Other bulletins in this series include:

Breast Surgery

Tuesday, 4 June 2019

Frequency and mortality of septic shock in Europe and North America: a systematic review and meta-analysis

Critical Care 2019 23:196 - Published: 31 May 2019

Septic shock is the most severe form of sepsis, in which profound underlying abnormalities in circulatory and cellular/metabolic parameters lead to substantially increased mortality. A clear understanding and up-to-date assessment of the burden and epidemiology of septic shock are needed to help guide resource allocation and thus ultimately improve patient care. The aim of this systematic review and meta-analysis was therefore to provide a recent evaluation of the frequency of septic shock in intensive care units (ICUs) and associated ICU and hospital mortality.

We searched MEDLINE, Embase, and the Cochrane Library from 1 January 2005 to 20 February 2018 for observational studies that reported on the frequency and mortality of septic shock. Four reviewers independently selected studies and extracted data. Disagreements were resolved via consensus. Random effects meta-analyses were performed to estimate pooled frequency of septic shock diagnosed at admission and during the ICU stay and to estimate septic shock mortality in the ICU, hospital, and at 28 or 30 days.

The literature search identified 6291 records of which 71 articles met the inclusion criteria. The frequency of septic shock was estimated at 10.4% (95% CI 5.9 to 16.1%) in studies reporting values for patients diagnosed at ICU admission and at 8.3% (95% CI 6.1 to 10.7%) in studies reporting values for patients diagnosed at any time during the ICU stay. ICU mortality was 37.3% (95% CI 31.5 to 43.5%), hospital mortality 39.0% (95% CI 34.4 to 43.9%), and 28-/30-day mortality 36.7% (95% CI 32.8 to 40.8%). Significant between-study heterogeneity was observed.

Our literature review reaffirms the continued common occurrence of septic shock and estimates a high mortality of around 38%. The high level of heterogeneity observed in this review may be driven by variability in defining and applying the diagnostic criteria, as well as differences in treatment and care across settings and countries.

Frequency of Screening for Weaning From Mechanical Ventilation: Two Contemporaneous Proof-of-Principle Randomized Controlled Trials*

Objectives: It is unknown whether more frequent screening of invasively ventilated patients, identifies patients earlier for a spontaneous breathing trial, and shortens the duration of ventilation. We assessed the feasibility of conducting a large trial to evaluate screening frequency in critically ill adults in the North American context.
Design: We conducted two contemporaneous, multicenter, pilot, randomized controlled trials (the Liberation from Mechanical Ventilation and Screening Frequency [RELEASE] and Screening Elderly Patients For Inclusion in a Weaning [SENIOR] trials) to address concerns regarding the potential for higher enrollment, fewer adverse events, and better outcomes in younger patients.
Setting: Ten and 11 ICUs in Canada, respectively.
Patients: Parallel trials of younger (RELEASE < 65 yr) and older (SENIOR ≥ 65 yr) critically ill adults invasively ventilated for at least 24 hours. Interventions: Each trial compared once daily screening to “at least twice daily” screening led by respiratory therapists.
Measurements and Main Results: In both trials, we evaluated recruitment (aim: 1–2 patients/month/ICU) and consent rates, reasons for trial exclusion, protocol adherence (target: ≥ 80%), crossovers (aim: ≤ 10%), and the effect of the alternative screening frequencies on adverse events and clinical outcomes. We included 155 patients (53 patients [23 once daily, 30 at least twice daily] in RELEASE and 102 patients [54 once daily, 48 at least twice daily] in SENIOR). Between trials, we found similar recruitment rates (1.32 and 1.26 patients/month/ICU) and reasons for trial exclusion, high consent and protocol adherence rates (> 92%), infrequent crossovers, and few adverse events. Although underpowered, at least twice daily screening was associated with a nonsignificantly faster time to successful extubation and more successful extubations but significantly increased use of noninvasive ventilation in both trials combined.
Conclusions: Similar recruitment and consent rates, few adverse events, and comparable outcomes in younger and older patients support conduct of a single large trial in North American ICUs assessing the net clinical benefits associated with more frequent screening.

An overview of positive cultures and clinical outcomes in septic patients: a sub-analysis of the Prehospital Antibiotics Against Sepsis (PHANTASi) trial

Critical Care  2019  23:182 - Published: 21 May 2019

Sepsis remains one of the most important causes of morbidity and mortality worldwide. In approximately 30–50% of cases of suspected sepsis, no pathogen is isolated, disabling the clinician to treat the patient with targeted antimicrobial therapy. Studies investigating the differences in the patient outcomes between culture-positive and culture-negative sepsis patients have only been conducted in subgroups of sepsis patients and results are ambiguous.

This is a sub-analysis of the PHANTASi (Prehospital Antibiotics Against Sepsis trial), a randomized controlled trial that focused on the effect of prehospital antibiotics in sepsis patients. We evaluated the outcome of cultures from different sources and determined what the clinical implications of having a positive culture compared to negative cultures were for patient outcomes. Furthermore, we looked at the effect of antibiotics on culture outcomes.

1133 patients (42.6%) with culture-positive sepsis were identified, compared to 1526 (56.4%) patients with culture-negative sepsis.
28-day mortality (RR 1.43 [95% CI 1.11–1.83]) and 90-day mortality (RR 1.41 [95% CI 1.15–1.71]) were significantly higher in culture-positive patients compared to culture-negative patients.
Culture-positive sepsis was also associated with ≥ 3 organ systems affected during the sepsis episode (RR 4.27 [95% CI 2.78–6.60]). Patients who received antibiotics at home more often had negative blood cultures (85.9% vs. 78%) than those who did not (p < 0.001).

Our results show that culture-positive sepsis is associated with a higher mortality rate and culture-positive patients more often have multiple organ systems affected during the sepsis episode.
Trial registration

The PHANTASi trial is registered at ClinicalTrials.gov, number NCT01988428. Date of registration: November 20, 2013.

High-flow nasal cannula oxygen therapy versus conventional oxygen therapy in patients after planned extubation: a systematic review and meta-analysis

Critical Care: 2019 23:180: Published: 17 May 2019

The effect of high-flow nasal cannula (HFNC) therapy in patients after planned extubation remains inconclusive. We aimed to perform a rigorous and comprehensive systematic meta-analysis to robustly quantify the benefits of HFNC for patients after planned extubation by investigating postextubation respiratory failure and other outcomes.

We searched MEDLINE, EMBASE, Web of Science, and the Cochrane Library from inception to August 2018. Two researchers screened studies and collected the data independently. Randomized controlled trials (RCTs) and crossover studies were included. The main outcome was postextubation respiratory failure.

Ten studies (seven RCTs and three crossover studies; HFNC group: 856 patients; Conventional oxygen therapy (COT) group: 852 patients) were included. Compared with COT, HFNC may significantly reduce postextubation respiratory failure (RR, 0.61; 95% CI, 0.41, 0.92; z = 2.38; P = 0.02) and respiratory rates (standardized mean differences (SMD), − 0.70; 95% CI, − 1.16, − 0.25; z = 3.03; P = 0.002) and increase PaO2 (SMD, 0.30; 95% CI, 0.04, 0.56; z = 2.23; P = 0.03). There were no significant differences in reintubation rate, length of ICU and hospital stay, comfort score, PaCO2, mortality in ICU and hospital, and severe adverse events between HFNC and COT group.

Our meta-analysis demonstrated that compared with COT, HFNC may significantly reduce postextubation respiratory failure and respiratory rates, increase PaO2, and be safely administered in patients after planned extubation. Further large-scale, multicenter studies are needed to confirm our results.

Clinical review: peripheral muscular ultrasound in the ICU

Annals of Intensive Care20199:57
Published: 17 May 2019

Muscular weakness developing from critical illness neuropathy, myopathy and muscle atrophy has been characterized as intensive care unit-acquired weakness (ICUAW). This entity occurs commonly during and after critical care stay. Various causal factors for functional incapacity have been proposed. Among these, individual patient characteristics (such as age, comorbidities and nutritional status), acting in association with sustained bed rest and pharmacological interventions (included the metabolic support approach), seem influential in reducing muscular mass. Long-term outcomes in heterogeneous ICUAW populations include transient disability in 30% of patients and persistent disabilities that may occur even in patients with nearly complete functional recovery. Currently available tools for the assessment of skeletal muscle mass are imprecise and difficult to perform in the ICU setting. A valid alternative to these imaging modalities is muscular ultrasonography, which allows visualization and classification of muscle characteristics by cross-sectional area, muscle layer thickness, echointensity by grayscale and the pennation angle). The aim of this narrative review is to describe the current literature addressing muscular ultrasound for the detection of muscle weakness and its potential impact on treatment and prognosis of critically ill patients when combined with biomarkers of muscle catabolism/anabolism and bioenergetic state. In addition, we suggest a practical flowchart for establishing an early diagnosis.

The Effect of Vitamin C on Clinical Outcome in Critically Ill Patients: A Systematic Review With Meta-Analysis of Randomized Controlled Trials*

Objectives: The effects of vitamin C administration on clinical outcome in critically ill patients remain controversial.
Data Sources: Online databases were searched up to October 1, 2018.
Study Selection: We included randomized controlled trials on the use of vitamin C (any regimen) in adult critically ill patients versus placebo or no therapy.
Data Extraction: Risk ratio for dichotomous outcome and standardized mean difference for continuous outcome with 95% CI were calculated using random-effects model meta-analysis.
Data Synthesis: Forty-four randomized studies, 16 performed in ICU setting (2,857 patients) and 28 in cardiac surgery (3,598 patients), published between 1995 and 2018, were included in the analysis. In ICU patients, vitamin C administration was not associated with a difference in mortality (risk ratio, 0.90; 95% CI, 0.74–1.10; p = 0.31), acute kidney injury, ICU or hospital length of stay compared with control. In cardiac surgery, vitamin C was associated to a reduction in postoperative atrial fibrillation (risk ratio, 0.64; 95% CI, 0.52–0.78; p < 0.0001), ICU stay (standardized mean difference, –0.28 d; 95% CI, –0.43 to –0.13 d; p = 0.0003), and hospital stay (standardized mean difference, –0.30 d; 95% CI, –0.49 to –0.10 d; p = 0.002). Furthermore, no differences in postoperative mortality, acute kidney injury, stroke, and ventricular arrhythmia were found.
Conclusions: In a mixed population of ICU patients, vitamin C administration is associated with no significant effect on survival, length of ICU or hospital stay. In cardiac surgery, beneficial effects on postoperative atrial fibrillation, ICU or hospital length of stay remain unclear. However, the quality and quantity of evidence is still insufficient to draw firm conclusions, not supporting neither discouraging the systematic administration of vitamin C in these populations. Vitamin C remains an attractive intervention for future investigations aimed to improve clinical outcome.

Short-Term Adverse Outcomes Associated With Hypoglycemia in Critically Ill Children

by Faustino, Edward Vincent S et al: Critical Care Medicine: May 2019 - Volume 47 - Issue 5 - p 706–714

Objectives: Previous studies report worse short-term outcomes with hypoglycemia in critically ill children. These studies relied on intermittent blood glucose measurements, which may have introduced detection bias. We analyzed data from the Heart And Lung Failure-Pediatric INsulin Titration trial to determine the association of hypoglycemia with adverse short-term outcomes in critically ill children.
Design: Nested case-control study.
Setting: Thirty-five PICUs. A computerized algorithm that guided the timing of blood glucose measurements and titration of insulin infusion, continuous glucose monitors, and standardized glucose infusion rates were used to minimize hypoglycemia.
Patients: Nondiabetic children with cardiovascular and/or respiratory failure and hyperglycemia. Cases were children with any hypoglycemia (blood glucose < 60 mg/dL), whereas controls were children without hypoglycemia. Each case was matched with up to four unique controls according to age group, study day, and severity of illness.
Interventions: None.
Measurements and Main Results: A total of 112 (16.0%) of 698 children who received the Heart And Lung Failure-Pediatric INsulin Titration protocol developed hypoglycemia, including 25 (3.6%) who developed severe hypoglycemia (blood glucose < 40 mg/dL). Of these, 110 cases were matched to 427 controls. Hypoglycemia was associated with fewer ICU-free days (median, 15.3 vs 20.2 d; p = 0.04) and fewer hospital-free days (0 vs 7 d; p = 0.01) through day 28. Ventilator-free days through day 28 and mortality at 28 and 90 days did not differ between groups. More children with insulin-induced versus noninsulin-induced hypoglycemia had zero ICU-free days (35.8% vs 20.9%; p = 0.008). Outcomes did not differ between children with severe versus nonsevere hypoglycemia or those with recurrent versus isolated hypoglycemia.
Conclusions: When a computerized algorithm, continuous glucose monitors and standardized glucose infusion rates were used to manage hyperglycemia in critically ill children with cardiovascular and/or respiratory failure, severe hypoglycemia (blood glucose < 40 mg/dL) was uncommon, but any hypoglycemia (blood glucose < 60 mg/dL) remained common and was associated with worse short-term outcomes.

Neutropenic Enterocolitis in Critically Ill Patients: Spectrum of the Disease and Risk of Invasive Fungal Disease

by Duceau Baptiste et al: Critical Care Medicine: May 2019 - Volume 47 - Issue 5 - p 668–676

Objectives: Neutropenic enterocolitis occurs in about 5.3% of patients hospitalized for hematologic malignancies receiving chemotherapy. Data from critically ill patients with neutropenic enterocolitis are scarce. Our objectives were to describe the population of patients with neutropenic enterocolitis admitted to an ICU and to investigate the risk factors of invasive fungal disease.
Design: A multicentric retrospective cohort study between January 2010 and August 2017.
Setting: Six French ICUs members of the Groupe de Recherche Respiratoire en Onco-Hématologie research network.
Patients: Adult neutropenic patients hospitalized in the ICU with a diagnosis of enteritis and/or colitis. Patients with differential diagnosis (Clostridium difficile colitis, viral colitis, inflammatory enterocolitis, mesenteric ischemia, radiation-induced gastrointestinal toxicity, and Graft vs Host Disease) were excluded. Interventions: None.
Measurement and Main Results: We included 134 patients (median Sequential Organ Failure Assessment 10 [8–12]), with 38.8% hospital mortality and 32.1% ICU mortality rates. The main underlying malignancies were acute leukemia (n = 65, 48.5%), lymphoma (n = 49, 36.6%), solid tumor (n = 14, 10.4%), and myeloma (n = 4, 3.0%). Patients were neutropenic during a median of 14 days (9–22 d). Infection was documented in 81 patients (60.4%), including an isolated bacterial infection in 64 patients (47.8%), an isolated fungal infection in nine patients (6.7%), and a coinfection with both pathogens in eight patients (5.0%). Radiologically assessed enteritis (odds ratio, 2.60; 95% CI, 1.32–7.56; p = 0.015) and HIV infection (odds ratio, 2.03; 95% CI, 1.21–3.31; p = 0.016) were independently associated with invasive fungal disease.
Conclusions: The rate of invasive fungal disease reaches 20% in patients with neutropenic enterocolitis when enteritis is considered. To avoid treatment delay, antifungal therapy might be systematically discussed in ICU patients admitted for neutropenic enterocolitis with radiologically assessed enteritis.

The Effect of Mechanical Ventilation on Peripheral Perfusion Index and Its Association With the Prognosis of Critically Ill Patients

by Su, Longxiang et al: Critical Care Medicine: May 2019 - Volume 47 - Issue 5 - p 685–690

Objectives: This study aimed to explore the relationship between the variables of mechanical ventilation and circulatory perfusion and its association with ICU mortality during the first day of mechanical ventilation.
Design: Retrospective cohort study.
Setting: The Department of Critical Care Medicine, Peking Union Medical College Hospital. Patients: Patients who have undergone mechanical ventilation. Interventions: None. Measurements and Main Results: This study used the main clinical data obtained from the real-time bedside messaging systems of mechanically ventilated patients during their first day in the ICU from May 2013 to May 2016, including data on the variables of mechanical ventilation and circulatory perfusion. An analysis was then performed on the association of the above data with the patient’s in-ICU mortality. There were 5,103 patients who received mechanical ventilation during this period, and of these, 309 patients died during their ICU treatment. Peak airway pressure, mean airway pressure, respiratory rate, heart rate, mean arterial pressure, FIO2, blood oxygen saturation, PO2, peripheral perfusion index, and lactate level were correlated with patient outcomes. A Cox logistic regression analysis suggested that mean airway pressure and perfusion index were the most independent risk and protective factors, respectively, for patient ICU mortality. The areas under the curve for a poor prognosis for mean airway pressure and perfusion index were 0.799 (95% CI, 0.77–0.829) and 0.759 (95% CI, 0.729–0.789), respectively. Further, mean airway pressure and perfusion index exhibited a causal interaction. The relative excess risk due to interaction was 2.061 (–0.691 to 4.814), the attributable proportion due to interaction was 0.210 (–0.027 to 0.447), and the synergy index was 1.306 (0.930–1.833).
Conclusions: A higher mean airway pressure and lower perfusion index provided a worse prognosis in mechanically ventilated patients, and it appears that these two variables have a casual interaction.

Effects of mean arterial pressure on arousal in sedated ventilated patients with septic shock: a SEPSISPAM post hoc exploratory study

by Youenn Jouan et al: Annals of Intensive Care20199:54 (2019)

It is unknown whether the recommended mean arterial pressure (MAP) target of 65 mmHg during initial resuscitation of septic shock is sufficient to maintain cerebral perfusion. Thus, we tested the hypothesis that a higher MAP target in patients with septic shock may improve level of arousal.

We performed a post hoc exploratory analysis of the SEPSISPAM trial, which assessed the effect of a “high-target” level of MAP (80–85 mmHg) versus the recommended “low-target” MAP (65–70 mm Hg) on mortality in patients with septic shock. Among the 776 patients originally recruited in SEPSISPAM trial, we selected those who were mechanically ventilated and sedated and with available evaluation of arousal level assessed by the Richmond Agitation and Sedation Scale (RASS).

We restricted our analysis to the period in which patients were treated with vasoactive drugs. Cumulative sedative drugs were assessed daily. A total of 532 patients were included in this study: 253 (47.6%) in the low-target group and 279 (52.4%) in the high-target group. Daily cumulative sedative drugs were similar in both groups. Compared to the low-target group, minimal and maximal RASS were significantly higher in the high-target group at day 2, 4 and 5. Furthermore, in order to consider the fact that multiple measures were done for each patient and to consider the global effect of time on these measures, we used a mixed linear regression and multivariate models: we confirmed that maximal RASS values were significantly higher in the high-target group.


In patients with septic shock who were mechanically ventilated and sedated, resuscitation with MAP target between 80 and 85 mmHg was associated with higher arousal level as compared to a MAP target between 65 and 70 mmHg.

Renal function after out-of-hospital cardiac arrest; the influence of temperature management and coronary angiography, a post hoc study of the target temperature management trial

by Malin Rundgren et al: Critical Care 2019 23:163

To elucidate the incidence of acute kidney injury (AKI) after out-of-hospital cardiac arrest (OHCA) and to examine the impact of target temperature management (TTM) and early coronary angiography on renal function.
Post hoc analysis of the TTM trial, a multinational randomised controlled trial comparing target temperature of 33 °C versus 36 °C in patients with return of spontaneous circulation after OHCA. The impact of TTM and early angiography (within 6 h of OHCA) versus late or no angiography on the development of AKI during the 7-day period after OHCA was analysed. AKI was defined according to modified KDIGO criteria in patients surviving beyond day 2 after OHCA.
Following exclusions, 853 of 939 patients enrolled in the main trial were analysed. Unadjusted analysis showed that significantly more patients in the 33 °C group had AKI compared to the 36 °C group [211/431 (49%) versus 170/422 (40%) p = 0.01], with a worse severity (p = 0.018). After multivariable adjustment, the difference was not significant (odds ratio 0.75, 95% confidence interval 0.54–1.06, p = 0.10].
Five hundred seventeen patients underwent early coronary angiography. Although the unadjusted analysis showed less AKI and less severe AKI in patients who underwent early angiography compared to patients with late or no angiography, in adjusted analyses, early angiography was not an independent risk factor for AKI (odds ratio 0.73, 95% confidence interval 0.50–1.05, p = 0.09).
In OHCA survivors, TTM at 33 °C compared to management at 36 °C did not show different rates of AKI and early angiography was not associated with an increased risk of AKI.
Trial registration
NCT01020916. Registered on www.ClinicalTrials.gov 26 November 2009 (main trial).