The spine intra-abdominal pressure (SIAP) trial. A prospective, observational, single arm, monocenter study looking at the evolutions of the IAP prior, during and after spine surgery.

BACKGROUND AND AIMS: Both anaesthesiologists and spine surgeons consider the intra-abdominal pressure (IAP) as an important peri-operative factor affected by patient positioning. We assessed the change in IAP caused by using a thoraco pelvic support (inflatable prone support, IPS) with the subject under general anesthesia. The IAP was measured before, during and immediately after surgery. METHODS: The Spine Intra-Abdominal Pressure study (SIAP trial) is a prospective, single-arm, monocenter, observational study looking at changes in IAP prior, during and after spine surgery. The objective is to assess the change in IAP, measured via an indwelling urinary catheter, using the inflatable prone support (IPS) device during prone positioning of patients in spinal surgery. RESULTS: Forty (40) subjects requiring elective lumbar spine surgery in prone position were enrolled after providing informed consent. The inflation of the IPS results in a significant decrease of IAP (from a median of 9.2 mmHg to 6.46 mmHg (p < 0.001)) in patients undergoing spine surgery in prone position. This decrease in IAP was maintained throughout the procedure despite the discontinuation of muscle relaxants. No serious adverse events or unexpected adverse events occurred. CONCLUSION: The use of the thoraco-pelvic support IPS device was able to significantly lower the IAP during spine surgery.

Necrotizing skin and soft-tissue infections in the intensive care unit.

BACKGROUND: Necrotizing skin and soft-tissue infections (NSTI) are rare but potentially life-threatening and disabling infections that often require intensive care unit admission. OBJECTIVES: To review all aspects of care for a critically ill individual with NSTI. SOURCES: Literature search using Medline and Cochrane library, multidisciplinary panel of experts. CONTENT: The initial presentation of a patient with NSTI can be misleading, as features of severe systemic toxicity can obscure sometimes less impressive skin findings. The infection can spread rapidly, and delayed surgery worsens prognosis, hence there is a limited role for additional imaging in the critically ill patient. Also, the utility of clinical scores is contested. Prompt surgery with aggressive debridement of necrotic tissue is required for source control and allows for microbiological sampling. Also, prompt administration of broad-spectrum antimicrobial therapy is warranted, with the addition of clindamycin for its effect on toxin production, both in empirical therapy, and in targeted therapy for monomicrobial group A streptococcal and clostridial NSTI. The role of immunoglobulins and hyperbaric oxygen therapy remains controversial. IMPLICATIONS: Close collaboration between intensive care, surgery, microbiology and infectious diseases, and centralization of care is fundamental in the approach to the severely ill patient with NSTI. As many aspects of management of these rare infections are supported by low-quality data only, multicentre trials are urgently needed.

Saturable elimination of piperacillin in critically ill patients: implications for continuous infusion.

The study aimed to evaluate saturation of piperacillin elimination in critically ill adult patients. Seventeen critically ill adult patients received continuous and intermittent infusion of piperacillin/tazobactam. Piperacillin plasma concentrations (n = 217) were analysed using population pharmacokinetic (PopPK) modelling. Post-hoc simulations were performed to evaluate the type I error rate associated with the study. Unseen data were used to validate the final model. The mean error (ME) and root mean square error (RMSE) were calculated as a measure of bias and imprecision, respectively. A PopPK model with parallel linear and non-linear elimination best fitted the data. The median and 95% confidence interval (CI) for the model parameters drug clearance (CL), volume of central compartment (V), volume of peripheral compartment (Vp) and intercompartmental clearance (Q) were 9 (7.69-11) L/h, 6.18 (4.93-11.2) L, 11.17 (7.26-12) L and 15.61 (12.66-23.8) L/h, respectively. The Michaelis-Menten constant (Km) and the maximum elimination rate for Michaelis-Menten elimination (Vmax) were estimated without population variability in the model to avoid overfitting and inflation of the type I error rate. The population estimates for Km and Vmax were 37.09 mg/L and 353.57 mg/h, respectively. The bias (ME) was -20.8 (95% CI -26.2 to -15.4) mg/L, whilst imprecision (RMSE) was 49.2 (95% CI 41.2-56) mg/L. In conclusion, piperacillin elimination is (partially) saturable. Moreover, the population estimate for Km lies within the therapeutic window and therefore saturation of elimination should be accounted for when defining optimum dosing regimens for piperacillin in critically ill patients.

Measuring antibiotics in exhaled air in critically ill, non-ventilated patients: A feasibility and proof of concept study.

PURPOSE: Measurement of antibiotic concentrations is increasingly used to optimize antibiotic therapy. Plasma samples are typically used for this, but other matrices such as exhaled air could be an alternative. MATERIALS AND METHODS: We studied 11 spontaneously breathing intensive care unit patients receiving either piperacillin/tazobactam or meropenem. Patients exhaled in the ExaBreath® device, from which the antibiotic was extracted. The presence of antibiotics was also determined in the condensate found in the device and in the plasma. RESULTS: Piperacillin or meropenem could be detected in the filter in 9 patients and in the condensate in 10. Seven patients completed the procedure as prescribed. In these patients the median quantity of piperacillin in the filter was 3083 pg/filter (range 988-203,895 pg/filter), and 45 pg (range 6-126 pg) in the condensate; meropenem quantity was 21,168 pg/filter, but the quantity in the condensate was below the lower limit of quantification. There was no correlation between the concentrations in the plasma and quantities detected in the filter or condensate. CONCLUSIONS: Piperacillin and meropenem can be detected and quantified in exhaled air of non-ventilated intensive care unit patients; these quantities did not correlate with plasma concentrations of these drugs.

Erratum to: Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA).

[This corrects the article DOI: 10.1186/s13017-016-0089-y.].

The role of infection models and PK/PD modelling for optimising care of critically ill patients with severe infections.

Critically ill patients with severe infections are at high risk of suboptimal antimicrobial dosing. The pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in these patients differ significantly from the patient groups from whose data the conventional dosing regimens were developed. Use of such regimens often results in inadequate antimicrobial concentrations at the site of infection and is associated with poor patient outcomes. In this article, we describe the potential of in vitro and in vivo infection models, clinical pharmacokinetic data and pharmacokinetic/pharmacodynamic models to guide the design of more effective antimicrobial dosing regimens. Individualised dosing, based on population PK models and patient factors (e.g. renal function and weight) known to influence antimicrobial PK, increases the probability of achieving therapeutic drug exposures while at the same time avoiding toxic concentrations. When therapeutic drug monitoring (TDM) is applied, early dose adaptation to the needs of the individual patient is possible. TDM is likely to be of particular importance for infected critically ill patients, where profound PK changes are present and prompt appropriate antibiotic therapy is crucial. In the light of the continued high mortality rates in critically ill patients with severe infections, a paradigm shift to refined dosing strategies for antimicrobials is warranted to enhance the probability of achieving drug concentrations that increase the likelihood of clinical success.

Amended Classification of the Open Abdomen.

BACKGROUND: In 2009, a classification system for the open abdomen was introduced. The aim of such a classification is to aid the (1) description of the patient's clinical course; (2) standardization of clinical guidelines for guiding open abdomen management; and (3) facilitation of comparisons between studies and heterogeneous patient populations, thus serving as an aid in clinical research. METHODS: As part of the revision of the definitions and clinical guidelines performed by the World Society of the Abdominal Compartment Syndrome, this 2009 classification system was amended following a review of experiences in teaching and research and published as part of updated consensus statements and clinical practice guidelines in 2013. Among 29 articles citing the 2009 classification system, nine were cohort studies. They were reviewed as part of the classification revision process. A total of 542 patients (mean: 60, range: 9-160) had been classified. Two problems with the previous classification system were identified: the definition of enteroatmospheric fistulae, and that an enteroatmospheric fistula was graded less severe than a frozen abdomen. RESULTS: The following amended classification was proposed: Grade 1, without adherence between bowel and abdominal wall or fixity of the abdominal wall (lateralization), subdivided as follows: 1A, clean; 1B, contaminated; and 1C, with enteric leak. An enteric leak controlled by closure, exteriorization into a stoma, or a permanent enterocutaneous fistula is considered clean. Grade 2, developing fixation, subdivided as follows: 2A, clean; 2B, contaminated; and 2C, with enteric leak. Grade 3, frozen abdomen, subdivided as follows: 3A clean and 3B contaminated. Grade 4, an established enteroatmospheric fistula, is defined as a permanent enteric leak into the open abdomen, associated with granulation tissue. CONCLUSIONS: The authors believe that, with these changes, the requirements on a functional and dynamic classification system, useful in both research and training, will be fulfilled. We encourage future investigators to apply the system and report on its merits and constraints.

Decompressive laparotomy for abdominal compartment syndrome.

BACKGROUND: The effect of decompressive laparotomy on outcomes in patients with abdominal compartment syndrome has been poorly investigated. The aim of this prospective cohort study was to describe the effect of decompressive laparotomy for abdominal compartment syndrome on organ function and outcomes. METHODS: This was a prospective cohort study in adult patients who underwent decompressive laparotomy for abdominal compartment syndrome. The primary endpoints were 28-day and 1-year all-cause mortality. Changes in intra-abdominal pressure (IAP) and organ function, and laparotomy-related morbidity were secondary endpoints. RESULTS: Thirty-three patients were included in the study (20 men). Twenty-seven patients were surgical admissions treated for abdominal conditions. The median (i.q.r.) Acute Physiology And Chronic Health Evaluation (APACHE) II score was 26 (20-32). Median IAP was 23 (21-27) mmHg before decompressive laparotomy, decreasing to 12 (9-15), 13 (8-17), 12 (9-15) and 12 (9-14) mmHg after 2, 6, 24 and 72 h. Decompressive laparotomy significantly improved oxygenation and urinary output. Survivors showed improvement in organ function scores, but non-survivors did not. Fourteen complications related to the procedure developed in eight of the 33 patients. The abdomen could be closed primarily in 18 patients. The overall 28-day mortality rate was 36 per cent (12 of 33), which increased to 55 per cent (18 patients) at 1 year. Non-survivors were no different from survivors, except that they tended to be older and on mechanical ventilation. CONCLUSION: Decompressive laparotomy reduced IAP and had an immediate effect on organ function. It should be considered in patients with abdominal compartment syndrome.

Epidemiology of augmented renal clearance in mixed ICU patients.

BACKGROUND: Augmented renal clearance (ARC) or renal hyperfiltration is increasingly reported in intensive care unit (ICU) patients. The goal of this analysis was to study the epidemiology of ARC in a cohort of mixed ICU patients METHODS: Single center retrospective cohort study of adult ICU patients (12/2008-2/2010). When data were available, urinary creatinine clearance (CLCR) was calculated for all patients throughout their ICU stay. ARC was defined as a body surface adjusted CLCR≥130 mL/min/1.73m2. We sought to study the incidence of ARC and identify patient characteristics associated with ARC. RESULTS: A total of 1081 patients were included in the analysis, generating 4472 ICU patient days. Median age was 62 y (IQR 50-72), and 63% were male. The initial CLCR was 86 (39-151) mL/min and the maximal CLCR was 145 (76-237) mL/min. ARC occurred in 55.8% of patients, and was about as frequent in men and women (37%% vs. 35%%, P=0.73). Patients with ARC were younger (57 vs. 67 years, P<0.001) and were less frequently treated with vasopressors (27% vs. 39%, P<0.01). ARC incidence was 36.6 ARC days per 100 ICU days. ARC throughout the ICU stay occurred in 32.8% of patients. CONCLUSION: ARC was a frequent finding in this cohort of ICU patients, with more than half of the patient expressing ARC at least once during their ICU stay, and an incidence of 36.6 ARC days/100 patient days.

Stability of generic brands of meropenem reconstituted in isotonic saline.

BACKGROUND: Meropenem is a relatively unstable compound when dissolved. Currently, all available data have been derived from tests on the original product from Astrazeneca, and it is unsure if these data can be extrapolated to the stability of other commercially available vials. The aim of this study was therefore to assess the stability of four different brands of meropenem to be used as a prolonged or continuous infusion. METHODS: Commercially available meropenem vials were reconstituted and mixed with 0.9% sodium chloride to produce solutions with concentrations of 10.20 and 40 mg/mL in polypropylene syringes, which were kept at 25 °C. Samples were taken immediately after preparation and up to 12 hours. Solutions retaining >90% of the initial concentration were considered stable. RESULTS: The stability was concentration-dependent. At 25 °C, all 10 and 20 mg/mL solutions were stable for 12 hours in 0.9% sodium chloride, while the 40 mg/mL solutions were stable for a maximum of 8 hours. Stability of the different vials of meropenem was comparable for the time period tested (related samples Friedman's two way of analysis of variance by ranks, P=0.282). CONCLUSION: All tested commercially available vials of meropenem in a concentration of 10 and 20 mg/mL were stable for 12 hours at 25 °C when diluted in 0.9% sodium chloride. The 40 mg/mL solutions were stable for a maximum of 8 hours. This report is the first to show equivalent stability between different commercially available vials of meropenem.

Variability in protein binding of teicoplanin and achievement of therapeutic drug monitoring targets in critically ill patients: lessons from the DALI Study.

The aims of this study were to describe the variability in protein binding of teicoplanin in critically ill patients as well as the number of patients achieving therapeutic target concentrations. This report is part of the multinational pharmacokinetic DALI Study. Patients were sampled on a single day, with blood samples taken both at the midpoint and the end of the dosing interval. Total and unbound teicoplanin concentrations were assayed using validated chromatographic methods. The lower therapeutic range of teicoplanin was defined as total trough concentrations from 10 to 20 mg/L and the higher range as 10-30 mg/L. Thirteen critically ill patients were available for analysis. The following are the median (interquartile range) total and free concentrations (mg/L): midpoint, total 13.6 (11.2-26.0) and free 1.5 (0.7-2.5); trough, total 11.9 (10.2-22.7) and free 1.8 (0.6-2.6). The percentage free teicoplanin for the mid-dose and trough time points was 6.9% (4.5-15.6%) and 8.2% (5.5-16.4%), respectively. The correlation between total and free antibiotic concentrations was moderate for both the midpoint (ρ = 0.79, P = 0.0021) and trough (ρ = 0.63, P = 0.027). Only 42% and 58% of patients were in the lower and higher therapeutic ranges, respectively. In conclusion, use of standard dosing for teicoplanin leads to inappropriate concentrations in a high proportion of critically ill patients. Variability in teicoplanin protein binding is very high, placing significant doubt on the validity of total concentrations for therapeutic drug monitoring in critically ill patients.

Aminoglycosides for life-threatening infections: a plea for an individualized approach using intensive therapeutic drug monitoring.

Aminoglycosides are potent antibiotics with a renewed interest due to the increase in multidrug resistant infections. Their use in life-threatening infections ­ in combination with other antibiotics ­ has been debated due to the lack of clear outcome benefits. However, based on recent pharmacokinetic-pharmacodynamic studies, conventional dosing may be inefficient in a considerable number of patients, which could preclude the efficiency of this potent drug class. Toxicity on the other hand remains a concern, with nephrotoxicity as the most relevant negative effect in the critically ill. Short term, intensively monitored treatment strategies - with monitoring both peak and trough levels - may increase efficacy as well as reduce toxicity in the critically ill patient.

Factors associated with inadequate early vancomycin levels in critically ill patients treated with continuous infusion.

Vancomycin administration using a loading dose and continuous infusion (CI) results in more rapid attainment of adequate concentrations. The aim of this retrospective study of ICU patients receiving vancomycin was to determine the efficacy of a vancomycin dosing protocol using a weight-based loading dose and to identify factors associated with inadequate concentrations. Patients received a loading dose (<65 kg, 1000 mg; ≥65 kg, 1500 mg), and 2000 mg/24 h CI with subsequent dose adaptation. Adequate levels were defined as concentrations ≥15 mg/L. In total, 227 patients (154 males) were included in the study (mean age 56.5 ± 16.1 years; mean APACHE II score 19.30 ± 7.7). The mean loading dose was 1129 ± 369 mg (15.07 ± 4.99 mg/kg). The dosing protocol was applied in 126 patients (55.5%). Mean vancomycin levels were 19.32 mg/L and 21.08 mg/L on Days 2 and 3, respectively. Vancomycin levels on Day 2 were adequate in 70.5% of patients, increasing to 84.1% on Day 3. Patients who received an appropriate loading dose more often had adequate vancomycin levels on Day 2. Older age, female sex, higher creatinine concentration, lower body temperature and use of a loading dose according to the vancomycin dosing protocol were independently associated with adequate vancomycin levels. A weight-based loading dose plus CI of vancomycin resulted in adequate concentrations in most patients and was superior compared with a non-standardised loading dose. Some patients may require higher doses, and factors other than weight, such as kidney function, age and sex, play a role.

Randomised clinical trial of moxifloxacin versus ertapenem in complicated intra-abdominal infections: results of the PROMISE study.

Antibiotic therapy for complicated intra-abdominal infections (cIAIs) should provide broad-spectrum coverage both Gram-positive and Gram-negative microorganisms. The PROMISE study compared the clinical and bacteriological efficacy and safety of moxifloxacin versus ertapenem for the treatment of cIAIs. This randomised, prospective, double-dummy, double-blind, multicentre trial was designed as a non-inferiority study. The safety and efficacy of 5-14 days of daily intravenous moxifloxacin (400mg) or ertapenem (1g) were compared in patients with cIAIs requiring surgery and parenteral antibiotic therapy. The primary and secondary endpoints included clinical and bacteriological responses at 21-28 days after the end of treatment (TOC), respectively. Of 830 enrolled patients, 699 were efficacy valid. Moxifloxacin was non-inferior to ertapenem regarding clinical success [89.5% (315/352) versus 93.4% (324/347); 95% confidence interval (CI) -7.9%, 0.4%]. There were no significant differences between groups for any of the primary causes or types of cIAI regarding clinical response. Bacteriological success was achieved in 86.5% (257/297) of moxifloxacin-treated patients and 90.2% (249/276) of ertapenem-treated patients (95% CI -9.0%, 1.5%). There were no major differences between groups regarding the frequency or types of organisms eradicated. The incidence of adverse events (AEs) was higher with moxifloxacin than ertapenem (P=0.039), however a similar number of drug-related AEs was seen in each group (P=1.000). Wound infections, nausea and increased lipase were the most commonly reported AEs with both agents. The results show that moxifloxacin is a valuable treatment option for a range of community-acquired cIAIs with mild-to-moderate severity.

Determinants of prescription and choice of empirical therapy for hospital-acquired and ventilator-associated pneumonia.

The objectives of this study were to assess the determinants of empirical antibiotic choice, prescription patterns and outcomes in patients with hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) in Europe. We performed a prospective, observational cohort study in 27 intensive care units (ICUs) from nine European countries. 100 consecutive patients on mechanical ventilation for HAP, on mechanical ventilation>48 h or with VAP were enrolled per ICU. Admission category, sickness severity and Acinetobacter spp. prevalence>10% in pneumonia episodes determined antibiotic empirical choice. Trauma patients were more often prescribed non-anti-Pseudomonas cephalosporins (OR 2.68, 95% CI 1.50-4.78). Surgical patients received less aminoglycosides (OR 0.26, 95% CI 0.14-0.49). A significant correlation (p<0.01) was found between Simplified Acute Physiology Score II score and carbapenem prescription. Basal Acinetobacter spp. prevalence>10% dramatically increased the prescription of carbapenems (OR 3.5, 95% CI 2.0-6.1) and colistin (OR 115.7, 95% CI 6.9-1,930.9). Appropriate empirical antibiotics decreased ICU length of stay by 6 days (26.3±19.8 days versus 32.8±29.4 days; p=0.04). The antibiotics that were prescribed most were carbapenems, piperacillin/tazobactam and quinolones. Median (interquartile range) duration of antibiotic therapy was 9 (6-12) days. Anti-methicillin-resistant Staphylococcus aureus agents were prescribed in 38.4% of VAP episodes. Admission category, sickness severity and basal Acinetobacter prevalence>10% in pneumonia episodes were the major determinants of antibiotic choice at the bedside. Across Europe, carbapenems were the antibiotic most prescribed for HAP/VAP.

Necrotizing fasciitis complicated by fatal multiple organ dysfunction due to Pasteurella multocida infection: a case report.

Necrotizing fasciitis is rarely caused by Pasteurella multocida, a facultative anaerobic gram-negative coccobacillus found in the flora of the oro-gastrointestinal tract of many animals. We describe a rare case with overwhelming septicaemia resulting in multiple organ failure.