Modeling Pharmacokinetics in Individual Patients Using Therapeutic Drug Monitoring and Artificial Population Quasi-Models: A Study with Piperacillin.

Population pharmacokinetic (pop-PK) models constructed for model-informed precision dosing often have limited utility due to the low number of patients recruited. To augment such models, an approach is presented for generating fully artificial quasi-models which can be employed to make individual estimates of pharmacokinetic parameters. Based on 72 concentrations obtained in 12 patients, one- and two-compartment pop-PK models with or without creatinine clearance as a covariate were generated for piperacillin using the nonparametric adaptive grid algorithm. Thirty quasi-models were subsequently generated for each model type, and nonparametric maximum a posteriori probability Bayesian estimates were established for each patient. A significant difference in performance was found between one- and two-compartment models. Acceptable agreement was found between predicted and observed piperacillin concentrations, and between the estimates of the random-effect pharmacokinetic variables obtained using the so-called support points of the pop-PK models or the quasi-models as priors. The mean squared errors of the predictions made using the quasi-models were similar to, or even considerably lower than those obtained when employing the pop-PK models. Conclusion: fully artificial nonparametric quasi-models can efficiently augment pop-PK models containing few support points, to make individual pharmacokinetic estimates in the clinical setting.

A Critical Reassessment of the Kidney Risk Caused by Tetrastarch Products in the Perioperative and Intensive Care Environments.

Purpose: To reassess the results of former meta-analyses focusing on the relationship between novel HES preparations (130/0.4 and 130/0.42) and acute kidney injury. Previous meta-analyses are based on studies referring to partially or fully unpublished data or data from abstracts only. Methods: The studies included in the former meta-analyses were scrutinized by the authors independently. We completed a critical analysis of the literature, including the strengths, weaknesses and modifiers of the studies when assessing products, formulations and outcomes. Results: Both the published large studies and meta-analyses show significant bias in the context of the deleterious effect of 6% 130/0.4-0.42 HES. Without (1) detailed hemodynamic data, (2) the exclusion of other nephrotoxic events and (3) a properly performed evaluation of the dose-effect relationship, the AKI-inducing property of 6% HES 130/0.4 or 0.42 should not be considered as evidence. The administration of HES is safe and effective if the recommended dose is respected. Conclusions: Our review suggests that there is questionable evidence for the deteriorating renal effect of these products. Further well-designed, randomized and controlled trials are needed. Additionally, conclusions formulated for resource-rich environments should not be extended to more resource-scarce environments without proper qualifiers provided.

Pneumoperitoneum and Acute Kidney Injury-An Integrative Clinical Concept Review.

An increased intraabdominal pressure, particularly when occurring during periods of hemodynamic instability or fluid overload, is regarded as a major contributor to acute kidney injury (AKI) in intensive care units. During abdominal laparoscopic procedures, intraoperative insufflation pressures up to 15 mmHg are applied, to enable visualization and surgical manipulation but with the potential to compromise net renal perfusion. Despite the widely acknowledged renal arterial autoregulation, net arterial perfusion pressure is known to be narrow, and the effective renal medullary perfusion is disproportionately impacted by venous and lymphatic congestion. At present, the potential risk factors, mitigators and risk-stratification of AKI during surgical pneumoperitoneum formation received relatively limited attention among nephrologists and represent an opportunity to look beyond mere blood pressure and intake-output balances. Careful charting and reporting duration and extent of surgical pneumoperitoneum represents an opportunity for anesthesia teams to better communicate intraoperative factors affecting renal outcomes for the postoperative clinical teams. In this current article, the authors are integrating preclinical data and clinical experience to provide a better understanding to optimize renal perfusion during surgeries. Future studies should carefully consider intrabdominal insufflation pressure as a key variable when assessing outcomes and blood pressure goals in these settings.

Assessment of Antibiotic Pharmacokinetics, Molecular Biomarkers and Clinical Status in Critically Ill Adults Diagnosed with Community-Acquired Pneumonia and Receiving Intravenous Piperacillin/Tazobactam and Hydrocortisone over the First Five Days of Intensive Care: An Observational Study (STROBE Compliant).

Severe community-acquired pneumonia (CAP) is a condition that frequently requires intensive care and, eventually, can cause to death. Piperacillin/tazobactam antibiotic therapy is employed as an empiric intravenous regimen, in many cases supplemented with intravenous bolus hydrocortisone treatment. The individual and condition-dependent pharmacokinetic properties of these drugs may lead to therapeutic failure. The impact of systemic inflammation, as well as of hydrocortisone on the altered pharmacokinetics of piperacillin is largely unknown. The protocol of a clinical study aimed at the characterization of the pharmacokinetics of piperacillin and tazobactam and its association with the concentrations of inflammatory markers and adrenal steroids during CAP therapy will be investigated in up to 40 critically ill patients. The serum concentrations of piperacillin and tazobactam, cortisol, cortisone, corticosterone and 11-deoxycortisol and interleukin-6 levels, as well as routine clinical chemistry and hematology parameters will be monitored from the beginning of treatment for up to five days. Nonparametric population pharmacokinetic modeling and Monte-Carlo simulations will be performed to make estimates of the pharmacokinetics of piperacillin and tazobactam and the probability of pharmacokinetic-pharmacodynamic target attainment. The observed individual characteristics and changes will be correlated with clinical and laboratory findings. The protocol of the observational study will be designed following the STROBE guideline.

Mediators of Regional Kidney Perfusion during Surgical Pneumo-Peritoneum Creation and the Risk of Acute Kidney Injury-A Review of Basic Physiology.

Acute kidney injury (AKI), especially if recurring, represents a risk factor for future chronic kidney disease. In intensive care units, increased intra-abdominal pressure is well-recognized as a significant contributor to AKI. However, the importance of transiently increased intra-abdominal pressures procedures is less commonly appreciated during laparoscopic surgery, the use of which has rapidly increased over the last few decades. Unlike the well-known autoregulation of the renal cortical circulation, medulla perfusion is modulated via partially independent regulatory mechanisms and strongly impacted by changes in venous and lymphatic pressures. In our review paper, we will provide a comprehensive overview of this evolving topic, covering a broad range from basic pathophysiology up to and including current clinical relevance and examples. Key regulators of oxidative stress such as ischemia-reperfusion injury, the activation of inflammatory response and humoral changes interacting with procedural pneumo-peritoneum formation and AKI risk will be recounted. Moreover, we present an in-depth review of the interaction of pneumo-peritoneum formation with general anesthetic agents and animal models of congestive heart failure. A better understanding of the relationship between pneumo-peritoneum formation and renal perfusion will support basic and clinical research, leading to improved clinical care and collaboration among specialists.

A randomized comparative evaluation of local infiltration analgesia, extended nerve blocks, and conventional analgesia in pain management after total knee arthroplasty.

OBJECTIVES: The aim of this study was to analyze the postoperative effects of extended nerve blocks and local infiltration analgesia (LIA) on postoperative pain control, muscle weakness, and blood loss after total knee arthroplasty (TKA). PATIENTS AND METHODS: Between February 24th 2020 and July 10th 2020, a total of 161 patients (55 males, 106 females; median age: 69.0 years [IQR 63.0-75.0], range, 41 to 81 years) who underwent primary TKA were randomly allocated into three parallel groups according to their concomitant procedure in a double-blind fashion: (i) those to whom nerve blockade was performed after competition of surgery under the duration of spinal anesthesia (n=50); (ii) those to whom LIA was performed during surgery (n=52), and (iii) control group (n=59). The content of LIA was 10-10 mL of 20 mg lidocaine with 0.01 mg adrenalin and 100 mg ropivacaine, 1 mL (30 mg) ketorolac, and 5 mL (500 mg) tranexamic acid was diluted by 50 mL 0.9% NaCl under aseptic conditions. Outcome parameters were the evaluation of pain until the evening of first postoperative day (24 to 36 h), mobilization, and blood loss within the first three postoperative days. RESULTS: The pain was maximal between 4 and 8 h postoperatively, when the effect of the spinal anesthetic drugs disappeared. During this critical period, tolerable pain (Numerical Rating Scale, NRS ≤3) was observed in 52%, 42%, and 19% of nerve blockade in LIA and control groups, respectively. None of the patients complained of high-intensity pain (NRS >8) in the LIA group, which was a significant difference from the block and control groups (10% and 14%, p<0.008, respectively). There was no significant muscle weakness associated with the use of this extended block. The decrease in hemoglobin level was significantly lower in the LIA group than in the control and block groups (odds ratio [OR]: 0.379, 95% confidence interval [CI]: 0.165-0.874 for nerve blockade vs. LIA, OR: 1.189, 95% CI: 0.491-2.880 for nerve blockade vs. control, OR: 0.319, 95% CI: 0.140-0.727, respectively). The common language effect size for pain in each referred interval in each group and for decrease of hemoglobin between the first and third postoperative days fell between 0.507 and 0.680. CONCLUSION: This study demonstrates that LIA technique offers a fast and safe treatment option for pain relief after TKA. No clinically relevant muscle weakness was observed among groups according to field block applications. Significant advantages were also achieved in blood loss.

Reinterpreting Renal Hemodynamics: The Importance of Venous Congestion and Effective Organ Perfusion in Acute Kidney Injury.

The significance of effective renal perfusion is relatively underemphasized in the current literature. From a renal standpoint, besides optimizing cardiac output, renal perfusion should be maximized as well. Among the several additional variables of the critically ill, such as intra-abdominal pressure, the presence of venous congestion and elevated central venous pressures, airway pressures generated by mechanical ventilation do affect net renal perfusion. These forces represent both a potential danger and an ongoing opportunity to improve renal outcomes in the critically ill and an opportunity to move beyond the simplified viewpoint of optimizing volume status. Therefore, to optimize nephron-protective therapies, nephrologists and intensive care physicians should be familiar with the concept of net renal perfusion pressure. This review appraises the background literature on renal perfusion pressure, including the initial animal data and historical human studies up to the most current developments in the field, exploring potential avenues to assess and improve renal blood supply.

The value of combined hemodynamic, respiratory and intra-abdominal pressure monitoring in predicting acute kidney injury after major intraabdominal surgeries.

BACKGROUND: The incidence of postoperative acute kidney injury (AKI) is predominantly determined by renal hemodynamics. Beside arterial blood pressure, the role of factors causing a deterioration of venous congestion (intraabdominal pressure, central venous pressure, mechanical ventilation) has emerged. The value of combined hemodynamic, respiratory and intra-abdominal pressure (IAP) monitoring in predicting postoperative acute kidney injury has received only limited exploration to date. METHODS: Data were collected for adult patients admitted after major abdominal surgery at nine Hungarian ICUs. Hemodynamic parameters were compared in AKI vs. no-AKI patients at the time of admission and 48 h thereafter. Regarding ventilatory support, we tested mean airway pressures (Pmean). Effective renal perfusion pressure (RPP) was calculated as MAP-(IAP + CVP + Pmean). The Mann-Whitney U and the chi-square tests were carried out for statistical analysis with forward stepwise logistic regression for AKI as a dependent outcome. RESULTS: A total of 84 patients (34 ventilated) were enrolled in our multicenter observational study. The median values of MAP were above 70 mmHg, IAP not higher than 12 mmHg and CVP not higher than 8 mmHg at all time-points. When we combined those parameters, even those belonging to the 'normal' range with Pmean, we found significant differences between no-AKI and AKI groups only at 12 h after ICU admission (median and IQR: 57 (42-64) vs. 40 (36-52); p < .05). Below it's median (40.7 mmHg) on admission, AKI developed in all patients. If above 40.7 mmHg on admission, they were protected against AKI, but only if it did not decrease within the first 12 h. CONCLUSIONS: Calculated effective RPP with the novel formula MAP-(IAP + CVP + Pmean) may predict the onset of AKI in the surgical ICU with a great sensitivity and specificity. Maintaining effective RPP appears important not only at ICU admission but during the next 12 h, as well. Additional, larger studies are needed to explore therapeutic interventions targeting this parameter.

Renoprotective Postoperative Monitoring: What Is the Best Method for Computing Renal Perfusion Pressure? An Observational, Prospective, Multicentre Study.

BACKGROUND: Low mean arterial pressure (MAP) is a well-known risk factor for postoperative acute kidney injury (AKI), but probably it is not the sole hemodynamic parameter that can influence the development of renal failure. There are data in cardiac patients supporting the role of renal venous congestion in the development of AKI. The aim of our study was to determine a combination of factors best predicting the development of AKI. METHODS: Data were collected prospectively for adult patients admitted after major abdominal surgery to 9 Hungarian intensive care units. Hemodynamic and laboratory parameters were compared in patients with AKI vs. no-AKI at the time of admission. Renal perfusion was computed by different methods from hemodynamic measurements involving MAP, central venous pressure (CVP), intraabdominal pressure (IAP), and mean airway pressures (Pmean). Twelve different, clinically interpretable equations were tested. Statistical evaluation was performed by the Mann-Whitney U test and ROC analysis. RESULTS: Eighty-four patients were enrolled in the study. Renal perfusion pressure was significantly lower in all equations. The equations MAP-IAP-Pmean (1-area under the curve [AUC]: 0.796; likelihood ratio [LR]+: 3.520; LR-: 0.337; p < 0.01), MAP-IAP-CVP-Pmean (1-AUC: 0.794; LR+: 2.743; LR-: 0.282; p < 0.01), and MAP-2 × IAP-CVP-Pmean (1-AUC: 0.791; LR+: 4.321; LR-: 0.262; p < 0.001) showed small to moderate effect on AKI but have better performance than severity score systems (SAPS II [AUC: 0.696; LR+: 3.143, LR-: 0.433; p < 0.01], SOFA [AUC: 0.717; LR+: 2.089; LR-: 0.528; p < 0.001]). CONCLUSION: We found that the best parameter predicting AKI is the MAP-2 × IAP-CVP-Pmean. Further investigation is needed to analyze the role of CVP and Pmean, and to characterize renal venous congestion and tubular pressure more in detail.