Procalcitonin-guided antibiotic therapy may shorten length of treatment and may improve survival-a systematic review and meta-analysis.

BACKGROUND: Appropriate antibiotic (AB) therapy remains a challenge in the intensive care unit (ICU). Procalcitonin (PCT)-guided AB stewardship could help optimize AB treatment and decrease AB-related adverse effects, but firm evidence is still lacking. Our aim was to compare the effects of PCT-guided AB therapy with standard of care (SOC) in critically ill patients. METHODS: We searched databases CENTRAL, Embase and Medline. We included randomized controlled trials (RCTs) comparing PCT-guided AB therapy (PCT group) with SOC reporting on length of AB therapy, mortality, recurrent and secondary infection, ICU length of stay (LOS), hospital LOS or healthcare costs. Due to recent changes in sepsis definitions, subgroup analyses were performed in studies applying the Sepsis-3 definition. In the statistical analysis, a random-effects model was used to pool effect sizes. RESULTS: We included 26 RCTs (n = 9048 patients) in the quantitative analysis. In comparison with SOC, length of AB therapy was significantly shorter in the PCT group (MD - 1.79 days, 95% CI: -2.65, - 0.92) and was associated with a significantly lower 28-day mortality (OR 0.84, 95% CI: 0.74, 0.95). In Sepsis-3 patients, mortality benefit was more pronounced (OR 0.46 95% CI: 0.27, 0.79). Odds of recurrent infection were significantly higher in the PCT group (OR 1.36, 95% CI: 1.10, 1.68), but there was no significant difference in the odds of secondary infection (OR 0.81, 95% CI: 0.54, 1.21), ICU and hospital length of stay (MD - 0.67 days 95% CI: - 1.76, 0.41 and MD - 1.23 days, 95% CI: - 3.13, 0.67, respectively). CONCLUSIONS: PCT-guided AB therapy may be associated with reduced AB use, lower 28-day mortality but higher infection recurrence, with similar ICU and hospital length of stay. Our results render the need for better designed studies investigating the role of PCT-guided AB stewardship in critically ill patients.

Effects of goal-directed crystalloid vs. colloid fluid therapy on microcirculation during free flap surgery: A randomised clinical trial.

BACKGROUND: Macro, and microcirculatory effects of crystalloids and colloids are difficult to compare, because interventions to achieve haemodynamic stability seldom follow similar criteria. OBJECTIVES: Our aim was to compare the effects of crystalloids and colloids on the microcirculation during free flap surgery when management was guided by detailed haemodynamic assessment. DESIGN: A randomised, controlled clinical trial. SETTINGS: The investigation was performed at the University of Szeged, Hungary. PATIENTS: Patients undergoing maxillofacial tumour resection and free flap reconstruction were randomised into groups treated with either intra-operative crystalloid (Ringerfundin, n = 15) or colloid (6% hydroxyethyl starch, HES, n = 15) solutions. INTERVENTIONS: Macrohaemodynamics were monitored by a noncalibrated device (PulsioFlex-PULSION). Central venous oxygen saturation, venous-to-arterial PCO2-gap, lactate levels and urine output were measured hourly. Maintenance fluid was Ringerfundin (1 ml kg h), and a multimodal, individualised, approach-based algorithm was applied to guide haemodynamic support. Hypovolaemia was treated with Ringerfundin or HES fluid boluses, respectively. The microcirculatory effects were assessed by laser-Doppler flowmetry (PeriFlux 5000 LDPM), with the probe placed on the flap and on a control area. Measurements were performed after the flap was prepared, then 1 and 12 h later. MAIN OUTCOME MEASURES: The primary end-point was microcirculatory perfusion as determined by laser-Doppler flowmetry. RESULTS: There was no difference between the groups regarding patient characteristics. Both groups remained haemodynamically stable throughout due to the use of approximately a 1.5 times higher total fluid volume in the Ringerfundin group than in the HES group: mean ±â€ŠSD: 2581 ±â€Š986 and 1803 ±â€Š497) ml, respectively, (P = 0.011). There was no significant difference in the microcirculatory blood flow between the groups. CONCLUSION: Our results showed that when fluid management was guided by detailed haemodynamic assessment, more crystalloid than colloid was needed to maintain haemodynamic stability, but there was no difference between the effects of crystalloids and colloids on the microcirculation. TRIAL REGISTRATION: ClinicalTrials.gov NCT03288051.

Extracorporeal cytokine adsorption in septic shock: A proof of concept randomized, controlled pilot study.

BACKGROUND: The aim of this proof of concept, prospective, randomized pilot trial was to investigate the effects of extracorporeal cytokine removal (CytoSorb®) applied as a standalone treatment in patients with septic shock. METHODS: 20 patients with early (<24 h) onset of septic shock of medical origin, on mechanical ventilation, norepinephrine>10 µg/min, procalcitonin (PCT) > 3 ng/mL without the need for renal replacement therapy were randomized into CytoSorb (n = 10) and Control groups (n = 10). CytoSorb therapy lasted for 24 h. Clinical and laboratory data were recorded at baseline (T0), T12, T24, and T48 hours. RESULTS: Overall SOFA scores did not differ between the groups. In the CytoSorb-group norepinephrine requirements and PCT concentration decreased significantly (norepinephrine: CytoSorb: T0 = 0.54[IQR:0.20-1.22], T48 = 0.16[IQR:0.07-0.48], p = .016; Controls: T0 = 0.43[IQR:0.19-0.64], T48 = 0.25[IQR:0.08-0.65] µg/kg/min; PCT: CytoSorb: T0 median = 20.6[IQR: 6.5-144.5], T48 = 5.6[1.9-54.4], p = .004; Control: T0 = 13.2[7.6-47.8], T48 = 9.2[3.8-44.2]ng/mL). Big-endothelin-1 concentrations were also significantly lower in the CytoSorb group (CytoSorb: T0 = 1.3 ±â€¯0.6, *T24 = 1.0 ±â€¯0.4, T48 = 1.4 ±â€¯0.8, *p = .003; Control: T0 = 1.1 ±â€¯0.7, T24 = 1.1 ±â€¯0.6, T48 = 1.2 ±â€¯0.6 pmol/L, p = .115). There were no CytoSorb therapy-related adverse events. CONCLUSIONS: This is the first trial to investigate the effects of early extracorporeal cytokine adsorption treatment in septic shock applied without renal replacement therapy. It was found to be safe with significant effects on norepinephrine requirements, PCT and Big-endothelin-1 concentrations compared to controls. TRIAL REGISTRATION: The study has been registered on ClinicalTrials.gov, under the registration number of NCT02288975, registered 13 November 2014.

Procalcitonin - Assisted Antibiotic Strategy in Sepsis.

Sepsis is one of the biggest challenges in critical care nowadays. Defining sepsis is a difficult task on its own and its diagnosis and treatment requires well trained, devoted personnel with interdisciplinary collaboration in order to provide the patients the best chance for survival. Immediate resuscitation, early adequate antimicrobial therapy, source control and highly sophisticated organ support on the intensive care units are all inevitable necessities for successful recovery. To help fast and accurate diagnosis biomarkers have been measured for decades. Procalcitonin (PCT) is one of the most studied, but the results are conflicting. Sepsis means a very loose cohort of a large heterogeneous patient population, hence defining certain cut off values for PCT to differentiate between different severities of the disease is almost impossible. Clinicians first have to understand the pathophysiological background of sepsis to be able to interpret correctly the PCT results. Nevertheless, PCT has been shown to have the best sensitivity and specificity to indicate infection, antibiotic appropriateness and stopping therapy. In this article we will focus on some important aspects of pathophysiology and advice on how to implement that in the everyday clinical practice. We believe that this multimodal evaluation of the clinical picture together with PCT results can be a useful tool to make the most out of the PCT results, and do the best for patients on the ICU.

Delta Procalcitonin Is a Better Indicator of Infection Than Absolute Procalcitonin Values in Critically Ill Patients: A Prospective Observational Study.

Purpose. To investigate whether absolute value of procalcitonin (PCT) or the change (delta-PCT) is better indicator of infection in intensive care patients. Materials and Methods. Post hoc analysis of a prospective observational study. Patients with suspected new-onset infection were included in whom PCT, C-reactive protein (CRP), temperature, and leukocyte (WBC) values were measured on inclusion (t 0) and data were also available from the previous day (t -1). Based on clinical and microbiological data, patients were grouped post hoc into infection- (I-) and noninfection- (NI-) groups. Results. Of the 114 patients, 85 (75%) had proven infection. PCT levels were similar at t -1: I-group (median [interquartile range]): 1.04 [0.40-3.57] versus NI-group: 0.53 [0.16-1.68], p = 0.444. By t 0 PCT levels were significantly higher in the I-group: 4.62 [1.91-12.62] versus 1.12 [0.30-1.66], p = 0.018. The area under the curve to predict infection for absolute values of PCT was 0.64 [95% CI = 0.52-0.76], p = 0.022; for percentage change: 0.77 [0.66-0.87], p < 0.001; and for delta-PCT: 0.85 [0.78-0.92], p < 0.001. The optimal cut-off value for delta-PCT to indicate infection was 0.76 ng/mL (sensitivity 80 [70-88]%, specificity 86 [68-96]%). Neither absolute values nor changes in CRP, temperature, or WBC could predict infection. Conclusions. Our results suggest that delta-PCT values are superior to absolute values in indicating infection in intensive care patients. This trial is registered with ClinicalTrials.gov identifier: NCT02311816.

Early procalcitonin kinetics and appropriateness of empirical antimicrobial therapy in critically ill patients: A prospective observational study.

PURPOSE: The purpose was to investigate the value of procalcitonin (PCT) kinetics in predicting the appropriateness of empirical antimicrobial treatment in critically ill patients. MATERIALS AND METHODS: This prospective observational study recruited patients in whom empirical antimicrobial therapy was started for suspected infection. Biochemical and physiological parameters were measured before initiating antimicrobials (t0), 8 hourly (t8, t16, t24), and then daily (day2-6). Patients were grouped post hoc into appropriate (A) and inappropriate (IA) groups. RESULTS: Of 209 patients, infection was confirmed in 67%. Procalcitonin kinetics were different between the IA (n = 33) and A groups (n = 108). In the IA group, PCT levels (median [interquartile range]) increased: t0= 2.8 (1.2-7.4), t16= 8.6 (4.8-22.1), t24= 14.5 (4.9-36.1), P< .05. In the A group, PCT peaked at t16 and started to decrease by t24: t0= 4.2 (1.9-12.8), t16= 6.99 (3.4-29.1), t24= 5.2 (2.0-16.7), P< .05. Receiver operating characteristic analysis revealed that a PCT elevation greater than or equal to 69% from t0 to t16 had an area under the curve for predicting inappropriate antimicrobial treatment of 0.73 (95% confidence interval, 0.63-0.83), P< .001; from t0 to t24, a greater than or equal to 74% increase had an area under the curve of 0.86 (0.77-0.94), P< .001. Hospital mortality was 37% in the A group and 61% in the IA group (P= .017). CONCLUSIONS: Early response of PCT in the first 24 hours of commencing empirical antimicrobials in critically ill patients may help the clinician to evaluate the appropriateness of therapy.

Goal-Directed Resuscitation Aiming Cardiac Index Masks Residual Hypovolemia: An Animal Experiment.

The aim of this study was to compare stroke volume (SVI) to cardiac index (CI) guided resuscitation in a bleeding-resuscitation experiment. Twenty six pigs were randomized and bled in both groups till baseline SVI (T bsl) dropped by 50% (T 0), followed by resuscitation with crystalloid solution until initial SVI or CI was reached (T 4). Similar amount of blood was shed but animals received significantly less fluid in the CI-group as in the SVI-group: median = 900 (interquartile range: 850-1780) versus 1965 (1584-2165) mL, p = 0.02, respectively. In the SVI-group all variables returned to their baseline values, but in the CI-group animals remained underresuscitated as indicated by SVI, heart rate (HR) and stroke volume variation (SVV), and central venous oxygen saturation (ScvO2) at T 4 as compared to T bsl: SVI = 23.8 ± 5.9 versus 31.4 ± 4.7 mL, HR: 117 ± 35 versus 89 ± 11/min SVV: 17.4 ± 7.6 versus 11.5 ± 5.3%, and ScvO2: 64.1 ± 11.6 versus 79.2 ± 8.1%, p < 0.05, respectively. Our results indicate that CI-based goal-directed resuscitation may result in residual hypovolaemia, as bleeding caused stress induced tachycardia "normalizes" CI, without restoring adequate SVI. As the SVI-guided approach normalized most hemodynamic variables, we recommend using SVI instead of CI as the primary goal of resuscitation during acute bleeding.

Sepsis: From Pathophysiology to Individualized Patient Care.

Sepsis has become a major health economic issue, with more patients dying in hospitals due to sepsis related complications compared to breast and colorectal cancer together. Despite extensive research in order to improve outcome in sepsis over the last few decades, results of large multicenter studies were by-and-large very disappointing. This fiasco can be explained by several factors, but one of the most important reasons is the uncertain definition of sepsis resulting in very heterogeneous patient populations, and the lack of understanding of pathophysiology, which is mainly based on the imbalance in the host-immune response. However, this heroic research work has not been in vain. Putting the results of positive and negative studies into context, we can now approach sepsis in a different concept, which may lead us to new perspectives in diagnostics and treatment. While decision making based on conventional sepsis definitions can inevitably lead to false judgment due to the heterogeneity of patients, new concepts based on currently gained knowledge in immunology may help to tailor assessment and treatment of these patients to their actual needs. Summarizing where we stand at present and what the future may hold are the purpose of this review.

Continuous central venous oxygen saturation assisted intraoperative hemodynamic management during major abdominal surgery: a randomized, controlled trial.

BACKGROUND: Major abdominal surgery is associated with significant risk of morbidity and mortality in the perioperative period. Optimising intraoperative fluid administration may result in improved outcomes. Our aim was to compare the effects of central venous pressure (CVP), and central venous oxygen saturation (ScvO2)-assisted fluid therapy on postoperative complications in patients undergoing high risk surgery. METHODS: Patients undergoing elective major abdominal surgery were randomised into control and ScvO2 groups. The target level of mean arterial pressure (MAP) was ≥ 60 mmHg in both groups. In cases of MAP < 60 mmHg patients received either a fluid or vasopressor bolus according to the CVP < 8 mmHg in the control group. In the ScvO2 group, in addition to the MAP, an ScvO2 of <75% or a >3% decrease indicated need for intervention, regardless of the actual MAP. Data are presented as mean ± standard deviation or median (interquartile range). RESULTS: We observed a lower number of patients with complications in the ScvO2 group compared to the control group, however it did not reach statistical significance (ScvO2 group: 10 vs. CONTROL GROUP: 19; p = 0.07). Patients in the ScvO2 group (n = 38) received more colloids compared to the control group (n = 41) [279(161) vs. 107(250) ml/h; p < 0.001]. Both groups received similar amounts of crystalloid (1126 ± 471 vs. 1049 ± 431 ml/h; p = 0.46) and norepinephrine [37(107) vs. 18(73) mcg/h; p = 0.84]. Despite similar blood loss in both groups, the ScvO2 group received more blood transfusions (63% vs. 37%; p = 0.018). More patients in the control group had a postoperative PaO2/FiO2 < 200 mmHg (23 vs. 10, p < 0.01). Twenty eight day survival was significantly higher in the ScvO2 group (37/38 vs. 33/41 p = 0.018). CONCLUSION: ScvO2-assisted intraoperative haemodynamic support provided some benefits, including significantly better postoperative oxygenation and 28 day survival rate, compared to CVP-assisted therapy without a significant effect on postoperative complications during major abdominal surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT02337010.

Lung recruitment can improve oxygenation in patients ventilated in continuous positive airway pressure/pressure support mode.

BACKGROUND: Recruitment maneuvers are often used in critical care patients with hypoxemic respiratory failure. Although continuous positive airway pressure/pressure support (CPAP/PS) ventilation is a frequently used approach, but whether lung recruitment also improves oxygenation in spontaneously breathing patients has not been investigated yet. The primary objective was to analyze the effect of recruitment maneuver on oxygenation in patients ventilated in CPAP/PS mode. METHODS: Following baseline measurements PEEP was increased by 5 cmH2O. Recruitment maneuver was applied for 40 s with 40 cmH2O of PS. Measurements of the difference in PaO2/FiO2 and airway parameters measured by the ventilator were recorded immediately after recruitment then 15 and 30 min later. Thirty patients ventilated in CPAP/PS mode with a PEEP ≥5 cmH2O were enrolled in this prospective, observational study if their PaO2/FiO2 ratio was <300 mmHg or required an FiO2 >0.5. RESULTS: Following recruitment maneuver patients were considered as non-responders (NR, n = 15) if difference of PaO2/FiO2 <20% and responders (R, n = 15) if difference of PaO2/FiO2 ≥20%. In the NR-group, PaO2/FiO2 decreased non-significantly from baseline: median [interquartile], PaO2/FiO2 = 176 [120-186] vs. after recruitment: 169 [121-182] mmHg, P = 0.307 while in the R-group there was significant improvement: 139 [117-164] vs. 230 [211-323] mmHg, P = 0.01. At the same time points, dead space to tidal volume ratio (Vds/Vte) significantly increased in the NR-group Vds/Vte = 32 [27-37] vs. 36 [25-42]%, P = 0.013 but no significant change was observed in the R-group: 26 [22-34] vs. 27 [24-33]%, P = 0.386. CONCLUSION: Recruitment maneuver improved PaO2/FiO2 ratio by ≥20% in 50% of patients ventilated in CPAP/PS mode.

Preconditioning with volatile anaesthetic sevoflurane in ischemic retinal lesion in rats.

Volatile anaesthetic agents have been recognized for their neuroprotective properties since the 1960s. However, little is known regarding the potential retinoprotective effects of preconditioning by anaesthetic drugs. Retinal ischemia can be modeled by permanent bilateral common carotid artery occlusion (BCCAO). Here we studied the degree of ischemic injury with preconditioning by sevoflurane in the rat retina. During the BCCAO operation and preconditioning Wistar rats were anaesthetized with 1 MAC of sevoflurane. The oxygen, carbon dioxide, and anaesthetic vapor concentration in the anaesthetizing box was monitored with a gas analyzer. We examined 4 groups: non- and preconditioning groups in control and BCCAO animals. The duration of preconditioning period was 1 h and it was performed 1 day before BCCAO. The retinas were processed for histological evaluation after 2 weeks survival to determine the cell number in the ganglion cell layer and the thickness of the whole retina and that of all retinal layers. BCCAO-induced retinal ischemic injury was ameliorated by sevoflurane preconditioning. Retinal thickness and the cell number in the ganglion cell layer were more retained in preconditioned animals after BCCAO compared to non-preconditioned group. These results suggest that preconditioning using sevoflurane could provide a new perspective in retinoprotective strategies.