Procalcitonin-guided therapy in intensive care unit patients with severe sepsis and septic shock – a systematic review and meta-analysis

Introduction

Procalcitonin (PCT) algorithms for antibiotic treatment decisions have been studied in adult patients from primary care, emergency department, and intensive care unit (ICU) settings, suggesting that procalcitonin-guided therapy may reduce antibiotic exposure without increasing the mortality rate. However, information on the efficacy and safety of this approach in the most vulnerable population of critically ill patients with severe sepsis and septic shock is missing.

Method

Two reviewers independently performed a systematic search in PubMed, Embase, ISI Web of Knowledge, BioMed Central, ScienceDirect, Cochrane Central Register of Controlled Trials, http://www.ClinicalTrials.gov and http://www.ISRCTN.org.Eligible studies had to be randomized controlled clinical trials or cohort studies which compare procalcitonin-guided therapy with standard care in severe sepsis patients and report at least one of the following outcomes: hospital mortality, 28-day mortality, duration of antimicrobial therapy, length of stay in the intensive care unit or length of hospital stay. Disagreements about inclusion of studies and judgment of bias were solved by consensus.

Results

Finally seven studies comprising a total of 1,075 patients with severe sepsis or septic shock were included in the meta-analysis.Both hospital mortality (RR [relative risk]: 0.91, 95%CI [confidence interval]: 0.61; 1.36) and 28-day mortality (RR: 1.02, 95%CI: 0.85; 1.23) were not different between procalcitonin-guided therapy and standard treatment groups.Duration of antimicrobial therapy was significantly reduced in favor of procalcitonin-guided therapy (HR [hazard ratio]: 1.27, 95%CI: 1.01; 1.53). Combined estimates of the length of stay in the ICU and in hospital did not differ between groups.

Conclusion

Procalcitonin-guided therapy is a helpful approach to guide antibiotic therapy and surgical interventions without a beneficial effect on mortality. The major benefit of PCT-guided therapy consists of a shorter duration of antibiotic treatment compared to standard care.Trials are needed to investigate the effect of PCT-guided therapy on mortality, length of ICU and in-hospital stay in severe sepsis patients.     

Phenylephrine versus norepinephrine for initial hemodynamic support of patients with septic shock: a randomized, controlled trial

Introduction

Previous findings suggest that a delayed administration of phenylephrine replacing norepinephrine in septic shock patients causes a more pronounced hepatosplanchnic vasoconstriction as compared with norepinephrine. Nevertheless, a direct comparison between the two study drugs has not yet been performed. The aim of the present study was, therefore, to investigate the effects of a first-line therapy with either phenylephrine or norepinephrine on systemic and regional hemodynamics in patients with septic shock.

Methods

We performed a prospective, randomized, controlled trial in a multidisciplinary intensive care unit in a university hospital. We enrolled septic shock patients (n = 32) with a mean arterial pressure below 65 mmHg despite adequate volume resuscitation. Patients were randomly allocated to treatment with either norepinephrine or phenylephrine infusion (n = 16 each) titrated to achieve a mean arterial pressure between 65 and 75 mmHg. Data from right heart catheterization, a thermodye dilution catheter, gastric tonometry, acid-base homeostasis, as well as creatinine clearance and cardiac troponin were obtained at baseline and after 12 hours. Differences within and between groups were analyzed using a two-way analysis of variance for repeated measurements with group and time as factors. Time-independent variables were compared with one-way analysis of variance.

Results

No differences were found in any of the investigated parameters.

Conclusions

The present study suggests there are no differences in terms of cardiopulmonary performance, global oxygen transport, and regional hemodynamics when phenylephrine was administered instead of norepinephrine in the initial hemodynamic support of septic shock.

Trial registration

ClinicalTrial.gov NCT00639015     

A prospective study of the impact of serial troponin measurements on the diagnosis of myocardial infarction and hospital and six-month mortality in patients admitted to ICU with non-cardiac diagnoses

Introduction

Troponin T (cTnT) elevation is common in patients in the Intensive Care Unit (ICU) and associated with morbidity and mortality. Our aim was to determine the epidemiology of raised cTnT levels and contemporaneous electrocardiogram (ECG) changes suggesting myocardial infarction (MI) in ICU patients admitted for non-cardiac reasons.

Methods

cTnT and ECGs were recorded daily during week 1 and on alternate days during week 2 until discharge from ICU or death. ECGs were interpreted independently for the presence of ischaemic changes. Patients were classified into four groups: (i) definite MI (cTnT ≥15 ng/L and contemporaneous changes of MI on ECG), (ii) possible MI (cTnT ≥15 ng/L and contemporaneous ischaemic changes on ECG), (iii) troponin rise alone (cTnT ≥15 ng/L), or (iv) normal. Medical notes were screened independently by two ICU clinicians for evidence that the clinical teams had considered a cardiac event.

Results

Data from 144 patients were analysed (42% female; mean age 61.9 (SD 16.9)). A total of 121 patients (84%) had at least one cTnT level ≥15 ng/L. A total of 20 patients (14%) had a definite MI, 27% had a possible MI, 43% had a cTNT rise without contemporaneous ECG changes, and 16% had no cTNT rise. ICU, hospital and 180-day mortality was significantly higher in patients with a definite or possible MI.Only 20% of definite MIs were recognised by the clinical team. There was no significant difference in mortality between recognised and non-recognised events.At the time of cTNT rise, 100 patients (70%) were septic and 58% were on vasopressors. Patients who were septic when cTNT was elevated had an ICU mortality of 28% compared to 9% in patients without sepsis. ICU mortality of patients who were on vasopressors at the time of cTnT elevation was 37% compared to 1.7% in patients not on vasopressors.

Conclusions

The majority of critically ill patients (84%) had a cTnT rise and 41% met criteria for a possible or definite MI of whom only 20% were recognised clinically. Mortality up to 180 days was higher in patients with a cTnT rise.     

Impaired cerebrovascular autoregulation in patients with severe sepsis and sepsis-associated delirium

Introduction

Sepsis-associated delirium (SAD) increases morbidity in septic patients and, therefore, factors contributing to SAD should be further characterized. One possible mechanism might be the impairment of cerebrovascular autoregulation (AR) by sepsis, leading to cerebral hypo- or hyperperfusion in these haemodynamically unstable patients. Therefore, the present study investigates the relationship between the incidence of SAD and the status of AR during sepsis.

Methods

Cerebral blood flow velocity was measured using transcranial Doppler sonography and was correlated with the invasive arterial blood pressure curve to calculate the index of AR Mx (Mx>0.3 indicates impaired AR). Mx was measured daily during the first 4 days of sepsis. Diagnosis of a SAD was performed using the confusion assessment method for ICU (CAM-ICU) and, furthermore the predominant brain electrical activity in electroencephalogram (EEG) both at day 4 after reduction of sedation to RASS >-2.

Results

30 critically ill adult patients with severe sepsis or septic shock (APACHE II 32 ± 6) were included. AR was impaired at day 1 in 60%, day 2 in 59%, day 3 in 41% and day 4 in 46% of patients; SAD detected by CAM-ICU was present in 76 % of patients. Impaired AR at day 1 was associated with the incidence of SAD at day 4 (p = 0.035).

Conclusions

AR is impaired in the great majority of patients with severe sepsis during the first two days. Impaired AR is associated with SAD, suggesting that dysfunction of AR is one of the trigger mechanisms contributing to the development of SAD.

Trial registration

clinicalTrials.gov ID NCT01029080     

Steroids in early ARDS?

Citation

Annane D, Sebille V, Bellissant E: Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome. Crit Care Med 2006, 34:22–30 [1].

Background

Experimental evidence suggests that corticosteroids may be beneficial in early acute respiratory distress syndrome (ARDS).

Methods

Objective

To investigate the efficacy of low doses of corticosteroids in septic shock patients with or without early ARDS by post hoc analysis of a previously completed clinical trial.

Design

Retrospective analysis of a placebo-controlled, randomized, double-blind trial of low doses of corticosteroids in septic shock.

Setting

Nineteen intensive care units in France.

Subjects

Among the 300 septic shock patients enrolled, we selected those meeting standard criteria for ARDS at inclusion.

Intervention

Seven-day treatment with 50 mg of hydrocortisone every 6 hrs and 50 μg of 9-alpha-fludrocortisone once a day.

Measurements and main results

There were 177 patients with ARDS (placebo, n = 92; corticosteroids, n = 85) including 129 (placebo, n = 67; corticosteroids, n = 62) nonresponders and 48 (placebo, n = 25; corticosteroids, n = 23) responders. In nonresponders, there were 50 deaths (75%) in the placebo group and 33 deaths (53%) in the steroid group (hazard ratio 0.57, 95% confidence interval 0.36–0.89, p = .013; relative risk 0.71, 95% confidence interval 0.54–0.94, p = .011). The number of days alive and off the ventilator was 2.6 +/- 6.6 in the placebo group and 5.7 +/- 8.6 in the steroid group (p = .006). There was no significant difference between groups in responders. There was no significant difference between groups in the two subsets of patients without ARDS. Adverse events rates were similar in the two groups.

Conclusion

This post hoc analysis shows that a 7-day treatment with low doses of corticosteroids was associated with better outcomes in septic shock-associated early ARDS nonresponders, but not in responders and not in septic shock patients without ARDS.     

A comparative study of varying doses of enoxaparin for thromboprophylaxis in critically ill patients: a double-blinded,randomised controlled trial

Introduction

Critically ill patients are predisposed to venous thromboembolism. We hypothesized that higher doses of enoxaparin would improve thromboprophylaxis without increasing the risk of bleeding. Peak anti-factor Xa (anti-Xa) levels of 0.1 to 0.4 IU/ml reflect adequate thromboprophylaxis for general ward patients. Studies conducted in orthopaedic patients demonstrated a statistically significant relationship between anti-Xa levels and wound haematoma and thrombosis. Corresponding levels for critically ill patients may well be higher, but have never been validated in large studies.

Methods

Eighty critically ill patients weighing 50 to 90 kilograms were randomised in a double-blinded study to receive subcutaneous (sc) enoxaparin: 40 mg once daily (QD), 30 mg twice daily (BID), 40 mg BID, or 1 mg/kg QD, each administered for three days. Anti-Xa activity was measured at baseline, and daily at 4, 12, 16 and 24 hours post administration. Antithrombin, fibrinogen, and platelets were measured at baseline and twice daily thereafter.

Results

Two patients were transferred prior to participation. On day 1, doses of 40 mg QD (n = 20) and 40 mg BID (n = 19) yielded mean peak anti-Xa of 0.20 IU/ml and 0.17 IU/ml respectively. A dose of 30 mg BID (n = 20) resulted in much lower levels (0.08 IU/ml). Patients receiving 1 mg/kg QD (n = 19) achieved near steady-state mean peak anti-Xa levels from day 1 (0.34 IU/ml). At steady state (day 3), mean peak anti-Xa levels of 0.13 IU/ml and 0.15 IU/ml were achieved with doses of 40 mg QD and 30 mg BID respectively. This increased significantly to 0.33 IU/ml and 0.40 IU/ml for doses of 40 mg BID and 1 mg/kg QD respectively. Thus anti-Xa response profiles differed significantly over the three days between enoxaparin treatment groups (P <0.0001). Doses of 40 mg BID and1 mg/kg QD enoxaparin yielded target anti-Xa levels for over 80% of the study period. There were no adverse effects.

Conclusions

Doses of 40 mg QD enoxaparin (Europe) or 30 mg BID (North America) yield levels of anti-Xa which may be inadequate for critically ill patients. A weight-based dose yielded the best anti-Xa levels without bioaccumulation, and allowed the establishment of near steady-state levels from the first day of enoxaparin administration.

Trial registration

Current Controlled Trials ISRCTN91570009.     

Standard operating procedures for antibiotic therapy and the occurrence of acute kidney injury: a prospective,clinical, non-interventional,observational study

Introduction

Acute kidney injury (AKI) occurs in 7% of hospitalized and 66% of Intensive Care Unit (ICU) patients. It increases mortality, hospital length of stay, and costs. The aim of this study was to investigate, whether there is an association between adherence to guidelines (standard operating procedures (SOP)) for potentially nephrotoxic antibiotics and the occurrence of AKI.

Methods

This study was carried out as a prospective, clinical, non-interventional, observational study. Data collection was performed over a total of 170 days in three ICUs at Charité – Universitaetsmedizin Berlin. A total of 675 patients were included; 163 of these had therapy with vancomycin, gentamicin, or tobramycin; were >18 years; and treated in the ICU for >24 hours. Patients with an adherence to SOP >70% were classified into the high adherence group (HAG) and patients with an adherence of <70% into the low adherence group (LAG). AKI was defined according to RIFLE criteria. Adherence to SOPs was evaluated by retrospective expert audit. Development of AKI was compared between groups with exact Chi²-test and multivariate logistic regression analysis (two-sided P <0.05).

Results

LAG consisted of 75 patients (46%) versus 88 HAG patients (54%). AKI occurred significantly more often in LAG with 36% versus 21% in HAG (P = 0.035). Basic characteristics were comparable, except an increased rate of soft tissue infections in LAG. Multivariate analysis revealed an odds ratio of 2.5-fold for LAG to develop AKI compared with HAG (95% confidence interval 1.195 to 5.124, P = 0.039).

Conclusion

Low adherence to SOPs for potentially nephrotoxic antibiotics was associated with a higher occurrence of AKI.

Trial registration

Current Controlled Trials ISRCTN54598675. Registered 17 August 2007.     

Methylglyoxal as a new biomarker in patients with septic shock: an observational clinical study

Introduction

The role of reactive carbonyl species, such as methylglyoxal (MG), has been overlooked within the context of the sepsis syndrome. The aims of this study were to assess the impact of MG formation in different inflammatory settings and to evaluate its use for early diagnosis as well as prognosis of the sepsis syndrome.

Methods

In total, 120 patients in three groups were enrolled in this observational clinical pilot study. The three groups included patients with septic shock (n = 60), postoperative controls (n = 30), and healthy volunteers (n = 30). Plasma samples from patients with septic shock were collected at sepsis onset and after 24 hours and 4, 7, 14, and 28 days. Plasma samples from postoperative controls were collected prior to surgery, immediately following the end of the surgical procedure as well as 24 hours later and from healthy volunteers once. Plasma levels of MG were determined by high-performance liquid chromatography. Additionally, plasma levels of procalcitonin, C-reactive protein, soluble CD14 subtype, and interleukin-6 were determined.

Results

Patients with septic shock showed significantly higher plasma levels of MG at all measured times, compared with postoperative controls. MG was found to identify patients with septic shock more effectively—area under the curve (AUC): 0.993—than procalcitonin (AUC: 0.844), C-reactive protein (AUC: 0.791), soluble CD14 subtype (AUC: 0.832), and interleukin-6 (AUC: 0.898) as assessed by receiver operating characteristic (ROC) analysis. Moreover, plasma levels of MG in non-survivors were significantly higher than in survivors (sepsis onset: *P = 0.018 for 90-day survival; **P = 0.008 for 28-day survival). Plasma levels of MG proved to be an early predictor for survival in patients with septic shock (sepsis onset: ROC-AUC 0.710 for 28-day survival; ROC-AUC 0.686 for 90-day survival).

Conclusions

MG was identified as a marker for monitoring the onset, development, and remission of sepsis and was found to be more useful than routine diagnostic markers. Further studies are required to determine the extent of MG modification in sepsis and whether targeting this pathway could be therapeutically beneficial to the patient.

Trial registration

German Clinical Trials Register DRKS00000505. Registered 8 November 2010.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-014-0683-x) contains supplementary material, which is available to authorized users.     

Noninvasive ventilation immediately after extubation improves weaning outcome after acute respiratory failure: a randomized controlled trial

Introduction

Noninvasive ventilation (NIV), as a weaning-facilitating strategy in predominantly chronic obstructive pulmonary disease (COPD) mechanically ventilated patients, is associated with reduced ventilator-associated pneumonia, total duration of mechanical ventilation, length of intensive care unit (ICU) and hospital stay, and mortality. However, this benefit after planned extubation in patients with acute respiratory failure of various etiologies remains to be elucidated. The aim of this study was to determine the efficacy of NIV applied immediately after planned extubation in contrast to oxygen mask (OM) in patients with acute respiratory failure (ARF).

Methods

A randomized, prospective, controlled, unblinded clinical study in a single center of a 24-bed adult general ICU in a university hospital was carried out in a 12-month period. Included patients met extubation criteria with at least 72 hours of mechanical ventilation due to acute respiratory failure, after following the ICU weaning protocol. Patients were randomized immediately before elective extubation, being randomly allocated to one of the study groups: NIV or OM. We compared both groups regarding gas exchange 15 minutes, 2 hours, and 24 hours after extubation, reintubation rate after 48 hours, duration of mechanical ventilation, ICU length of stay, and hospital mortality.

Results

Forty patients were randomized to receive NIV (20 patients) or OM (20 patients) after the following extubation criteria were met: pressure support (PSV) of 7 cm H₂O, positive end-expiratory pressure (PEEP) of 5 cm H₂O, oxygen inspiratory fraction (FiO₂) ≤ 40%, arterial oxygen saturation (SaO₂) ≥ 90%, and ratio of respiratory rate and tidal volume in liters (f/TV) < 105. Comparing the 20 patients (NIV) with the 18 patients (OM) that finished the study 48 hours after extubation, the rate of reintubation in NIV group was 5% and 39% in OM group (P = 0.016). Relative risk for reintubation was 0.13 (CI = 0.017 to 0.946). Absolute risk reduction for reintubation showed a decrease of 33.9%, and analysis of the number needed to treat was three. No difference was found in the length of ICU stay (P = 0.681). Hospital mortality was zero in NIV group and 22.2% in OM group (P = 0.041).

Conclusions

In this study population, NIV prevented 48 hours reintubation if applied immediately after elective extubation in patients with more than 3 days of ARF when compared with the OM group.

Trial Registration number

ISRCTN: 41524441.     

Procalcitonin-guided antibiotics in severe sepsis

Citation

Nobre V, Harbarth S, Graf JD, Rohner P, Pugin J: Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial. Am J Respir Crit Care Med 2008, 177: 498–505 [1].

Background

The duration of antibiotic therapy in critically ill patients with sepsis can result in antibiotic overuse, increasing the risk of developing bacterial resistance. Procalcitonin (PCT)-guided antibiotic use reduces antibiotic exposure in community-acquired pneumonia. Whether it might also reduce antibiotic exposure in severe sepsis is unknown.

Methods

Objective

To test the hypothesis that an algorithm based on serial measurements of PCT allows reduction in the duration of antibiotic therapy compared with empirical rules, and does not result in more adverse outcomes in patients with severe sepsis and septic shock.

Design

Single-center, non-blinded randomized controlled trial.

Setting

Mixed medical and surgical ICU at a university teaching hospital.

Subjects

79 adult patients with suspected severe sepsis or septic shock.

Intervention

All patients had circulating PCT levels drawn daily. In patients randomly assigned to the intervention group, antibiotics were stopped when PCT levels had decreased 90% or more from the initial value (if clinicians agreed) but not before Day 3 (if baseline PCT levels were <1 mg/L) or Day 5 (if baseline PCT levels were >1 mg/L). In control patients, clinicians decided on the duration of antibiotic therapy based on empirical rules.

Outcome

Systemic antibiotic exposure, measured using three variables: 1) duration of antibiotic treatment, 2) antibiotic exposure days per 1000 inpatient days, and 3) days alive without antibiotics within the 28-day follow-up period.

Results

Patients assigned to the PCT group had 3.5-day shorter median duration of antibiotic therapy for the first episode of infection than control subjects (intention-to-treat, n = 79, P = 0.15). In patients in whom a decision could be taken based on serial PCT measurements, PCT guidance resulted in a 4-day reduction in the duration of antibiotic therapy (per protocol, n = 68, P = 0.003) and a smaller overall antibiotic exposure (P = 0.0002). A similar mortality and recurrence of the primary infection were observed in PCT and control groups. A 2-day shorter intensive care unit stay was also observed in patients assigned to the PCT group (P = 0.03).

Conclusion

Our results suggest that a protocol based on serial PCT measurement allows reducing antibiotic treatment duration and exposure in patients with severe sepsis and septic shock without apparent harm.     

CORTICUS: The end of unconditional love for steroid use?

Citation

Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J: Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008, 358: 111–124 [1].

Background

Hydrocortisone is widely used in patients with septic shock, even though a survival benefit has been reported only in patients who remained hypotensive after fluid and vasopressor resuscitation and whose plasma cortisol levels did not rise appropriately after the administration of corticotropin.

Methods

Objective

To evaluate the efficacy and safety of low-dose hydrocortisone therapy in a broad population of patients with septic shock – in particular, patients who had had a response to a corticotropin test, in whom a benefit was unproven.

Design

Multi-center, prospective randomized, double-blind, placebo-controlled trial.

Setting

International study involving 52 intensive care units.

Subjects

499 patients 18 years or older with the diagnosis of septic shock.

Intervention

251 patients received 50 mg of intravenous hydrocortisone and 248 patients received placebo every 6 hours for 5 days; the dose was then tapered over a 6-day period. A short corticotropin test was performed from blood samples taken immediately before and 60 minutes after an intravenous administration of 250 mcg of cosyntropin prior to administration of hydrocortisone.

Outcomes

Primary outcome was the mortality rate at 28 days in patients who did not have a response to corticotropin. Secondary outcomes included 28-day mortality in corticotropin responders and in all patients; length of stay; reversal of organ failure; and rates of new infection, hypernatremia and hyperglycemia.

Results

Of the 499 patients in the study, 233 (46.7%) did not have a response to corticotropin (125 in the hydrocortisone group and 108 in the placebo group). At 28 days, there was no significant difference in mortality between patients in the two study groups who did not have a response to corticotropin (39.2% in the hydrocortisone group and 36.1% in the placebo group, P = 0.69) or in patients who had a response to corticotropin (28.8% in the hydrocortisone group and 28.7% in the placebo group, P = 1.00). Mortality at 28 days included 86 of 251 patients in the hydrocortisone group (34.3%) and 78 of 248 patients in the placebo group (31.5%) (P = 0.51). Shock reversal was quicker in the hydrocortisone group compared to the placebo group. However, there were more episodes of super infection, including new sepsis and septic shock in the hydrocortisone group.

Conclusion

Hydrocortisone did not improve survival in patients with septic shock, either overall or in patients who did not have a response to corticotropin. However, hydrocortisone hastened reversal of shock in all study patients.

Trial Registration

(ClinicalTrials.gov number, {"type":"clinical-trial","attrs":{"text":"NCT00147004","term_id":"NCT00147004"}}NCT00147004.)     

Epinephrine: Is it really the black sheep of vasoactive agents?

Citation

Annane D, Vignon P, Renault A, Bollaert PE, Charpentier C, Martin C, Troche G, Ricard JD, Nitenberg G, Papazian L, Azoulay E, Bellissant E: Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Lancet 370:676-684 [1].

Background

International guidelines for management of septic shock recommend that dopamine or norepinephrine are preferable to epinephrine. However, no large comparative trial has yet been done.

Methods

Objective

To compare the efficacy and safety of norepinephrine plus dobutamine (whenever needed) with those of epinephrine alone in septic shock.

Design

Prospective, multicenter, randomized, double-blind study.

Setting

19 participating intensive care units in France.

Subjects

330 adult patients with septic shock. Inclusion criteria were the presence for less than 7 days of: evidence of infection; at least 2 of the 4 criteria of systemic inflammatory response syndrome (SIRS); and at least two signs of tissue hypoperfusion or organ dysfunction. Additionally, subjects had to have had to meet the three following criteria for less than 24 hours: systolic blood pressure less than 90 mm Hg or mean BP less than 70 mm Hg; administration of fluid bolus of at least 1000 mL or capillary wedge pressure between 12 and 18 mm Hg; and need for more than 15 μg per kg bodyweight per min of dopamine or any dose of epinephrine or norepinephrine. Specific exclusion criteria were established to ensure other causes of shock were excluded.

Intervention

Participants were assigned to receive epinephrine (n = 161) or norepinephrine plus dobutamine (n = 169), which were titrated to maintain mean blood pressure at 70 mm Hg or more.

Outcomes

The primary outcome was 28-day all-cause mortality. The secondary outcomes were survival distribution from randomization to day 90; mortality rates at day 7, 14, at discharge from intensive care and from hospital, and at day 90; systemic hemodynamics; arterial pH and lactate; SOFA score; time to hemodynamic success and time to vaspressor withdrawal. Analyses were by intention to treat.

Results

There were no patients lost to follow-up; one patient withdrew consent after 3 days. At day 28, there were 64 (40%) deaths in the epinephrine group and 58 (34%) deaths in the norepinephrine plus dobutamine group (p = 0.31; relative risk 0.86, 95% CI 0.65-1.14). There was no significant difference between the two groups in mortality rates at discharge from intensive care (75 [47%] deaths vs. 75 [44%] deaths, p = 0.69), at hospital discharge (84 [52%] vs. 82 [49%], p = 0.51), and by day 90 (84 [52%] vs. 85 [50%], p = 0.73), time to hemodynamic success (log-rank p = 0.67), time to vasopressor withdrawal (log-rank p = 0.09), and time course of SOFA score. Rates of serious adverse events were also similar.

Conclusions

There is no evidence for a difference in efficacy and safety between epinephrine alone and norepinephrine plus dobutamine for the management of septic shock.

Trial Registration

(ClinicalTrials.gov number, NCT00148278).     

Individual component analysis of the multi-parametric cardiovascular magnetic resonance protocol in the CE-MARC trial

Background

The CE-MARC study assessed the diagnostic performance investigated the use of cardiovascular magnetic resonance (CMR) in patients with suspected coronary artery disease (CAD). The study used a multi-parametric CMR protocol assessing 4 components: i) left ventricular function; ii) myocardial perfusion; iii) viability (late gadolinium enhancement (LGE)) and iv) coronary magnetic resonance angiography (MRA). In this pre-specified CE-MARC sub-study we assessed the diagnostic accuracy of the individual CMR components and their combinations.

Methods

All patients from the CE-MARC population (n = 752) were included using data from the original blinded-read. The four individual core components of the CMR protocol was determined separately and then in paired and triplet combinations. Results were then compared to the full multi-parametric protocol.

Results

CMR and X-ray angiography results were available in 676 patients. The maximum sensitivity for the detection of significant CAD by CMR was achieved when all four components were used (86.5 %). Specificity of perfusion (91.8 %), function (93.7 %) and LGE (95.8 %) on its own was significantly better than specificity of the multi-parametric protocol (83.4 %) (all P < 0.0001) but with the penalty of decreased sensitivity (86.5 % vs. 76.9 %, 47.4 % and 40.8 % respectively). The full multi-parametric protocol was the optimum to rule-out significant CAD (Likelihood Ratio negative (LR-) 0.16) and the LGE component alone was the best to rue-in CAD (LR+ 9.81). Overall diagnostic accuracy was similar with the full multi-parametric protocol (85.9 %) compared to paired and triplet combinations. The use of coronary MRA within the full multi-parametric protocol had no additional diagnostic benefit compared to the perfusion/function/LGE combination (overall accuracy 84.6 % vs. 84.2 % (P = 0.5316); LR- 0.16 vs. 0.21; LR+ 5.21 vs. 5.77).

Conclusions

From this pre-specified sub-analysis of the CE-MARC study, the full multi-parametric protocol had the highest sensitivity and was the optimal approach to rule-out significant CAD. The LGE component alone was the optimal rule-in strategy. Finally the inclusion of coronary MRA provided no additional benefit when compared to the combination of perfusion/function/LGE.

Trial registration

Current Controlled Trials ISRCTN77246133     

Midazolam and propofol used alone or sequentially for long-term sedation in critically ill,mechanically ventilated patients: a prospective,randomized study

Introduction

Midazolam and propofol used alone for long-term sedation are associated with adverse effects. Sequential use may reduce the adverse effects, and lead to faster recovery, earlier extubation and lower costs. This study evaluates the effects, safety, and cost of midazolam, propofol, and their sequential use for long-term sedation in critically ill mechanically ventilated patients.

Methods

A total of 135 patients who required mechanical ventilation for >3 days were randomly assigned to receive midazolam (group M), propofol (group P), or sequential use of both (group M-P). In group M-P, midazolam was switched to propofol until the patients passed the spontaneous breathing trial (SBT) safety screen. The primary endpoints included recovery time, extubation time and mechanical ventilation time. The secondary endpoints were pharmaceutical cost, total cost of ICU stay, and recollection to mechanical ventilation-related events.

Results

The incidence of agitation following cessation of sedation in group M-P was lower than group M (19.4% versus 48.7%, P = 0.01). The mean percentage of adequate sedation and duration of sedation were similar in the three groups. The recovery time, extubation time and mechanical ventilation time of group M were 58.0 (interquartile range (IQR), 39.0) hours, 45.0 (IQR, 24.5) hours, and 192.0 (IQR, 124.0) hours, respectively; these were significantly longer than the other groups, while they were similar between the other two groups. In the treatment-received analysis, ICU duration was longer in group M than group M-P (P = 0.016). Using an intention-to-treat analysis and a treatment-received analysis, respectively, the pharmaceutical cost of group M-P was lower than group P (P <0.01) and its ICU cost was lower than group M (P <0.01; P = 0.015). The proportion of group M-P with unbearable memory of the uncomfortable events was lower than in group M (11.7% versus 25.0%, P <0.01), while the proportion with no memory was similar (P >0.05). The incidence of hypotension in group M-P was lower than group (P = 0.01).

Conclusion

Sequential use of midazolam and propofol was a safe and effective sedation protocol, with higher clinical effectiveness and better cost-benefit ratio than midazolam or propofol used alone, for long-term sedation of critically ill mechanically ventilated patients.

Trial registration

Current Controlled Trials ISRCTN01173443. Registered 25 February 2014.     

Mechanism of action of tranexamic acid in bleeding trauma patients: an exploratory analysis of data from the CRASH-2 trial

Introduction

To investigate the mechanism of action of tranexamic acid (TXA) in bleeding trauma patients, we examined the timing of its effect on mortality. We hypothesised that if TXA reduces mortality by decreasing blood loss, its effect should be greatest on the day of the injury when bleeding is most profuse. However, if TXA reduces mortality via an anti-inflammatory mechanism its effect should be greater over the subsequent days.

Methods

Exploratory analysis, including per-protocol analyses, of data from the CRASH-2 trial, a randomised placebo controlled trial of the effect of TXA on mortality in 20,211 trauma patients with, or at risk of, significant bleeding. We examined hazard ratios (HR) and 95% confidence intervals for all-cause mortality, deaths due to bleeding and non-bleeding deaths, according to the day since injury. The CRASH-2 trial is registered as ISRCTN86750102 and ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00375258","term_id":"NCT00375258"}}NCT00375258.

Results

The effect of TXA on mortality is greatest for deaths occurring on the day of the injury (HR all-cause mortality = 0.83, 0.73 to 0.93). This survival benefit is only evident in patients in whom treatment is initiated within 3 hours of their injury (HR ≤3 hours = 0.78, 0.68 to 0.90; HR >3 hours = 1.02, 0.76 to 1.36). Initiation of TXA treatment within 3 hours of injury reduced the hazard of death due to bleeding on the day of the injury by 28% (HR = 0.72, 0.60 to 0.86). TXA treatment initiated beyond 3 hours of injury appeared to increase the hazard of death due to bleeding, although the estimates were imprecise.

Conclusions

Early administration of tranexamic acid appears to reduce mortality primarily by preventing exsanguination on the day of the injury.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-014-0685-8) contains supplementary material, which is available to authorized users.     

Muscle ultrasound for early assessment of critical illness neuromyopathy in severe sepsis

Introduction

Muscle ultrasound is emerging as a promising tool in the diagnosis of neuromuscular diseases. The current observational study evaluates the usefulness of muscle ultrasound in patients with severe sepsis for assessment of critical illness polyneuropathy and myopathy (CINM) in the intensive care unit.

Methods

28 patients with either septic shock or severe sepsis underwent clinical neurological examinations, muscle ultrasound, and nerve conduction studies on days 4 and 14 after onset of sepsis. 26 healthy controls of comparable age underwent clinical neurological evaluation and muscle ultrasound only.

Results

26 of the 28 patients exhibited classic electrophysiological characteristics of CINM, and all showed typical clinical signs. Ultrasonic echogenicity of muscles was graded semiquantitatively and fasciculations were evaluated in muscles of proximal and distal arms and legs. 75% of patients showed a mean echotexture greater than 1.5, which was the maximal value found in the control group. A significant difference in mean muscle echotexture between patients and controls was found at day 4 and day 14 (both p < 0.001). In addition, from day 4 to day 14, the mean grades of muscle echotexture increased in the patient group, although the values did not reach significance levels (p = 0.085). Controls revealed the lowest number of fasciculations. In the patients group, fasciculations were detected in more muscular regions (lower and upper arm and leg) in comparison to controls (p = 0.08 at day 4 and p = 0.002 at day 14).

Conclusions

Muscle ultrasound represents an easily applicable, non-invasive diagnostic tool which adds to neurophysiological testing information regarding morphological changes of muscles early in the course of sepsis. Muscle ultrasound could be useful for screening purposes prior to subjecting patients to more invasive techniques such as electromyography and/or muscle biopsy.

Trial registration

German Clinical Trials Register, DRKS-ID: DRKS00000642.     

The effect of earplugs during the night on the onset of delirium and sleep perception: a randomized controlled trial in intensive care patients

Introduction

This study hypothesised that a reduction of sound during the night using earplugs could be beneficial in the prevention of intensive care delirium. Two research questions were formulated. First, does the use of earplugs during the night reduce the onset of delirium or confusion in the ICU? Second, does the use of earplugs during the night improve the quality of sleep in the ICU?

Methods

A randomized clinical trial included adult intensive care patients in an intervention group of 69 patients sleeping with earplugs during the night and a control group of 67 patients sleeping without earplugs during the night. The researchers were blinded during data collection. Assignment was performed by an independent nurse researcher using a computer program. Eligible patients had an expected length of stay in the ICU of more than 24 hours, were Dutch- or English-speaking and scored a minimum Glasgow Coma Scale of 10. Delirium was assessed using the validated NEECHAM scale, sleep perception was reported by the patient in response to five questions.

Results

The use of earplugs during the night lowered the incidence of confusion in the studied intensive care patients. A vast improvement was shown by a Hazard Ratio of 0.47 (95% confidence interval (CI) 0.27 to 0.82). Also, patients sleeping with earplugs developed confusion later than the patients sleeping without earplugs. After the first night in the ICU, patients sleeping with earplugs reported a better sleep perception.

Conclusions

Earplugs may be a useful instrument in the prevention of confusion or delirium. The beneficial effects seem to be strongest within 48 hours after admission. The relation between sleep, sound and delirium, however, needs further research.

Trial registration

Current Controlled Trials ISRCTN36198138