Sex dependence of postoperative pulmonary complications - A post hoc unmatched and matched analysis of LAS VEGAS.

STUDY OBJECTIVE: Male sex has inconsistently been associated with the development of postoperative pulmonary complications (PPCs). These studies were different in size, design, population and preoperative risk. We reanalysed the database of 'Local ASsessment of Ventilatory management during General Anaesthesia for Surgery study' (LAS VEGAS) to evaluate differences between females and males with respect to PPCs. DESIGN, SETTING AND PATIENTS: Post hoc unmatched and matched analysis of LAS VEGAS, an international observational study in patients undergoing intraoperative ventilation under general anaesthesia for surgery in 146 hospitals across 29 countries. The primary endpoint was a composite of PPCs in the first 5 postoperative days. Individual PPCs, hospital length of stay and mortality were secondary endpoints. Propensity score matching was used to create a similar cohort regarding type of surgery and epidemiological factors with a known association with development of PPCs. MAIN RESULTS: The unmatched cohort consisted of 9697 patients; 5342 (55.1%) females and 4355 (44.9%) males. The matched cohort consisted of 6154 patients; 3077 (50.0%) females and 3077 (50.0%) males. The incidence in PPCs was neither significant between females and males in the unmatched cohort (10.0 vs 10.7%; odds ratio (OR) 0.93 [0.81-1.06]; P = 0.255), nor in the matched cohort (10.5 vs 10.0%; OR 1.05 [0.89-1.25]; P = 0.556). New invasive ventilation occurred less often in females in the unmatched cohort. Hospital length of stay and mortality were similar between females and males in both cohorts. CONCLUSIONS: In this conveniently-sized worldwide cohort of patients receiving intraoperative ventilation under general anaesthesia for surgery, the PPC incidence was not significantly different between sexes. REGISTRATION: LAS VEGAS was registered at clinicaltrial.gov (study identifier NCT01601223).

[Prone positioning for acute respiratory distress syndrome in adults : Update on the physiological effects, indications and implementation]. / Bauchlagerung beim akuten Lungenversagen des Erwachsenen : Update zu den physiologischen Effekten, den Indikationen und der Durchführung.

The prone position is an immediately available and easily implemented procedure that was introduced more than 50 years ago as a method for improvement of gas exchange in patients with acute respiratory distress syndrome (ARDS). In the meantime, a survival advantage could also be shown in patients with severe ARDS, which led to the recommendation of the prone position for treatment of severe ARDS by expert consensus and specialist society guidelines. The continuing coronavirus disease 2019 (COVID-19) pandemic moved the prone position to the forefront of medicine, including the widespread implementation of the prone position for awake, spontaneously breathing nonintubated patients with acute hypoxemic respiratory insufficiency. The survival advantage is possible due to a reduction of the ventilator-associated lung damage. In this article, the physiological effects, data on clinical results, practical considerations and open questions with respect to the prone position are discussed.

Guideline on positioning and early mobilisation in the critically ill by an expert panel.

A scientific panel was created consisting of 23 interdisciplinary and interprofessional experts in intensive care medicine, physiotherapy, nursing care, surgery, rehabilitative medicine, and pneumology delegated from scientific societies together with a patient representative and a delegate from the Association of the Scientific Medical Societies who advised methodological implementation. The guideline was created according to the German Association of the Scientific Medical Societies (AWMF), based on The Appraisal of Guidelines for Research and Evaluation (AGREE) II. The topics of (early) mobilisation, neuromuscular electrical stimulation, assist devices for mobilisation, and positioning, including prone positioning, were identified as areas to be addressed and assigned to specialist expert groups, taking conflicts of interest into account. The panel formulated PICO questions (addressing the population, intervention, comparison or control group as well as the resulting outcomes), conducted a systematic literature review with abstract screening and full-text analysis and created summary tables. This was followed by grading the evidence according to the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence and a risk of bias assessment. The recommendations were finalized according to GRADE and voted using an online Delphi process followed by a final hybrid consensus conference. The German long version of the guideline was approved by the professional associations. For this English version an update of the systematic review was conducted until April 2024 and recommendation adapted based on new evidence in systematic reviews and randomized controlled trials. In total, 46 recommendations were developed and research gaps addressed.

High positive end-expiratory pressure ventilation mitigates the progression from unilateral pulmonary contusion to ARDS: An animal study.

BACKGROUND: Pulmonary contusion (PC) is common in severely traumatized patients and can lead to respiratory failure requiring mechanical ventilation (MV). Ventilator-induced lung injury (VILI) might aggravate lung damage. Despite underrepresentation of trauma patients in trials on lung-protective MV, results are extrapolated to these patients, potentially disregarding important pathophysiological differences. METHODS: Three MV protocols with different positive end-expiratory pressure (PEEP) levels: ARDSnetwork lower PEEP (ARDSnet-low), ARDSnetwork higher PEEP (ARDSnet-high), and open lung concept (OLC) were applied in swine for 24 hours following PC. Gas exchange, lung mechanics, quantitative computed tomography, and diffuse alveolar damage (DAD) score were analyzed. Results are given as median (interquartile range) at 24 hours. Statistical testing was performed using general linear models (group effect) over all measurement points and pairwise Mann-Whitney U tests for DAD. RESULTS: There were significant differences between groups: PEEP ( p < 0.0001) ARDSnet-low (8 [8-10] cmH 2 O), ARDSnet-high (12 [12-12] cmH 2 O), OLC (21 [20-22] cmH 2 O). The fraction of arterial partial pressure of oxygen and inspired oxygen fraction ( p = 0.0016) was lowest in ARDSnet-low (78 (73-111) mm Hg) compared with ARDSnet-high (375 (365-423) mm Hg) and OLC (499 (430-523) mm Hg). The end-expiratory lung volume (EELV) differed significantly ( p < 0.0001), with highest values in OLC (64% [60-70%]) and lowest in ARDSnet-low (34% [24-37%]). Costa's surrogate for mechanical power differed significantly ( p < 0.0001), with lowest values for ARDSnet-high (73 [58-76]) compared with OLC (105 [108-116]). Diffuse alveolar damage was lower in ARDSnet-high compared with ARDSnet-low (0.0007). CONCLUSION: Progression to ARDS, 24 hours after PC, was mitigated by OLC and ARDSnet-high. Both concepts restored EELV. ARDSnet-high had the lowest mechanical power surrogate and DAD. Our data suggest, that ARDSnet-high restored oxygenation and functional lung volume and reduced physiological and histological surrogates for VILI. ARDSnet-low generated unfavorable outcomes, such as loss of EELV, increased mechanical power and DAD after PC in swine. The high respiratory rate in the OLC may blunt favorable effects of lung recruitment.

Intraoperative individualization of positive-end-expiratory pressure through electrical impedance tomography or esophageal pressure assessment: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: This systematic review of randomized-controlled trials (RCTs) with meta-analyses aimed to compare the effects on intraoperative arterial oxygen tension to inspired oxygen fraction ratio (PaO2/FiO2), exerted by positive end-expiratory pressure (PEEP) individualized trough electrical impedance tomography (EIT) or esophageal pressure (Pes) assessment (intervention) vs. PEEP not tailored on EIT or Pes (control), in patients undergoing abdominal or pelvic surgery with an open or laparoscopic/robotic approach. METHODS: PUBMED®, EMBASE®, and Cochrane Controlled Clinical trials register were searched for observational studies and RCTs from inception to the end of August 2022. Inclusion criteria were: RCTs comparing PEEP titrated on EIT/Pes assessment vs. PEEP not individualized on EIT/Pes and reporting intraoperative PaO2/FiO2. Two authors independently extracted data from the enrolled investigations. Data are reported as mean difference and 95% confidence interval (CI). RESULTS: Six RCTs were included for a total of 240 patients undergoing general anesthesia for surgery, of whom 117 subjects in the intervention group and 123 subjects in the control group. The intraoperative mean PaO2/FiO2 was 69.6 (95%CI 32.-106.4 ) mmHg higher in the intervention group as compared with the control group with 81.4% between-study heterogeneity (p < 0.01). However, at meta-regression, the between-study heterogeneity diminished to 44.96% when data were moderated for body mass index (estimate 3.45, 95%CI 0.78-6.11, p = 0.011). CONCLUSIONS: In patients undergoing abdominal or pelvic surgery with an open or laparoscopic/robotic approach, PEEP personalized by EIT or Pes allowed the achievement of a better intraoperative oxygenation compared to PEEP not individualized through EIT or Pes. PROSPERO REGISTRATION NUMBER: CRD 42021218306, 30/01/2023.

Quality indicators in intensive care medicine for Germany - fourth edition 2022.

The measurement of quality indicators supports quality improvement initiatives. The German Interdisciplinary Society of Intensive Care Medicine (DIVI) has published quality indicators for intensive care medicine for the fourth time now. After a scheduled evaluation after three years, changes in several indicators were made. Other indicators were not changed or only minimally. The focus remained strongly on relevant treatment processes like management of analgesia and sedation, mechanical ventilation and weaning, and infections in the ICU. Another focus was communication inside the ICU. The number of 10 indicators remained the same. The development method was more structured and transparency was increased by adding new features like evidence levels or author contribution and potential conflicts of interest. These quality indicators should be used in the peer review in intensive care, a method endorsed by the DIVI. Other forms of measurement and evaluation are also reasonable, for example in quality management. This fourth edition of the quality indicators will be updated in the future to reflect the recently published recommendations on the structure of intensive care units by the DIVI.

Do we need pre-hospital resuscitative endovascular balloon occlusion of the aorta (REBOA) in the civilian helicopter emergency medical services (HEMS)?

Pre-hospital resuscitative endovascular balloon occlusion of the aorta (REBOA) can be a life-saving procedure for patients with non-compressible torso hemorrhage. We aimed to evaluate the potential eligibility for REBOA in trauma patients of a civilian helicopter emergency medical service (HEMS) using a stepwise approach. A retrospective analysis using the electronic database (HEMSDER) of "DRF Luftrettung" HEMS covering the period from January 2015 to June 2021 was performed. Trauma patients aged ≥ 16 years and with a National Advisory Committee for Aeronautics (NACA) score of ≥ 4 were assessed for potential REBOA eligibility using two different decision trees based on assumed severe bleeding due to injuries of the abdomen, pelvis, and/or lower extremities and different vital signs on the scene and at hospital handover. Non-parametric statistical methods were used for comparison. A total of 22.426 patients met the inclusion criteria for data analysis. Of these, 0.15-2.24% were possible candidates for pre-hospital REBOA. No significant differences between groups on scene and at hospital handover regarding demographics, assumed injuries, and pre-hospital interventions were found. In the on-scene group, 21.1% of the patients remained unstable even at hospital handover despite pre-hospital care. In the handover group, 42.8% of the patients seemed initially stable but then deteriorated during the pre-hospital course. The number of potential pre-hospital REBOA in severely injured patients with a NACA score of ≥ 4 is < 3% or can be even < 1% if more strict criteria are used. There are some patients who may benefit from pre-hospital REBOA as a life-saving procedure. Further research on earlier diagnosis of life-threatening bleeding and proper indications of REBOA in trauma patients is needed.

[Safe position check of gastric tubes: an often underestimated topic to prevent possible severe complications]. / Sichere Lagekontrolle von Magensonden: ein oft unterschätztes Thema zur Vermeidung potenziell schwerwiegender Komplikationen.

The insertion of a gastric tube in the operating room (OR) or in an intensive care unit (ICU) is a routine procedure. Although the tube is often inserted by nursing staff, the indications and selection of the procedure for position control remain the physician's responsibility. For immediate position control, the injection of air through the inserted tube with simultaneous auscultation of the epigastrium is probably the most simple and common clinical method. A typical "bubbling" is often regarded as a sufficiently reliable sign of correct gastric tube position. This procedure can be described as a routine standard both in the OR and the ICU; however, numerous examples from clinical practice and quality reviews show gastric tube mispositioning in esophageal, bronchial, pulmonary or even pleural positions in individual cases. Since auscultation findings are misinterpreted as tracheal, bronchial, or pleural secretions, mispositioning may remain undetected. In addition, adequate documentation of the procedure is lacking. In the worst case, hyperosmolar tube feeding occurs via the malpositioned tube into the lungs or pleural space causing subsequent severe pneumonia or pleuritis, which is often fatal for the patient outcome. In contrast to many other similar procedures in intensive care medicine, such as the installation of central venous catheters or endotracheal intubation, to our knowledge there is no uniform standard for forensic verification of the correct position after gastric tube positioning. The present work provides an overview of existing practices and the scientific background for confirmation of gastric tube positioning without ionizing radiation.

Distribution of ventilation and oxygenation in surgical obese patients ventilated with high versus low positive end-expiratory pressure: A substudy of a randomised controlled trial.

BACKGROUND: Intra-operative ventilation using low/physiological tidal volume and positive end-expiratory pressure (PEEP) with periodic alveolar recruitment manoeuvres (ARMs) is recommended in obese surgery patients. OBJECTIVES: To investigate the effects of PEEP levels and ARMs on ventilation distribution, oxygenation, haemodynamic parameters and cerebral oximetry. DESIGN: A substudy of a randomised controlled trial. SETTING: Tertiary medical centre in Geneva, Switzerland, between 2015 and 2018. PATIENTS: One hundred and sixty-two patients with a BMI at least 35 kg per square metre undergoing elective open or laparoscopic surgery lasting at least 120 min. INTERVENTION: Patients were randomised to PEEP of 4 cmH 2 O ( n  = 79) or PEEP of 12 cmH 2 O with hourly ARMs ( n  = 83). MAIN OUTCOME MEASURES: The primary endpoint was the fraction of ventilation in the dependent lung as measured by electrical impedance tomography. Secondary endpoints were the oxygen saturation index (SaO 2 /FIO 2 ratio), respiratory and haemodynamic parameters, and cerebral tissue oximetry. RESULTS: Compared with low PEEP, high PEEP was associated with smaller intra-operative decreases in dependent lung ventilation [-11.2%; 95% confidence interval (CI) -8.7 to -13.7 vs. -13.9%; 95% CI -11.7 to -16.5; P  = 0.029], oxygen saturation index (-49.6%; 95% CI -48.0 to -51.3 vs. -51.3%; 95% CI -49.6 to -53.1; P  < 0.001) and a lower driving pressure (-6.3 cmH 2 O; 95% CI -5.7 to -7.0). Haemodynamic parameters did not differ between the groups, except at the end of ARMs when arterial pressure and cardiac index decreased on average by -13.7 mmHg (95% CI -12.5 to -14.9) and by -0.54 l min -1  m -2 (95% CI -0.49 to -0.59) along with increased cerebral tissue oximetry (3.0 and 3.2% on left and right front brain, respectively). CONCLUSION: In obese patients undergoing abdominal surgery, intra-operative PEEP of 12 cmH 2 O with periodic ARMs, compared with intra-operative PEEP of 4 cmH 2 O without ARMs, slightly redistributed ventilation to dependent lung zones with minor improvements in peripheral and cerebral oxygenation. TRIAL REGISTRATION: NCT02148692, https://clinicaltrials.gov/ct2.

Tigecycline Soft Tissue Penetration in Obese and Non-obese Surgical Patients Determined by Using In Vivo Microdialysis.

BACKGROUND AND OBJECTIVE: Tigecycline, a broad-spectrum glycylcycline antibiotic, is approved for use at a fixed dose irrespective of body weight. However, its pharmacokinetics may be altered in obesity, which would impact on the antibiotic's effectiveness. The objective of this study was to investigate the plasma and subcutaneous tissue concentrations of tigecycline in obese patients compared with those in a non-obese control group. METHODS: Fifteen obese patients (one class II and 14 class III) undergoing bariatric surgery and 15 non-obese patients undergoing intra-abdominal surgery (mainly tumour resection) received a single dose of 50 or 100 mg tigecycline as an intravenous short infusion. Tigecycline concentrations were measured up to 8 h after dosing in plasma (total concentration), in ultrafiltrate of plasma (free concentration), and in microdialysate from subcutaneous tissue, respectively. RESULTS: In obese patients, total peak plasma concentration (1.31 ± 0.50 vs 2.27 ± 1.40 mg/L) and the area under the concentration-time curve from 0 to 8 h (AUC8h,plasma: 2.15 ± 0.42 vs 2.74 ± 0.73 h⋅mg/L), as normalized to a 100 mg dose, were significantly lower compared with those of non-obese patients. No significant differences were observed regarding the free plasma concentration, as determined by ultrafiltration, or the corresponding AUC8h (fAUC8h,plasma). Concentrations in interstitial fluid (ISF) of subcutaneous tissue were lower than the free plasma concentrations in both groups, and they were lower in obese compared to non-obese patients: the AUC8h in ISF (AUC8h,ISF) was 0.51 ± 0.22 h⋅mg/L in obese and 0.79 ± 0.23 h⋅mg/L in non-obese patients, resulting in a relative tissue drug exposure (AUC8h,ISF/fAUC8h,plasma) of 0.38 ± 0.19 and 0.63 ± 0.24, respectively. CONCLUSION: Following a single dose of tigecycline, concentrations in the ISF of subcutaneous adipose tissue are decreased in heavily obese subjects, calling for an increased loading dose. EU CLINICAL TRIALS REGISTRATION NUMBER: EudraCT No. 2012-004383-22.

Methods for Determination of Individual PEEP for Intraoperative Mechanical Ventilation Using a Decremental PEEP Trial.

(1) Background: Individual PEEP settings (PEEPIND) may improve intraoperative oxygenation and optimize lung mechanics. However, there is uncertainty concerning the optimal procedure to determine PEEPIND. In this secondary analysis of a randomized controlled clinical trial, we compared different methods for PEEPIND determination. (2) Methods: Offline analysis of decremental PEEP trials was performed and PEEPIND was retrospectively determined according to five different methods (EIT-based: RVDI method, Global Inhomogeneity Index [GI], distribution of tidal ventilation [EIT VT]; global dynamic and quasi-static compliance). (3) Results: In the 45 obese and non-obese patients included, PEEPIND using the RVDI method (PEEPRVD) was 16.3 ± 4.5 cm H2O. Determination of PEEPIND using the GI and EIT VT resulted in a mean difference of −2.4 cm H2O (95%CI: −1.2;−3.6 cm H2O, p = 0.01) and −2.3 cm H2O (95% CI: −0.9;3.7 cm H2O, p = 0.01) to PEEPRVD, respectively. PEEPIND selection according to quasi-static compliance showed the highest agreement with PEEPRVD (p = 0.67), with deviations > 4 cm H2O in 3/42 patients. PEEPRVD and PEEPIND according to dynamic compliance also showed a high level of agreement, with deviations > 4 cm H2O in 5/42 patients (p = 0.57). (4) Conclusions: High agreement of PEEPIND determined by the RVDI method and compliance-based methods suggests that, for routine clinical practice, PEEP selection based on best quasi-static or dynamic compliance is favorable.

Geo-economic variations in epidemiology, ventilation management and outcome of patients receiving intraoperative ventilation during general anesthesia- posthoc analysis of an observational study in 29 countries.

BACKGROUND: The aim of this analysis is to determine geo-economic variations in epidemiology, ventilator settings and outcome in patients receiving general anesthesia for surgery. METHODS: Posthoc analysis of a worldwide study in 29 countries. Lower and upper middle-income countries (LMIC and UMIC), and high-income countries (HIC) were compared. The coprimary endpoint was the risk for and incidence of postoperative pulmonary complications (PPC); secondary endpoints were intraoperative ventilator settings, intraoperative complications, hospital stay and mortality. RESULTS: Of 9864 patients, 4% originated from LMIC, 11% from UMIC and 85% from HIC. The ARISCAT score was 17.5 [15.0-26.0] in LMIC, 16.0 [3.0-27.0] in UMIC and 15.0 [3.0-26.0] in HIC (P = .003). The incidence of PPC was 9.0% in LMIC, 3.2% in UMIC and 2.5% in HIC (P < .001). Median tidal volume in ml kg- 1 predicted bodyweight (PBW) was 8.6 [7.7-9.7] in LMIC, 8.4 [7.6-9.5] in UMIC and 8.1 [7.2-9.1] in HIC (P < .001). Median positive end-expiratory pressure in cmH2O was 3.3 [2.0-5.0]) in LMIC, 4.0 [3.0-5.0] in UMIC and 5.0 [3.0-5.0] in HIC (P < .001). Median driving pressure in cmH2O was 14.0 [11.5-18.0] in LMIC, 13.5 [11.0-16.0] in UMIC and 12.0 [10.0-15.0] in HIC (P < .001). Median fraction of inspired oxygen in % was 75 [50-80] in LMIC, 50 [50-63] in UMIC and 53 [45-70] in HIC (P < .001). Intraoperative complications occurred in 25.9% in LMIC, in 18.7% in UMIC and in 37.1% in HIC (P < .001). Hospital mortality was 0.0% in LMIC, 1.3% in UMIC and 0.6% in HIC (P = .009). CONCLUSION: The risk for and incidence of PPC is higher in LMIC than in UMIC and HIC. Ventilation management could be improved in LMIC and UMIC. TRIAL REGISTRATION: Clinicaltrials.gov , identifier: NCT01601223.

Evaluating prediction methods for glomerular filtration to optimise drug doses in obese and nonobese patients.

AIMS: The most suitable method for predicting the glomerular filtration rate (GFR) in obesity is currently debated. Therefore, multiple GFR/creatinine clearance prediction methods were applied to (morbidly) obese and nonobese patients ranging from moderate renal impairment to glomerular hyperfiltration and their predictions were rated based on observed fosfomycin pharmacokinetics, as this model drug is exclusively eliminated via glomerular filtration. METHODS: The GFR/creatinine clearance predictions via the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease (MDRD; indexed and de-indexed by body surface area) and creatinine clearance via the Cockcroft-Gault formula (CLCRCG ) using different body size descriptors were compared to the fosfomycin clearance (CLFOF ) from 30 surgical patients (body mass index = 20.1-52.0 kg m-2 ), receiving 8000 mg as intravenous infusion. RESULTS: The concordance between CLFOF and creatinine clearance predictions was highest for CLCRCG employing either ideal body weight or adjusted body weight (if body mass >1.3 ideal body weight; CLCRCG_ABW-Schwartz , concordance-correlation coefficient [95% confidence interval] = 0.474 [0.156; 0.703], CCC) and GFR predictions via the de-indexed MDRD equation (concordance-correlation coefficient = 0.452 [0.137; 0.685]). The proportion of predicted GFR values within ±30% of the observed CLFOF (P30 = 72.3-76.7%) was only marginally lower than the reported P30 in the original CKD-EPI and MDRD publications (P30 = 84.1-90.0%). CONCLUSION: This analysis represents a successful proof-of-concept for evaluating GFR/creatinine clearance prediction methods: Across all body mass index classes CLCRCG_ABW-Schwartz or the de-indexed MDRD were most suitable for predicting creatinine clearance/GFR also in (morbidly) obese, CKD stage <3B individuals in therapeutic use. Their application is proposed in optimising doses for vital therapies in obese patients requiring monitoring of renal function (e.g. methotrexate dosing).

Comparative Plasma and Interstitial Tissue Fluid Pharmacokinetics of Meropenem Demonstrate the Need for Increasing Dose and Infusion Duration in Obese and Non-obese Patients.

BACKGROUND AND OBJECTIVES: A quantitative evaluation of the PK of meropenem, a broad-spectrum ß-lactam antibiotic, in plasma and interstitial space fluid (ISF) of subcutaneous adipose tissue of obese patients is lacking as of date. The objective of this study was the characterisation of meropenem population pharmacokinetics in plasma and ISF in obese and non-obese patients for identification of adequate dosing regimens via Monte-Carlo simulations. METHODS: We obtained plasma and microdialysate concentrations after administration of meropenem 1000 mg to 15 obese and 15 non-obese surgery patients from a prospective clinical trial. After characterizing plasma- and microdialysis-derived ISF pharmacokinetics via population pharmacokinetic analysis, we simulated thrice-daily (TID) meropenem short-term (0.5 h), prolonged (3.0 h), and continuous infusions. Adequacy of therapy was assessed by the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment (PTA) analysis based on time unbound concentrations exceeded minimum inhibitory concentrations (MIC) on treatment day 1 (%fT > MIC) and the sum of PTA weighted by relative frequency of MIC values for infections by pathogens commonly treated with meropenem. To avoid interstitial tissue fluid concentrations below MIC for the entire dosing interval during continuous infusions, a more conservative PK/PD index was selected (%fT > 4 × MIC). RESULTS: Adjusted body weight (ABW) and calculated creatinine clearance (CLCRCG_ABW) of all patients (body mass index [BMI] = 20.5-81.5 kg/m2) explained a considerable proportion of the between-patient pharmacokinetic variability (15.1-31.0% relative reduction). The ISF:plasma ratio of %fT > MIC was relatively similar for MIC ≤ 2 mg/L but decreased for MIC = 8 mg/L over ABW = 60-120 kg (0.50-0.20). Steady-state concentrations were 2.68 times (95% confidence interval [CI] = 2.11-3.37) higher in plasma than in ISF, supporting PK/PD targets related to four times the MIC during continuous infusions to avoid suspected ISF concentrations constantly below the MIC. A 3000 mg/24 h continuous infusion was sufficient at MIC = 2 mg/L for patients with CLCRCG_ABW ≤ 100 mL/min and ABW < 90 kg, whereas 2000 mg TID prolonged infusions were adequate for those with CLCRCG_ABW ≤ 100 mL/min and ABW > 90 kg. For MIC = 2 mg/L and %fT> MIC = 95, PTA was adequate in patients over the entire investigated range of body mass and renal function using a 6000 mg continuous infusion. A prolonged infusion of meropenem 2000 mg TID was sufficient for MIC ≤ 8 mg/L and all investigated ABW and CLCRCG_ABW when employing the PK/PD target %fT > MIC = 40. Short-term infusions of 1000 mg TID were sufficient for CLCRCG_ABW ≤ 130 mL/min and distributions of MIC values for Escherichia coli, Citrobacter freundii, and Klebsiella pneumoniae but not for Pseudomonas aeruginosa. CONCLUSIONS: This analysis indicated a need for higher doses (≥ 2000 mg) and prolonged infusions (≥ 3 h) for obese and non-obese patients at MIC ≥ 2 mg/L. Higher PTA was achieved with prolonged infusions in obese patients and with continuous infusions in non-obese patients. TRIAL REGISTRATION: EudraCT: 2012-004383-22.

Similar Piperacillin/Tazobactam Target Attainment in Obese versus Nonobese Patients despite Differences in Interstitial Tissue Fluid Pharmacokinetics.

Precision dosing of piperacillin/tazobactam in obese patients is compromised by sparse information on target-site exposure. We aimed to evaluate the appropriateness of current and alternative piperacillin/tazobactam dosages in obese and nonobese patients. Based on a prospective, controlled clinical trial in 30 surgery patients (15 obese/15 nonobese; 0.5-h infusion of 4 g/0.5 g piperacillin/tazobactam), piperacillin pharmacokinetics were characterized in plasma and at target-site (interstitial fluid of subcutaneous adipose tissue) via population analysis. Thereafter, multiple 3-4-times daily piperacillin/tazobactam short-term/prolonged (recommended by EUCAST) and continuous infusions were evaluated by simulation. Adequacy of therapy was assessed by probability of pharmacokinetic/pharmacodynamic target-attainment (PTA ≥ 90%) based on time unbound piperacillin concentrations exceed the minimum inhibitory concentration (MIC) during 24 h (%fT>MIC). Lower piperacillin target-site maximum concentrations in obese versus nonobese patients were explained by the impact of lean (approximately two thirds) and fat body mass (approximately one third) on volume of distribution. Simulated steady-state concentrations were 1.43-times, 95%CI = (1.27; 1.61), higher in plasma versus target-site, supporting targets of %fT>2×MIC instead of %fT>4×MIC during continuous infusion to avoid target-site concentrations constantly below MIC. In all obesity and renally impairment/hyperfiltration stages, at MIC = 16 mg/L, adequate PTA required prolonged (thrice-daily 4 g/0.5 g over 3.0 h at %fT>MIC = 50) or continuous infusions (24 g/3 g over 24 h following loading dose at %fT>MIC = 98) of piperacillin/tazobactam.