Micro- and macrocirculation in septic shock and severe sepsis
Dobutamine has been widely advocated to improve (inadequate) cardiac output in septic
shock. However, on the basis of the double-blind, crossover, randomized study from
Hernandez et al. [1], the microcirculatory and regional effects, despite improvement
of the macrocirculation, seem to be limited. Indeed despite an increase in cardiac
output and heart rate, with dobutamine, they found no significant impact on lactate
level and sublingual vessel perfused density. This is in contrast to some other studies.
The question now is were the results of these earlier studies wrong or is the current
baseline resuscitation of critically ill patients so different from these earlier
days that the state of the vasculature of our patients is now different when compared
to those earlier days?
A change of case-mix related to these critical endothelial factors such as variations
of endothelial protein C receptor polymorphisms [2] or of endothelial derived microparticles
[3] might also have led to these different results. Maybe even the resuscitation measures
used, in and of itself, influence endothelial activation/injury. Targeting these sepsis-induced
coagulation abnormalities that are critically linked to endothelial injury was reviewed
by Levi and van der Poll [4]. The impressive effect of recombinant human soluble thrombomodulin
on disseminated intravascular coagulation (DIC) and prognosis in a pilot uncontrolled
study published in the journal this year merits further investigations in patients
with severe sepsis [5]. Another question arises from this study: what is a clinically
relevant endpoint of resuscitation? We more or less agree that macrocirculatory endpoints
might not be adequate in many cases. At least in fluid resuscitation patients the
microcirculation might prove to be more important than macrocirculation [6]. Adequate
microcirculatory perfusion might even permit one to have abnormal macrocirculatory
parameters; however, the scientific bases for these endpoints need to be laid out
[7].
One of the molecular regulatory systems which has been reported to contribute to endothelial
activation and vascular permeability control in sepsis and other diseases is the angiopoietin/Tie2
system. Kurniati et al. [8] demonstrated that the endothelial expression of Tie2 in
vivo is dependent on flow. A decrease of flow leads to a decrease in Tie2 expression.
This has major implications for basal research on sepsis mediators and its effects
on endothelial cells. The translation from these preclinical findings to human sepsis
is more complicated, but the study suggests that interventions in sepsis patients
aimed at normalizing diminished blood flow may be able to prevent downregulation of
Tie2 and potentially counteract microvascular dysfunction and permeability in this
devastating condition.
The exact impact of early goal-directed therapy (EGDT) in the prognosis of sepsis
is still challenging. Importantly, three large randomized controlled trials (RCTs)
were conducted this year, one each in the USA (ProCESS: protocolized care for early
septic shock), Australasia (ARISE: Australasian resuscitation in sepsis evaluation),
and the UK (ProMISe: protocolized management in sepsis). All three trials conform
to CONSORT guidelines, address the same fundamental questions, and share key design
elements. Each trial is a patient-level, equal-randomized, parallel-group superiority
trial that seeks to enroll emergency department patients with inclusion criteria that
are consistent with the original EGDT trial (suspected or confirmed infection, two
or more systemic inflammatory response syndrome criteria, and refractory hypotension
or elevated lactate), is powered to detect a 6–8 % absolute mortality reduction (hospital
or 90-day), and uses trained teams to deliver EGDT. Let us hope that these studies
will provide homogeneous results [9].
Immune dysfunction during sepsis and antimicrobial dose variability
Septic patients develop immune dysfunctions with an increased risk of adverse outcomes.
A better understanding of the pathophysiological mechanisms induced after severe injury
is a prerequisite to the initiation of immune adjuvant therapies. MerTK is a protein
tyrosine kinase that with Tyro-3 and Axl comprises the TAM receptor family. In their
very interesting and elegant study, Guignant et al. [10] prospectively evaluated 98
patients with septic shock and severe trauma to investigate the expression patterns
of TAM receptors in circulating white blood cells. They observed that the evolution
of MerTK expression in circulating monocytes over time is associated with adverse
outcome in patients with septic shock. MerTK expression decreased between day 1/2
after the onset of injury and day 3/4 in patients with septic shock who recovered
uneventfully, but remained elevated in patients who died or developed a nosocomial
episode. Patients with persistent overexpression in whom MerTK expression remained
elevated at day 3/4 may actually be at risk of deleterious outcome. These observations
suggest that the development of a putative biomarker evaluating the risk of death
or infection after severe injury may require dynamic measurements over time to be
more informative than a single value, and the evolution of monocyte MerTK overexpression
in patients with septic shock over time may be predictive of adverse outcome.
Prognostic biomarkers in severe sepsis and septic shock
Lactate level and lactate clearance remained major prognostic factors. This year Kim
et al. [11] confirmed their value in predicting the outcome of pediatric patients
with septic shock.
In a prospective cohort of 137 patients, Suberviola et al. [12] tested the added prognostic
value of new biomarkers proadrenomedullin (proADM) and urokinase-type plasminogen
activator receptor (suPAR) as compared to traditional procalcitonin (PCT) and C-reactive
protein (CRP) and severity scores. In this study, they found that the recently introduced
biomarkers suPAR (area under the receiver operating characteristic curve (AUC ROC) = 0.67;
95 % CI 0.57–0.77) and proADM (AUC ROC = 0.63; 95 % CI 0.52–0.73) performed better
than the commonly used biomarkers CRP and PCT in predicting hospital survival of patients
with severe sepsis and septic shock. However, their accuracy in assessing the risk
of mortality was lower than for current severity scores, and their addition to these
only slightly improved their ability to predict in-hospital mortality.
However, it should be borne in mind that the choice of the outcome variable (outcome
after 1, 3, or 6 months) in the intensive care unit (ICU) population may largely influence
the accuracy of predictive models [13].
Antibiotic pharmacokinetics in severe sepsis
Severe sepsis induces multiple organ dysfunction, including renal dysfunction, causing
a decrease in antibiotic clearance. In the ICU, vancomycin is widely used as a first-line
antibacterial agent in patients with sepsis and often patients have shown much lower
concentrations of vancomycin than expected. In these patients, an increased vancomycin
dose was suggested in order to reach the recommended target concentration of vancomycin.
In their interesting study, Shimamoto et al. [14] evaluated 105 patients with sepsis
treated with vancomycin in a department of critical care in Osaka, Japan. In this
study, systemic inflammatory response syndrome (SIRS) patients were further classified
into three subgroups according to the number of criteria met. They found considerable
differences in vancomycin concentrations among the three SIRS subgroups. Consistent
with these concentration measurements, the area under the curve/minimum inhibitory
concentration ratio (AUC/MIC) of vancomycin showed a decreasing trend with increasing
SIRS score. The AUC/MIC is the most important pharmacokinetic/pharmacodynamic parameter
correlating with efficacy and the target AUC/MIC has been reported to be more than
400. In this study, 39 % of patients with SIRS-2, 60 % of those with SIRS-3, and 69 %
of those with SIRS-4 did not reach the target AUC/MIC of 400. This study clearly demonstrated
changes in the pharmacokinetic profile of vancomycin in patients assessed using the
SIRS criteria for the first time in a Japanese population. That is, the vancomycin
clearance increased as the SIRS score increased in SIRS patients without renal failure.
A major component of the inflammatory response in sepsis is the development of a vasodilated,
hyperdynamic cardiovascular state characterized by high cardiac output and increased
blood flow to the major organs. Since vancomycin is cleared predominantly by the kidneys,
increased renal clearance probably due to increased blood flow in the kidneys could
enhance elimination of vancomycin via the urine and result in lower plasma vancomycin
concentrations.
The study suggests that suggests that age and SIRS criteria could be easily accessible
references for determining approximate clearance of vancomycin in patients with sepsis.
In combination with renal function and vancomycin monitoring, the vancomycin dose
requirement can be adjusted accordingly to quickly hit and maintain target concentrations.
In a self-explanatory and well-documented review, Udy et al. [15] discussed available
data on possible solutions for optimizing antimicrobial pharmacodynamics. In particular
they proposed many pragmatic solutions to daily concerns of physicians at the bedside.
Bloodstream infections
Catheter-related bloodstream infection (CRBSI) is defined as the presence of bacteremia
originating from an intravenous catheter. It is one of the most frequent, lethal,
and costly complications of central venous catheterization. It is also the most common
cause of nosocomial bacteremia. Although the use of central venous catheters (CVC)
is increasing, there is evidence that the problem of CRBSI can be reduced. In their
distinguished and complex study Harron et al. [16] studied all the cases of BSI in
two English children’s hospitals in the period 2003–2010. They calculated trends of
pediatric ICU (PICU)-acquired BSI, defined as BSI occurring between at least 2 days
after admission until up to 2 days following discharge. In one PICU, they compared
rates of all PICU-acquired BSI with clinically significant PICU-acquired BSI submitted
to the national surveillance system. The results showed that the rate of PICU-acquired
BSI per 1,000 bed-days was 15.17 (14.45–15.86). The rate of PICU-acquired BSI decreased
by 9 % (95 % CI 7–11 %) each year during the study period. This corresponded to a
44 % reduction in the rate of PICU-acquired BSI between 2003 and 2010 associated with
the introduction of a bundle of catheter care and maintenance. However, only 321 (41 %)
BSIs were classified as clinically significant. Indeed, of the 445 PICU-acquired BSIs
due to skin organisms (mainly coagulase negative staphylococci), only 155 (34.5 %)
were clinically significant. Although definitions for classification of healthcare-associated
BSI exist, there are no clear criteria to guide clinical judgment on classification
of clinically significant positive isolates that are reported to the national surveillance
system. Clinicians need to make daily judgments about the care and treatment of patients,
but national monitoring requires objective outcome measures to achieve fair comparisons.
Automated downloads of laboratory data to the voluntary surveillance system, introduced
in recent years, offer the opportunity to capture all positive BSI data. Analyses
based on these data would overestimate the total burden of clinically significant
BSI acquired in the PICU, as happened in the described study.
Conventional methods for the diagnosis of CRBSI require catheter removal and tip culture
using either semiquantitative or quantitative methods [17]. Conservative or in situ
techniques to assess CRBSI include paired quantitative blood cultures, differential
time to positivity (DTP), and semiquantitative superficial cultures (SQSC) of the
skin entry site and catheter hubs.
In their very interesting study Gowardman et al. [18] prospectively evaluated 120
episodes of clinically suspected CRBSI in 101 patients in an ICU center in Australia
to assess two conservative methods (superficial skin and hub cultures, and DTP) for
the diagnosis of BSI and catheter tip colonization (CTC). For the diagnosis of CRBSI,
DTP had high accuracy (94 %, 95 % CI 92–98 %), specificity (98 %, 95 % CI 93–100 %),
negative predictive value (NPV; 96 %, 95 % CI 90–98), and positive predictive value
(PPV; 67 %, 95 % CI 24–94), while superficial cultures had a PPV of 14 % (95 % CI
6–26 %), NPV of 97 % (95 % CI 89–99 %), sensitivity of 78 % (95 % CI 41–96 %), specificity
of 60 % (50–69 %), and accuracy of 74 % (65–82 %). In combination, the two methods
had maximum sensitivity (100 %, 95 % CI 63–100 %) and NPV (100 %, 95 % CI 93–100 %).
This study demonstrated the utility of DTP and SQSC for the diagnosis of both CRBSI
and CTC in critically ill patients. DTP was the more accurate of the two approaches;
however, both DTP and SQSC displayed very high NPV. The clinical utility may be optimized
by performing both DTP and superficial cultures concurrently.
The role of ultrasound in limiting catheter misplacement and mechanical complications
has been addressed by two studies.
In a prospective randomized trial, Airapetian [19] compared quick-look ultrasound
with skin mark, landmark (LM), and ultrasound-guided (UG) canulation of jugular and
femoral veins by inexperienced operators. The success rate was higher in the UG group
than in the LM and UM groups (100, 74, and 73 %, respectively; p = 0.01). The total
number of mechanical complications (arterial puncture, local or visible hematoma)
was higher in the LM and UM groups than in the UG group (24 and 36 vs. 0 %, respectively;
p = 0.01) but severe mechanical complications (pneumothorax, hemothorax, severe bleeding)
never occurred. The insertion technique used had no impact on catheter colonization
rate.
In a prospective study of 101 catheter placements in 98 patients, Bedel et al. [20]
looked at the ability of transthoracic echocardiography (TTE) to localize the guidewire
and detect catheter misplacement during the procedure. Catheter misplacement was detected
by TTE with a sensitivity of 96 % (CI 90–98 %), a specificity of 83 % (CI 44–97 %),
a PPV of 98 %, and a NPV of 55 %.
Antimicrobial resistance
The prevalence of gram-negative bacterial pathogens resistant to multiple antimicrobial
agents is increasing in hospitals, and particularly in ICU settings [21].
Carbapenems and colistin are currently considered to be the preferred agents for the
treatment of serious bacterial infections caused by multidrug-resistant gram-negative
pathogens, mainly Enterobacteriaceae, Pseudomonas aeruginosa, and nonfermenters, e.g.,
Acinetobacter baumannii [22]. However, the emergence of carbapenem and colistin resistance
among gram-negative pathogens has been increasingly reported worldwide and is a matter
of great concern, because it complicates both empirical and guided treatment.
Greece is the European country with the highest level of resistance to carbapenems
in enterobacteriaceae. In their excellent study Routsi et al. [23] prospectively evaluated
1,096 patients admitted to a 25-bed university ICU in Athens to identify risk factors
for acquisition of carbapenem-resistant (CR) gram-negative bacteremia (GNB). Of the
842 evaluable patients, 43 patients developed only gram-positive bacteremia and/or
candidemia and 169 developed GNB giving an incidence of 16.3 per 1,000 patient-ICU
days, of which 85 patients had bacteremia due to CR isolates. CR-GNBs were most commonly
due to A. baumannii (32 patients, 37.6 %) and P. aeruginosa (31 patients, 36.5 %).
Patients with CR-GNB, as compared to those with carbapenem-susceptible (CS)-GNB, had
longer hospitalization and longer length of ICU stay prior to bacteremia, a significantly
longer duration of mechanical ventilation, and a longer total length of ICU stay.
Finally, patients with CR-GNB had a significantly longer prior exposure to carbapenems,
colistin, glycopeptides, and antifungals compared with that of patients with CS-GNB.
A significant relationship was found between duration of exposure to carbapenems (OR
1.079 per day of exposure, 95 % CI 1.022–1.139, p = 0.006) and colistin (OR 1.113
per day of exposure, 95 % CI 1.046–1.184, p = 0.001).
Owing to the worldwide emergence of multiresistant gram-negative bacteria, colistin
has become increasingly important as a last-resort antibiotic, especially for patients
in ICU. Colistin has been widely used for selective digestive decontamination (SDD)
and selective oropharyngeal decontamination (SOD); however, the effects of this topical
use on colistin resistance have not been determined rigorously, although some data
suggest that prolonged use induces colistin resistance. Oostdijk et al. [24] tried
to quantify the rates of colistin resistance among GNB in the intestinal and respiratory
tract of patients receiving SDD or SOD in two large Dutch cohorts of ICU patients.
The authors demonstrated that the prolonged use of colistin as part of SDD and SOD
was not associated with increased acquisition of colistin-resistant GNB in the respiratory
tract. Moreover, acquisition rates of colistin-resistant GNB in the intestinal tract
during SDD ranged from 1.2 to 3.2 per 1,000 patient-days at risk. The overall conversion
rate from colistin susceptibility to resistance in the intestinal tract was below
1 conversion per 1,000 patient-days at risk. Although the overall risk of acquisition
of colistin-resistant GNB and conversion rates to colistin resistance were low the
study identified the circumstances in which this risk is higher. The conversion rate
was about fivefold higher during persistent intestinal carriage with GNB, and about
15-fold higher during intestinal colonization with tobramycin-resistant GNB. On the
basis of the results of this study and the worrisome result of another study [25],
the authors recommend SDD or SOD in settings with low levels of antibiotic resistance.
If SDD or SOD is used, it should be accompanied by careful monitoring of tobramycin
and colistin resistance in GNB.
Schultsz et al. [26] performed an interesting prospective study to determine the predominant
routes of acquisition of five prevalent nosocomial pathogens in a dedicated tetanus
ICU in Vietnam. After the implementation of the infection control program, adherence
to hand hygiene prior to and after patient contact was 54 % and adherence to glove
use, including removal of gloves, was 70 %. Ceftazidime usage decreased by 53 % (95 %
CI 45–60 %) in year 2. The use of piperacillin–tazobactam and ciprofloxacin increased
7.2-fold (95 % CI 4.6–11.8) and 4.5-fold (95 % CI 3.1–6.6), respectively. Imipenem
usage decreased by 40 % (95 % CI 26–52 %). The combined measures were highly effective
in reducing exogenous methicillin-resistant Staphylococcus aureus (MRSA) transmission,
but failed to reduce the prevalence of drug-resistant gram-negative bacteria. Using
Markov chain modeling, they observed clear differences in the predominant acquisition
routes between MRSA and gram-negative microorganisms. The conclusions of this study
were that combination of simple infection control measures and antibiotic mixing was
highly effective in reducing the prevalence of MRSA, but not of gram-negative microorganisms
and are in line with the recently published study of the MOSAR group [27] and may
suggest other interventions to reduce the spread of multiresistant gram-negative bacteria
in the ICU.
The absence of positive effects of contact isolation is also important considering
its possible adverse impact. After careful adjustment for confounding variables and
use of appropriate time-adjusted models, Zahar et al. [28] found that hypoglycemia,
hyperglycemia, error in anticoagulant prescription, and ventilator-acquired pneumonia
due to multidrug-resistant organisms were the medication errors or adverse events
observed significantly more often in isolated patients. It confirms the results of
studies performed in hospital wards outside of ICUs and suggests that the use of isolation
may cause patients to receive less medical attention and less healthcare worker-to-patient
contact; it may also result in more frequent medical errors and adverse events.
Fungal infections
The level of uncertainty surrounding the diagnosis and management of candidiasis in
ICUs encourages further investigations. Remarkably little is known about invasive
candidiasis in pediatric ICUs. In a study involving seven PICUs in Greece the incidence
of candidemia was 6.4 cases/1,000 admissions with large differences between units
[29]. A multidisciplinary expert panel reported conclusions about the treatment of
intra-abdominal candidiasis [30]. The report clearly reviewed available data and the
level of evidence about diagnosis, prevention, and treatment of intra-abdominal candidiasis
and areas of uncertainty. In particular, they clearly stated that diagnosis should
be based on perioperative samples or percutaneous puncture and not from samples obtained
from drain tubes. They recommended the treatment of patients when direct examinations
of purulent and necrotic intra-abdominal specimens obtained during surgery or by percutaneous
puncture are positive in all patients with non-appendicular abdominal infections or
when culture of the same specimens are positive for Candida. The possible role of
non-culture diagnostic methods is discussed as well as the reasons for empirical antifungal
treatment.
Ventilator-acquired pneumonia
Comorbidities may play a role in mortality in patients that develop ventilator-acquired
pneumonia (VAP) and hospital-acquired pneumonia (HAP). Knowledge of the impact of
comorbidities in VAP/HAP mortality is very important when interpreting results from
RCTs. Di Pasquale et al. [31] examined the impact of chronic liver disease (CLD) on
mortality in patients with VAP or HAP acquired in the ICU. Of 343 consecutive patients
with ICU-acquired pneumonia, 67 (20 %) had chronic liver disease (67 % had liver cirrhosis
with a MELD score of 26 ± 9, 20 % Child–Pugh class C). They presented higher severity
scores than patients without CLD both on admission and at onset of pneumonia. Levels
of C-reactive protein were lower in patients with liver cirrhosis. The presence of
liver cirrhosis in patients with VAP or HAP was independently associated with decreased
28- and 90-day survival. As concluded by the authors, the presence of liver cirrhosis
has to be taken into account when analyzing mortality in clinical trials involving
ICU-acquired pneumonia.
The current algorithm for the empirical treatment of VAP divides patients into those
with early onset without risk factors and those with late or early onset with risk
factors. The rationale of this classification is that potentially resistant microorganisms
(PRMs) rarely belong to the group of early onset without risk factors. Martin-Loeches
et al. [32] performed a secondary analysis of a prospective, observational, multicenter
cohort study conducted in 27 ICUs from nine European countries. From a total of 689
patients with nosocomial pneumonia who required mechanical ventilation, 485 patients
with confirmed etiology and antibiotic susceptibility were further analyzed. Of these
patients, 152 (31 %) were allocated to group 1 with early-onset pneumonia and no risk
factors for PRM acquisition, and 333 (69 %) were allocated to group 2 with early-onset
pneumonia with risk factors for PRM or late onset pneumonia. Group 2 patients were
older and had more chronic renal failure and more severe illness (SAPS II score, 44.6 ± 16.5
vs. 47.4 ± 17.8, p = 0.04) than group 1 patients. In group 1, 77 patients (51 %) had
PRM in spite of the absence of classic risk factors recognized by the current guidelines.
A logistic regression analysis identified that presence of severe sepsis/septic shock
(OR = 3.79) and pneumonia developed in centers with greater than 25 % prevalence of
PRM (OR = 11.3 were independently associated with multidrug resistance in group 1
patients. In patients admitted to ICUs with a prevalence of multidrug resistance greater
than 25 % or with severe sepsis/septic shock, empiric therapy for group 1 nosocomial
pneumonia requiring mechanical ventilation should also include agents likely to be
effective for multidrug-resistant (MDR) pathogens. These factors should be taken into
account when updating VAP/HAP guidelines.
P. aeruginosa is one of the more frequent microorganisms causing VAP. Typically, it
causes VAP in patients with late-onset pneumonia or with risk factors such as previous
administration of antibiotics. The increasing rate of MDR Pseudomonas is a concern
and a challenge for clinicians. The presence of MDR is a clear factor for a higher
initial inadequate treatment and higher mortality. Tumbarello and colleagues [33]
conducted a retrospective analysis of prospective data collected in an ICU of a tertiary
hospital in Italy. They included 110 VAP patients with confirmed P. aeruginosa. In
42 % of cases, the Pseudomonas was MDR. Sixty percent of the patients received initial
inadequate therapy and 49 (44.5 %) died. Initial inadequate therapy, diabetes mellitus,
higher SAPS II score, and older age were independently associated with ICU mortality.
Among patients that survive, those with MDR Pseudomonas and those with initial inadequate
therapy had significant longer periods of post-pneumonia onset mechanical ventilation
days. These findings highlight the importance of initial adequacy of antibiotic treatment
and that of the early detection of MDR Pseudomonas.
In a nice “What’s new” article, Rello et al. [34] summarized up-to-date information
about risk factors for VAP due to P. aeruginosa that may have an impact on the choice
of preventive strategies and the optimization of probable treatment of VAP.
The use of surveillance cultures (SC) to predict the microbial etiology of VAP is
controversial. The studies performed have shown different results. The discrepancies
found are due to different populations studied, different sequences of SC taken, and
which SC culture is taken as a reference. Brusselaers and colleagues [35] performed
a systematic review and meta-analysis including 14 eligible studies with a total of
791 VAP patients. The meta-analysis showed a high accuracy of SC, with a pooled sensitivities
up to 0.75 and specificities up to 0.92 in culture-positive VAP. The AUC of the hierarchical
summary ROC curve demonstrates moderate accuracy (AUC 0.90) in predicting multidrug
resistance. A sampling frequency of greater than 2 per week and consideration of only
the most recent surveillance culture are associated with a higher accuracy of prediction.
The authors concluded that the meta-analysis provided evidence of SC in predicting
MDR bacterial pathogens in VAP. However, they acknowledged the heterogeneity of this
meta-analysis.
The risk of acquiring VAP or ventilator-acquired tracheobronchitis (VAT) in patients
that need mechanical ventilation for more than 48 h is increased in patients after
major heart surgery (MHS). A lot of preventive measures have been recommended. There
is little information about the efficacy of pre-emptive antibiotic treatment in these
patients. Bouza and colleagues [36] performed an open-label randomized trial comparing
linezolid and meropenem, and the control group, which received the standard of care.
The main outcome was the development of VAP or VAT. Overall, of the 78 patients included
in the study, 40 were in the intervention group and 38 in the control group. Both
groups were comparable. Data for the intervention and control groups, respectively,
were as follows: VAP + VAT/1,000 days was 31.79 vs. 64.78 (p = 0.03), median length
of MV before the first episode of VAP or VAT 9 vs. 4.5 days (p = 0.02). No significant
differences were observed in median length of stay in the ICU, median length of hospital
stay, antibiotic use, Clostridium difficile infection, and overall mortality rate.
They detected linezolid-resistant coagulase-negative and coagulase-positive staphylococci
in the MHS ICU after the study period. This study suggested that a pre-emptive approach
with broad-spectrum antibiotics may be effective in reducing the incidence and delaying
the onset of VAP + VAT after MHS. The ecological consequences have to be carefully
evaluated in future trials.
An up-to-date editorial about the key rules of treatment of respiratory hypoxemia
was published in the journal this year [37].
Aerosol therapy is a type of treatment that it is frequently used during mechanical
ventilation. With the increase of MDR patients with VAP this therapy has gained importance
as regards the administration of antibiotics. Ehrmann and colleagues [38] performed
a multicenter survey in France with the aim of knowing the current aerosol therapy
practices during mechanical ventilation. Of the respondents, who represented 611 departments
in 70 countries, 99 % reported using aerosol therapy during mechanical ventilation
(including noninvasive), 43 % exclusively used nebulizers and 55 % also used metered
dose inhalers. Nebulization relied on jet, ultrasonic, and vibrating mesh nebulizers
(55, 44, and 14 % of respondents, respectively). During nebulization, ventilator settings
were never changed by 77 % of respondents, 65 % reported placing a filter on the expiratory
limb, and of these 28 % never changed it. Only 22 % of respondents using heated humidifiers
reported turning them off during nebulization. A majority of respondents (87 %) thought
that ultrasonic nebulizers outperform jet nebulizers, whereas 69 % had no opinion
concerning mesh nebulizers. This study emphasized the importance of improving knowledge
and skills of aerosol therapy in the ICU. Educational programs and research focusing
on a better bench-to-bedside transfer of knowledge are needed.
Community-acquired pneumonia
The association between metabolomics and outcomes has not been widely studied in community-acquired
pneumonia (CAP). Seymour and colleagues [39] selected an outcome-stratified case–control
sample from a prospective study of 1,895 patients hospitalized with CAP and sepsis.
Cases (n = 15) were adults who died before 90 days, and controls (n = 15) were adults
who survived, matched on demographics, infection type, and PCT. They determined the
global metabolomic profile in the first emergency department blood sample using non-targeted
mass spectrometry and they derived metabolite-based prognostic models for 90-day mortality.
A total of 423 small molecules were identified; of these, the relative levels of 70
(17 %) were different between survivors and non-survivors (p ≤ 0.05). Broad differences
were present in pathways of oxidative stress, bile acid metabolism, and stress response.
Metabolite-based prognostic models for 90-day survival performed modestly (AUC = 0.67).
Five nucleic acid metabolites were greater in non-survivors (p ≤ 0.05). Of these metabolites,
pseudouridine increased monocyte expression of TNF-α and IL-1β vs. controls (p ≤ 0.05).
Pseudouridine was also increased in liver and kidney homogenates from CLP mice vs.
sham (p ≤ 0.05 for both). Although replication is required, the study showed that
the global metabolomic profile in plasma broadly differs between survivors and non-survivors
of CAP and sepsis. Metabolite-based prognostic models had modest performance, though
metabolites of oxidative stress may act as putative damage-associated molecular patterns.
Macrolides are a family of antibiotics frequently used in the treatment of severe
CAP in addition to beta-lactams. They are preferred to quinolones because some observational
studies have shown a decreased mortality when comparing the two types of combination
in favor of macrolides. It has been hypothesized that this beneficial effect is due
to the anti-inflammatory and immunomodulatory effects of macrolides. However, the
potential effects in pure viral pneumonia are unknown. Martin-Loeches et al. [40]
investigated the potential effects of macrolides in patients with severe pure H1N1
pneumonia. Primary viral pneumonia was present in 733 ICU patients with pandemic influenza
A (H1N1) virus infection with severe respiratory failure. Macrolide-based treatment
was administered to 190 (26 %) patients. Patients who received macrolides more often
had chronic obstructive pulmonary diseases. Length of ICU stay in survivors was not
significantly different in patients who received macrolides compared to patients who
did not [10 (IQR 4–20) vs. 10 (IQR 5–20), p = 0.9]. ICU mortality was 24.1 % (n = 177).
Patients with macrolide-based treatment had lower ICU mortality in the univariate
analysis (19.2 vs. 28.1 %, p = 0.02); however, a propensity score analysis showed
no effect of macrolide-based treatment on ICU mortality (OR = 0.87). A separate analysis
of patients under mechanical ventilation yielded similar results (OR = 0.77; 95 %
CI 0.44–1.35, p = 0.4). These results suggest that macrolide-based treatment was not
associated with improved survival in critically ill H1N1 patients with primary viral
pneumonia.
Fiberoptic bronchoscopy (FOB) is a frequently needed procedure in patients with severe
acute respiratory failure without intubation. A prospective, multicenter, observational
study was carried out in eight French adult ICUs [41]. The study included 169 FOBs
performed in patients with a PaO2/FIO2 ratio ≤300. The main endpoint was intubation
rate. The secondary endpoint was rate of increased ventilatory support defined as
an increase in oxygen requirement [50 %, the need to start noninvasive positive pressure
ventilation (NIPPV) or increase NIPPV support. Within 24 h, an increase in ventilatory
support was required following 59 bronchoscopies (35 %), of which 25 (15 %) led to
endotracheal intubation. The existence of chronic obstructive pulmonary disease (COPD;
OR 5) or immunosuppression (OR 5.4) was significantly associated with the need for
intubation in the multivariable analysis. None of the baseline physiological parameters,
including the PaO2/FiO2 ratio, was associated with intubation. Bronchoscopy is often
followed by an increase in ventilatory support in hypoxemic critically ill patients,
but less frequently by the need for intubation. COPD and immunosuppression is associated
with the need for invasive ventilation in the 24 h following bronchoscopy. Bronchoscopists
and intensivists have to be aware of these risk factors for intubation when performing
FOB in patients with acute respiratory failure.
When intubation is needed, the choice between traditional laryngoscopy technique and
combo videolaryngoscope groups is debated. In a before–after study of 210 procedures,
Jong et al. [42] found that the incidence of difficult laryngoscopy and/or difficult
intubation is lower with the combo videolaryngoscope as compared to the classical
technique (4 vs. 16 %, p = 0.01). However, the severe life-threatening complications
related to intubation did not differ between groups (16 vs. 14 %, p = 0.79).
Pediatrics
Primum non nocere
De Gast-Bakker and colleagues from Leiden presented a randomized control study comparing
two transfusion thresholds [Hb 10.8 g/dL (6.8 mmol/L) and Hb 8.0 g/dL (5.0 mmol/L)]
in non-cyanotic children undergoing surgery for congenital cardiac disease involving
bypass. In contrast to previous work, the interventions were applied during anesthesia
and surgery and not just postoperative ICU care. In the restrictive group less blood
was used, costs were lower, and, most importantly, the length of hospital stay was
reduced [restrictive median 8 (IQR 7–11) vs. liberal 9 (IQR 7–14) days, p = 0.047]
[43]. The accompanying editorial reminds us once again of the central importance of
primum non nocere [44]. This theme recurred throughout the year.
Medications and patient safety
Perhaps the simplest observation we published this year was that a case–mix adjusted
increase in risk of death with increasing number of drugs administered in over 1,000
admissions (estimated odds ratio for PICU death per additional drug = 1.13, 95 % CI
1.01–1.27, p = 0.034) [45]. Of course this may represent the limitations of our risk
adjustment models but it does remind us of the constant need to consider the risks
of all our treatments.
The risks of medications is an emerging theme within patient safety. Vet and colleagues
systematically reviewed sedation practice in pediatric intensive care. They highlighted
that oversedation is common and brings with it prolonged stay, tolerance, and withdrawal
[46]. The use of propofol in 4 of the 25 studies identified was noteworthy especially
in the light of the new reports of propofol infusion syndrome [47].
Garcia Guerra and colleagues highlighted another cause of unwanted variability in
managing medications. They measured milrinone blood levels in the first 48 h after
surgical repair of congenital heart disease. More than half of the measured values
were outside the therapeutic range and high levels were associated with low cardiac
output syndrome [48].
Smulders et al. reviewed the literature assessing the impact of central line and ventilator
bundles on healthcare-associated infections in critically ill neonates and children.
Although there were few studies available (10 in children and 2 in neonates) and a
therefore a real risk of publication bias, the authors suggest that bundles do seem
to be effective in these age groups. They particularly highlight the importance of
the need for ongoing care of central venous lines in children [49].
PICU outcomes and organization
Inclusive, high-quality national and international registries and databases are crucial
for us to understand the real-world risks and benefits of our care of critically ill
children where children are no longer admitted to adult ICUs [50]. The high value
of these sources including the Extracorporeal Life Support Organization registry (http://www.elsonet.org),
the UK and Ireland Paediatric Intensive Care Audit Network (www.picanet.org.uk), the
Dutch Pediatric Intensive Care Evaluation (www.pice.nl) registries, and more recent
initiatives such as Iberoamerican Pediatric Cardiac Arrest Study Network (RIBEPCI)
were demonstrated in the journal in 2013.
Polito and colleagues [51] described the epidemiology of acute neurological complications
in 7,190 neonates supported with ECMO between 2005 and 2009. Twenty percent of cases
(1,412) had an acute neurological complication noted and 13 % had a documented intracranial
hemorrhage. Complications were increased by low birth weight (<3 kg), gestational
age (<34 weeks) need for CPR pre-ECMO, low pH and bicarbonate use, and the use of
veno-arterial ECMO.
Madderom and colleagues [52] also described the neurological consequences of ECMO,
but did so in more depth in a cohort of 135 survivors at 8 years of age. Intelligence,
concentration, coordination, and behavior were assessed. Although IQ was within the
normal range (99.9), 9 % of this cohort received special education and 39 % extra
support in regular education. Concentration scores were lower than those of the controls
and there were some subtle differences in behavior. These two papers combine to provide
invaluable data for improving our understanding of risks and benefits and having meaningful
informed consent discussions with families [53].
Ramnarayan and colleagues from the Intensive Care National Audit and Research Centre
(ICNARC) reported the outcome of the 13,430 children admitted to adult ICUs in the
UK between 1996 and 2011. This covers a period during which a shift towards fewer
larger regional PICUs took place. Children represented a small (1.3 %) and decreasing
proportion of over the more than million admissions to the 210 adult units reported.
Crude mortality fell from 6.7 to 2.8 % and the proportion transferred out to a PICU
rose from 18.9 to 51.4 %. These are important data in understanding the impact of
increased regionalization of PICU services [50].
Visser el al. assessed the performance of a range of variants of the PIM2 and PRISM
outcome prediction models amongst more than 12,000 critically ill Dutch children.
They concluded that the freely available PIM2 and the proprietary PRISMIII-24 models
displayed good calibration and discrimination but they warn about their utility in
patients remaining in the ICU for a week or more [54].
The ACTION study investigators reported the impact of congenital heart disease (CHD)
on outcome for 3,684 preterm infants of gestational age 22–31 weeks. CHD was more
than twice as common as in term infants and carried significant additional risk of
complications and death [55].
Lopez-Herce and collaborators in 12 countries reported a prospective observational
study of 502 children suffering an in-hospital cardiac arrest. The figures of return
of circulation in 69.5 %, with 39.2 % surviving to hospital discharge of whom 88.9 %
have a good neurological outcome, are better than many series. The authors urge us
to focus our efforts on preventing cardiac arrests, especially outside of the ICU,
as well as our resuscitation techniques [56].
Oualha and colleagues addressed the challenge of outcome prediction after cardiac
arrest. In a small but novel study they suggest that early diffusion-weighted magnetic
resonance imaging may be a useful adjunct to standard clinical and electrophysiologic
outcome prediction tools [57].
A novel method of ultrasound dilution for measuring cardiac output in pediatric patients
after biventricular repair of congenital heart disease was also published [58].
Respiratory and mechanical ventilation
The Respiratory Section of the European Society for Pediatric and Neonatal Intensive
Care undertook a multicenter study to validate the Berlin definition of ARDS in infants
and young children. The definition had impressive validity in this group. The subgroup
with severe ARDS (PaO2/FiO2 < 100 mmHg with a PEEP > 5 cmH2O) had a hazard ratio of
3 (95 % CI 1.1–7.9) for death or ECMO use after adjustment for age, sex, PRISM-III24,
ARDS type (primary/secondary), and study center [59].
Attempts to create ECMO criteria for newborns with persistent pulmonary hypertension
after inhaled nitric oxide and/or high-frequency oscillatory ventilation were also
published in the journal and required external validation [60].
The journal published a new way of measuring resistance and reactance using forced
oscillation technique (FOT) measurement in preterm newborns that may help to understand
lung mechanics. FOT is very sensitive to its changes with PEEP, making this method
a promising technique for the noninvasive bedside titration of mechanical ventilation
in preterm newborns [61].
The effects of high-flow humidified oxygen on infant respiratory failure due to respiratory
syncytial virus (RSV) were assessed in 21 infants by Milesi et al. [62]. Significant
but small increments in pharyngeal pressure were observed even with flow rates as
low as 2 L/kg/min. Absolute flow rates of greater 6 L/min maintained a positive pharyngeal
pressure throughout the respiratory cycle and were associated with improvements in
measures of respiratory distress.
Evidence for the superiority of a strategy employing first-line nasal continuous positive
airway pressure (nCPAP) in comparison to intermittent positive pressure ventilation
(IPPV) for RSV was reported by Essouri and colleagues. They compared 193 cases between
1996 and 2000, when nCPAP was rarely used, with 332 cases between 2006 and 2010, when
nCPAP was the dominant mode of respiratory support. Their analysis suggests a clinical
and cost improvement of nCPAP including a shorter duration of ventilatory support
(hazard ratio 1.8, 95 % CI 1.5–2.2, p < 0.001) and a 3-day reduction in both PICU
and hospital length of stay. They estimate savings in their unit of around €700,000/year
with this approach [63].
Lee et al. reviewed the role of high-flow nasal cannula (HFNC) systems as a respiratory
support modality in the infant, pediatric, but also adult populations as an alternative
to noninvasive positive pressure ventilation [64].
With this increasing use of noninvasive ventilation, contemporary predictors of failure
of NIV are required. Mayordomo-Colunga [65] reported an 81 % success rate for 369
patients receiving NIV in a prospective multicenter cohort study. This fell to 50 %
in the subgroup with ARDS. Standardized criteria for intubation were used and SpO2/FiO2
ratios were recommended as useful predictors of NIV failure. An SpO2/FiO2 threshold
of 193 provided a clinically useful AUC ROC curve of 0.75 for failure in the first
6 h.
Polygraphic respiratory events during sleep with noninvasive ventilation in children
was very common. In a prospective evaluation, unintentional leaks, patient–ventilator
asynchronies, decrease in ventilatory drive, upper airway obstruction with or without
reduction of ventilatory drive, and mixed events were observed in 27, 33, 10, 11,
12, and 3 % of the patients, respectively [66].
Jouvet and colleagues’ innovative exploratory RCT of 30 children may provide us with
a glimpse of the future for mechanical ventilation. They compared duration of weaning
with a computer-driven protocol vs. standard care. The median duration of weaning
was dramatically reduced with the protocol (21 h, range 3–142 h) compared to standard
care (90 h, range 4–552 h, p = 0.007) [67].
Severe asthma
Although a great proportion of asthmatic patients are well controlled there are still
a small percentage that require ICU admission for an exacerbation both in pediatric
and adult populations. Magnesium sulfate has been advocated as a coadjuvant treatment
when patients do not respond to standard medications. Egelund et al. [68] carried
out a prospective cohort study within a 20-bed PICU in an academic community hospital.
Patients 2–18 years of age admitted with status asthmaticus between October 2009 and
August 2010 were included in the study. All patients received standard therapy for
asthma, whereas the treatment group received an intravenous magnesium sulfate bolus
of 50–75 mg/kg (0.2–0.3 mmol/kg) followed by 40 mg/kg/h (0.16 mmol/kg/h) for 4 h.
Patients were monitored for cardiorespiratory complications. The treatment group underwent
four blood draws to assess pharmacokinetic parameters. Nineteen patients were in the
treatment group and 38 patients in the control group after consideration of exclusion
criteria and consenting were included. No clinically significant differences were
found between groups. There were no interventions or discontinuations of MgSO4 due
to adverse events. In the treatment group, three patients had mild infusion-related
reactions. Heart rate and respiratory rate were statistically significantly lower
in the magnesium treatment group. The continuous infusions of MgSO4 were safe at the
studied doses and maintained serum magnesium (SrMg) and ionized magnesium levels similar
to levels required to produce smooth muscle relaxation in other clinical settings.
Further studies are needed to investigate the efficacy of high-dose continuous MgSO4
infusion as an adjunctive treatment for severe asthma treatment and determine the
SrMg level required to maintain airway smooth muscle relaxation.
Sepsis and biomarkers
Deep et al. [69] used serial suprasternal Doppler estimations of stroke volume in
36 children with evolving sepsis. They confirmed wide variability in presentation
hemodynamics ranging from vasoconstricted low cardiac output, cold shock, to vasoplegic
warm shock. They also confirmed the association between shock physiology and etiology
of sepsis. Most interestingly, however, they demonstrated a complex nonlinear relationship
between cardiac output and ScvO2. There is not a threshold cardiac output above which
ScvO2 is in the target range, but rather a ‘sweet spot’ of cardiac index around 4–5.5 L/min/m2
(not too low but also not too high) associated with peak ScvO2 values.
Diastolic dysfunction was documented in a subset of patients with acute meningococcal
disease by Paize and colleagues. A possible association with raised N-terminal pro-B-type
natriuretic peptide was observed. These clinical studies assist in designing new algorithms
by reminding us of the need for individualized resuscitation [70].
The heterogeneity of the entity we call ‘sepsis’ was also highlighted in an elegant
study of cytokine profiles in early sepsis amongst pediatric hematology/oncology cases
from Xu and colleagues in Hangzhou, China. They demonstrated distinct profiles of
early cytokine responses in gram-negative sepsis (threefold IL-6 levels, tenfold IL-10
levels, and double TNF levels) in contrast to gram-positive sepsis. The clinical utility
of this observation is limited but the implications for different responses to attempts
at immunomodulation or risk stratification are clear [71].
One approach to this complexity is to use increasingly complex panels of biomarkers
to assess risk. Schlapbach et al. described a further analysis of the Neonatal Procalcitonin
Intervention Study in three Swiss hospitals. Early-onset neonatal sepsis occurred
in 33 of their cohort of 137 ‘at risk’ cases. PCT alone was outperformed by a combination
of PCT and pancreatic stone protein. Importantly the NPV of the combined parameters
below threshold values was 100 %. Although this must be validated elsewhere, this
bioscore therefore has potential utility [72].
Spaeder reported a remarkable series of 100 cases of severe adenovirus infection admitted
to PICU. Co-infection with other viruses was present in 50 cases. Seven children died,
five of whom were immunocompromised (odds ratio for death 136, p = 0.001). Only one
immunocompromised patient with adenovirus survived ICU [73].