisolone to patients requiring catecholamines, oxygen administration to achieve an oxygen saturation greater than 90 %, semi-recumbent and/or lateral position, non-invasive ventilation for increased work of breathing or hypoxemia despite oxygen therapy, administration of adequate antimicrobials, investigation for infectious source identification, fluid/tissue sampling and microbiological work-up, removal, drainage, or debridement of the infectious source. Post-acute interventions include regular re-assessment of antimicrobial therapy, administration of antimicrobials for an adequate but not prolonged duration, avoidance of hypoglycemia, pharmacological or mechanical deep vein thrombosis prophylaxis, resumption of oral food intake after resuscitation and regaining of consciousness, careful use of opioids and sedatives, early mobilization, and active weaning of invasive support. The authors concluded that scarce evidence exists for the management of pediatric and adult sepsis in resource-limited settings. These recommendations were endorsed by ESICM, the World Federation of Pediatric Intensive and Critical Care Societies (WFPICCS), the Global Sepsis Alliance (GSA), the Federation of Austrian Societies of Intensive Care Medicine (FASICM), the Ugandan Society of Intensive Care Medicine (USICM), and the Mongolian Society of Anesthesiology and Intensive Care Medicine (MSAICM).
Sepsis is a complex syndrome and adjunctive therapies to the conventional treatment might be of some benefit. Acetyl salicylic acid (ASA, aspirin) and non-steroidal anti-inflammatory drugs (NSAIDs) may have potential as adjunctive agents for sepsis. A review article [
29] discussed the basis for sepsis therapy with ASA. ASA and NSAIDs have beneficial effects in numerous experimental models of sepsis. Low doses of ASA of 100 mg/day or less trigger synthesis of lipoxins, which are anti-inflammatory and aid in resolution of inflammation. Higher doses of ASA and NSAIDs act to reduce NF-κB stimulation and inhibit numerous septic pathways. While a previous randomized controlled trial of ibuprofen failed to show a reduction in mortality in sepsis, it did reduce clinical manifestations of sepsis. More recent observational studies have shown reduction in sepsis or acute lung injury leading to lower mortality in ICU patients treated with ASA. The author concluded that low-dose ASA appears to be beneficial in the prevention and treatment of sepsis and SIRS. If proven, this intervention would have a major, cost-effective impact on sepsis care.
Rare infections can be caused by criminal actions. A fraudulent use of
Bacillus anthracis (anthrax) can be highly lethal. Two recent outbreaks related to contaminated mail in the USA and heroin in the UK and Europe and its potential as a bioterrorist weapon have greatly increased concerns over anthrax in the developed world. Hicks et al. [
30] summarized the microbiology, pathogenesis, diagnosis, and management of anthrax.
B. anthracis, a gram-positive bacterium, has typically been associated with three forms of infection: cutaneous, gastrointestinal, and inhalational. However, the anthrax outbreak among injection drug users has emphasized the importance of what is now considered a fourth disease form (i.e., injectional anthrax) that is characterized by severe soft tissue infection. While cutaneous anthrax is most common, its early stages are distinct and prompt appropriate treatment commonly produces a good outcome. However, early symptoms with the other three disease forms can be non-specific and mistaken for less lethal conditions. As a result, patients with gastrointestinal, inhalational, or injectional anthrax may have advanced infection at presentation that can be highly lethal. Once anthrax is suspected, the diagnosis can usually be made with gram stain and culture from blood or tissue followed by confirmatory testing (e.g., PCR). While antibiotics (ciprofloxacin/doxycycline/clindamycin) are the mainstay of anthrax treatment, use of adjunctive therapies such as anthrax toxin antagonists are a consideration. Prompt surgical therapy appears to be important for successful management of injectional anthrax.
Coagulation and hemostasis
Coagulation balances are considerably modified in severe ICU patients. Sepsis induces hypercoagulability, hypofibrinolysis, microthrombosis, and endothelial dysfunction leading to multiple organ failure. Recently, thrombin generation tests (TG) and point-of-care thromboelastography (TEG) or thromboelastometry emerged as dynamic global tests of hemostasis. Massion et al. [
31] prospectively investigated analytical coagulation tests, TG assays, and thromboelastometric analyses from admission to day 7 in 29 patients with septic shock. The levels of most procoagulant factors were increased, as well as both delayed time and deficit in TG. Interestingly, prolonged aPTT (
p = 0.007) and persistence of TG deficit (
p = 0.024) on day 3 were independent predictors of mortality, independently from APACHE II score. The mechanisms of persistent coagulopathy as a potential new therapeutic avenue need further investigations.
Bleeding and thrombotic events are common in ICU. Bleeding events are common complications in patients with extracorporeal life support (ECLS) usually owing to mixed factors. Also, ECLS may promote high molecular weight multimers of Von Willebrand factor to uncoil and to be cleaved into less effective smaller multimers. It leads to acquired Von Willebrand syndrome (AVWS). In a prospective observational study, Heilmann and colleagues [
32] confirmed that AVWS during ECLS was almost constant (31/32 patients) and associated with bleeding events in 22 cases. The relative contribution of AVWS and other coagulation disorders in bleeding events remained to be studied.
Even when standard of care subcutaneous prophylaxis is administrated, proximal deep venous thrombosis (DVT) rates in ICU patients may reach rates as high as 44 %. The thromboprophylaxis use in ICU does not follow international guidelines. In a survey performed in 59 Austrian ICUs, despite a median of four risk factors of DVT, the implementation of pharmacological and mechanical methods for thromboprophylaxis is only applied in 39 % of patients, whereas 5 % of the patients did not receive thromboprophylaxis at all. Current practice of thromboprophylaxis is predominantly based on the administration of low molecular weight heparins prescribed at rather arbitrary doses without a discernible relationship to drug monitoring, thromboembolic risk factors, vasopressor use, or fluid balance. The poor application of guidelines may reflect limited level of proof of the recommendation, or insufficient communication and physician knowledge of the guidelines [
33].
Cheng et al. [
34] confirmed that usual thromboprophylaxis is likely not adequate for ICU patients. Fifty patients from a surgical ICU having had major abdominal surgery for cancer were randomly allocated to either unfractionated heparin, subcutaneously three times daily (SQH) versus unfractionated heparin via intravenous infusion, titrated to an activated partial thromboplastin time of 40–45 s (IVH). Patients in the SQH group had no detectable peak anti-factor Xa (aFXa) activity for 5 days after surgery, whereas patients in the IVH group had statistically elevated levels compared to the SQH group on days 3–5. SQH patients demonstrated a hypercoagulable profile, whereas IVH patients displayed a normal profile. Current dosing schedules of unfractionated heparin for VTE prophylaxis may therefore be inappropriate in post-surgical ICU patients with cancer.
Organization, quality of care, and outcome
Medication errors are common in hospital. Opportunities for errors are maximized in ICUs. One simple way to limit errors in medication administration is to improve color-coded drug labelling. ISO norm 26825 for color drug labelling has been created in anesthesiology and extended for use in intensive care and emergency medicine. In a survey endorsed by ESICM, Balzer et al. [
67] found that only 35 % of the respondents reported that standardized drug labelling was used hospital-wide, and 39 % reported that standardized drug syringe labelling (DSL) was used in their ICU (Europe: Northern 53 %, Western 52 %, Eastern 17 %, Southern 22 %). The ISO norm 26825 was used by 30 %, an adapted version by 19 %, and local versions by 45 %. The improvement of adherence to this simple norm should be an important tool for decreasing medication errors.
Variability of critical care bed numbers in Europe has been studied by Rhodes et al. [
68]. Data were derived from large international databases and validated by the national council representative for the ESICM. In countries where data were still not available, personal contacts were used and numbers were estimated according to local sample assessment. They identified 409 acute care beds and 11.5 critical care beds on average per 100,000 inhabitants. The rates per 100,000 inhabitants were markedly different between countries: from 29.2 for Germany, 12.5 for Italy, 11.6 for France, 9.7 for Spain, 6 for Greece, to 4.2 for Portugal. The rates of critical care beds were correlated with percentage of gross domestic product dedicated to health expenditure with marked differences between countries.
Recent studies conducted on ICU patients have shown an advantage for patients treated in high volume centers and some have shown benefit with the adoption of centralized services for ICUs as well. Kanhere et al. [
69] conducted a systematic review to assess if outcomes in adult ICUs are related to hospital and ICU patient volume. Twenty-five articles were relevant to this study. After further evaluation a total of 13 studies including 596,259 patients across 1,068 ICUs met the inclusion criteria and were reviewed. All were observational cohort studies. Four of the studies included all admissions to ICU, five included mechanically ventilated patients, two reported on patients admitted with sepsis, and one study each reported on patients admitted with medical diagnoses and post-cardiac arrest patients admitted to ICU, respectively. There was a wide variability in the quantitative definition of volume and classification of hospitals and ICUs on this basis. Methodological heterogeneity amongst the studies precluded a formal meta-analysis. A trend towards favorable outcomes for high volume centers was observed in all studies. Risk-adjusted mortality rates revealed a survival advantage for a specific group of patients in high volume centers in ten studies but no significant difference in outcomes was evident in three studies. It was concluded that outcomes of certain subsets of ICU patients (especially those on MV, high-risk patients, and patients with severe sepsis) are better in high volume centers within the constraints of risk adjustments.
Burnout syndrome (BOS) has frequently been reported in health-care workers, and precipitating factors include communication problems in the workplace and stress related to end-of-life situations. In a before–after study, Quenot et al. [
70] evaluated the effect of an intensive communication strategy on BOS among caregivers working in ICU. The intervention was multifactorial, with mixed changes in ward organization (including unrestricted visiting hours, fixed appointments with families, staff psychologist availability) and in communication on BOS strategy. They found a significant difference between periods in all three components of the Maslach Burnout Inventory (MBI) (emotional exhaustion,
p = 0.04; depersonalization,
p = 0.04; personal accomplishment,
p = 0.01). MBI classified burnout as severe in 15 (28 %) caregivers in period 1 versus 7 (14 %) in period 2,
p < 0.01, hence a 50 % risk reduction. Symptoms of depression as evaluated by the CES-D were present in 9 (17 %) caregivers in period 1 versus 3 (6 %) in period 2,
p < 0.05, hence a risk reduction of almost 60 %. Further randomized trials focused on interventions on communication factors are needed to confirm these results.
Outcome and quality of life after ICU
The age distribution of the population may contribute to the need for ICU beds to ensure the elderly beneficiate from ICU stay. In a retrospective study based on a database from the Beth Israel Diaconess Hospital in Boston, Fuchs et al. [
71] evaluated the 28-day and 1-year impact of age while carefully taking into account comorbid condition and severity of the patients. Patients were divided into three age groups: 65–74, 75–84, and 85 and above. The analysis focused on the 7,265 non-planned admissions of patients above the age of 65 (45.7 % of the total ICU population). From the first to third age group there was an increased prevalence of cardiac comorbid illnesses, but a reduced prevalence of diabetes complications (7.5–2.4 %), alcohol abuse (4.1–0.6 %), metastatic cancer (8.3–3.6 %), chronic obstructive pulmonary disease (COPD) (24.4–17.4 %), and liver failure (5.0–1.0 %). Do not resuscitate order (DNRO) at admission increased from 6.8 % in the 65–74 age group to 15.4 % in the 75–84 group and 29.6 % in the 85 and over group (
p < 0.001). Logistic regression analysis adjusted for gender, SOFA, DNRO, and Elixhauser comorbidity score found that patients from the second and third age group had ORs of 1.38 (95 % CI 1.19–1.59) and 1.53 (95 % CI 1.29–1.81) for 28-day mortality as compared with the first age group. Interestingly effect of age on the 1-year mortality was similar in the Cox regression analysis [75–84: adjusted hazard ratio 1.21 (95 % CI 1.06–1.38); 85 years and over: adjusted hazard ratio 1.59 (95 % CI 1.37–1.85)]. In conclusion, the effect of age adjusted for confounders was linear, although there was a non-significant modification in the slope of 1-year mortality over 84 years.
The impact of the precocity of ICU intervention in the prognosis of cancer patients is also an important matter of interest. In a retrospective monocenter study from Korea, Song et al. [
72] studied the impact of an early intervention of a medical emergency team (MET) on the prognosis of cancer patients. They analyzed 199 critically ill cancer patients admitted to the ICU for in-hospital mortality. Median time from physiological derangement to intervention (time to intervention) prior to ICU admission was 1.5 (IQR 0.6–4.3) h. Median time to intervention was significantly shorter in survivors than in non-survivors (0.9 vs. 3.0 h;
p < 0.001). Early intervention was associated with a lower SOFA score. Independent of the severity of illness, performance status, hematologic malignancy, stem-cell transplantation, presence of three or more abnormal physiological variables, presence of infection, need for MV and vasopressor, and low PaO
2/FiO
2 ratio, the time from derangement to ICU admission was still significantly associated with hospital mortality (adjusted OR 1.45, 95 % CI 1.22–1.72). The retrospective monocentric study argued for an early ICU admission of cancer patients. Further prospective study prospectively taking into account the reason for MET call, physician belief, and lead time bias (SOFA was measured only during MET intervention but not at the beginning of the acute care process) is warranted to confirm and quantify the effect.
Agitation and delirium are common in the critically ill. Nicotine withdrawal has been identified as a contributing factor to this. Nicotine replacement therapy may decrease withdrawal and improve ICU delirium and outcome. But nicotine replacement therapy was associated with an increased hospital mortality in a retrospective case control study likely owing to the sympathomimetic cardiovascular effect of nicotine. In a large retrospective cohort study of 423 smokers, after careful adjustment for confounders, and using various statistical models, Gillies et al. [
73] did not find any association between NRT and hospital mortality. An RCT is therefore feasible to test the effect of NRT on delirium and patients’ outcome.
Traumatic aortic injury is relatively infrequent but associated with a subsequent mortality if therapeutic management is delayed [
74]. In a multicenter retrospective study involving 640 major trauma patients with associated blunt chest trauma, 76 were associated with aortic injury. They found that widened mediastinum, hypotension less than 90 mmHg, long bone fracture, pulmonary contusion, left scapula fracture, hemothorax, and pelvic fracture were independently associated with aortic injury. They proposed a risk score with an excellent accuracy (AUC ROC curve 0.96). External multicenter validation is needed to confirm this result.
It is important to decrease psychologic sequelae during recovery. In a multicenter RCT, McKinley and co-workers [
75] studied the effect of physical rehabilitation on depression, anxiety, stress, and quality of sleep. The authors found that ICU survivors had impaired mental health and symptoms of depression, anxiety, stress, and psychological distress in the form of intrusive and avoidance post-traumatic stress symptoms. Anxiety symptoms persisted for one quarter of the patients after 8 and 26 weeks. Although physical rehabilitation did not decrease the psychological sequelae, they found that female gender, early levels of increased stress, and sleeping problems are associated with worse psychological recovery.
Echography and imaging
An expert panel conference report provided evidence-based consensus recommendations for lung ultrasound with a focus on emergency and critical care settings [
76]. A multidisciplinary panel of 28 experts from eight countries was involved. The process used to develop these evidence-based recommendations involved two phases: determining the level of quality of evidence and developing the recommendation. The quality of evidence was assessed by the grading of recommendation, assessment, development, and evaluation (GRADE) method. However, the GRADE system does not enforce a specific method on how the panel should reach decisions during the consensus process. The methodology committee decided to utilize the RAND appropriateness method for panel judgment and decisions/consensus. Statements on pneumothorax, interstitial syndrome (pneumonia, atelectasis, pleural disease, etc.), monitoring of lung diseases (cardiogenic pulmonary edema, lung reaeration in ARDS, etc.), and neonatal and pediatric pulmonary problems were produced. It was concluded that the document was elaborated to guide implementation, development, and training on the use of lung ultrasound in all relevant settings.
Another group of experts provided recommendations on ultrasound guidance during vascular access [
77]. Also these authors used the GRADE and the GRADE-RAND methods to develop recommendations. The recommendations suggest the advantage of 2D vascular screening prior to cannulation and that real-time ultrasound needle guidance with an in-plane/long-axis technique optimizes the probability of needle placement. Ultrasound guidance can be used not only for central venous cannulation but also in peripheral and arterial cannulation. Ultrasound can be used in order to check for immediate and life-threatening complications as well as the catheter’s tip position. Educational courses and training are required to achieve competence and minimal skills when cannulation is performed with ultrasound guidance. This technique allows the reduction of infectious and mechanical complications. A recommendation to create an ultrasound curriculum on vascular access was proposed. It was concluded that given the evidence from literature and experts’ opinion, ultrasound guidance has to be suggested as the method of choice for any kind of vascular cannulation given its higher safety and efficacy.
A review article discusses technical requirements for Doppler assessment of the small intra-renal vessels, factors influencing Doppler-based renal resistive index (RI), and to provide an updated description of its interest with a special focus on the critically ill [
78]. Data suggest that renal Doppler may help to assess perfusion of native or transplanted kidneys, and recent studies suggest that it may be useful in critically ill patients. Renal Doppler has proven to be valuable for assessing large arterial or venous abnormalities and has been suggested to assess renal perfusion and to predict AKI in critically ill patients. However, numerous factors have been shown to influence renal Doppler and may constitute potential confounding factors. It was concluded that Doppler-based RI seems to be a promising tool in the critically ill to assess the risk of AKI, help in differentiating persistent from transient AKI, or assess changes in renal perfusion as consequences of therapeutic intervention. The authors also pointed out that the role of renal Doppler as a monitoring tool in the ICU will remain unclear until additional studies are conducted and the potential confounding factors are properly assessed.
Lakhal et al. [
79] analyzed the current practices of chest radiograph (CXR) prescription and their clinical impact in French ICUs with a prospective snapshot observational study (on RadioDay) combined with a survey. On RadioDay, 854 CXRs (in 804 patients) were ordered. For the “CXRs morning round”, the prescription policy was declared to be “on-demand” (in 63 % of the ICUs), “daily routine only in mechanically ventilated patients (MV)” (30 %) or, less frequently, “daily routine in all patients” (7 %). When analyzing the two main local policies, as compared with “daily routine only in MV” ICUs, in “on-demand” ICUs: (1) fewer CXRs were ordered (0.6 ± 0.3 vs. 0.9 ± 0.2 CXRs/patient,
p < 0.001) with no increase in the rate of unscheduled CXRs (i.e., CXRs performed outside the morning round), and (2) individual CXRs were more often followed by a therapeutic intervention (which would not have occurred without the CXR): 34 vs. 25 % of the CXRs (
p < 0.05). Nearly two-thirds of the participating ICUs adopted the “on-demand” strategy of prescription, which was associated with a lower rate of CXRs with no increase in unscheduled CXRs and was of higher clinical value than a “daily routine in MV” strategy.
Rohacek et al. [
80] performed a prospective survey among the emergency physicians on the reason for ordering a CT pulmonary angiography (CTPA) in the emergency room. The most frequent reasons for ordering a CTPA were to confirm/rule out pulmonary embolism (PE) (93 %), elevated D-dimers (66 %), fear of missing PE (55 %), and Wells/simplified revised Geneva score (53 %). Interestingly, a positive answer for “fear of missing PE” was inversely associated with positive CTPA (OR 0.36, 95 % CI 0.14–0.92,
p = 0.033), and “Wells/simplified revised Geneva score” was associated with positive CTPA (OR 3.28, 95 % CI 1.24–8.68,
p = 0.017). The proportion of positive CTPA was higher if a questionnaire was completed (26.4 vs. 14.5 %, OR 2.12, 95 % CI 1.36–3.29,
p < 0.001).