Pre-hospital care after return of spontaneous circulation: Are we achieving our targets?

Background: Early restoration of normal physiology when return of spontaneous circulation (ROSC) is obtained after an out-of-hospital cardiac arrest (OHCA) reduces the risk of developing post-cardiac arrest syndrome (PCAS). This study aims to investigate if (and to which extent) this can be achieved within the scope of practice of standard emergency medical services (EMS) crews. Methods: A prospective mixed-methods quantitative and qualitative cohort study was performed including adult patients with a non-traumatic OHCA presented to a university hospital emergency department (ED) in the Netherlands after pre-hospital ROSC was obtained. Primary endpoint was the percentage of patients with deranged physiology post-ROSC in whom EMS crews were able to reach recommended treatment targets. Results: During a 32-month period, 160 patients presenting with ROSC after OHCA were included. Median (IQR) pre-hospital treatment duration was 40 (34-51) minutes. When deranged physiology was present (n = 133), it could be restored by EMS crews in 29% of the patients. Although average etCO2 and SpO2 improved gradually over time during pre-hospital treatment, recommended treatment targets could not be achieved in respectively 55% (30/55) and 43% (20/46) of the patients. Similarly, airway problems (24/46, 52%), hypotension (20/23, 87%) and post-anoxic agitation (16/43, 37%) could often not be resolved by EMS crews. The ability to restore normal physiology by EMS could not be predicted based on patient characteristics or in-arrest variables. Conclusion: Deranged physiology after an OHCA is commonly encountered, and often difficult to treat within the scope of practice of regular EMS crews. Involvement of advanced critical care teams with a wider scope of practice at an early stage may contribute to a better outcome for these patients.

Comparing the haemodynamic effects of high- and low-dose opioid anaesthesia: a secondary analysis of a randomised controlled trial.

Post-induction hypotension (MAP < 65 mmHg) occurs frequently and is usually caused by the cardiovascular adverse effects of the anaesthetic induction drugs used. We hypothesize that a clinically significant difference in the incidence and severity of hypotension will be found when different doses of propofol and remifentanil are used for induction of anaesthesia. METHODS: This is a secondary analysis of a randomised controlled trial wherein four groups (A-D) of patients received one out of four different combinations of propofol and remifentanil, titrated to a predicted equipotency in probability of tolerance to laryngoscopy (PTOL) according to the Bouillon interaction model. In group A, a high dose of propofol and a low dose of remifentanil was administered, and across the groups this ratio was gradually changed until it was reversed in group D. Mean and systolic arterial blood pressure (MAP, SAP) were compared at four time points (Tbaseline, Tpost-bolus, T3min, Tnadir) within and between groups Heart rate, bispectral index (BIS) and the incidence of hypotension were compared. RESULTS: Data from 76 patients was used. At Tpost-bolus a statistically significant lower MAP and SAP was found in group A versus D (p = 0.011 and p = 0.002). A significant higher heart rate was found at T3min and Tnadir between groups A and B when compared to groups C and D (p = < 0.001 and p = 0.002). A significant difference in BIS value was found over all groups at T3min and Tnadir (both p < 0.001). All other outcomes did not differ significantly between groups. CONCLUSION: Induction of anaesthesia with different predicted equipotent combinations of propofol and remifentanil did result in statistically different but clinically irrelevant differences in haemodynamic endpoints during induction of anaesthesia. Our study could not identify preferable drug combinations that decrease the risk for hypotension after induction, although they all yield a similar predicted PTOL.

Anaesthetic efficacy and postinduction hypotension with remimazolam compared with propofol: a multicentre randomised controlled trial.

Remimazolam, a short-acting benzodiazepine, may be used for induction and maintenance of total intravenous anaesthesia, but its role in the management of patients with multiple comorbidities remains unclear. In this phase 3 randomised controlled trial, we compared the anaesthetic efficacy and the incidence of postinduction hypotension during total intravenous anaesthesia with remimazolam vs. propofol. A total of 365 patients (ASA physical status 3 or 4) scheduled for elective surgery were assigned randomly to receive total intravenous anaesthesia with remimazolam (n = 270) or propofol (n = 95). Primary outcome was anaesthetic effect, quantified as the percentage of time with Narcotrend® Index values ≤ 60, during surgery (skin incision to last skin suture), with a non-inferiority margin of -10%. Secondary outcome was the incidence of postinduction hypotensive events. Mean (SD) percentage of time with Narcotrend Index values ≤ 60 during surgery across all patients receiving remimazolam (93% (20.7)) was non-inferior to propofol (99% (4.2)), mean difference (97.5%CI) -6.28% (-8.89-infinite); p = 0.003. Mean (SD) number of postinduction hypotension events was 62 (38.1) and 71 (41.1) for patients allocated to the remimazolam and propofol groups, respectively; p = 0.015. Noradrenaline administration events (requirement for a bolus and/or infusion) were also lower in patients allocated to remimazolam compared with propofol (14 (13.5) vs. 20 (14.6), respectively; p < 0.001). In conclusion, in patients who were ASA physical status 3 or 4, the anaesthetic effect of remimazolam was non-inferior to propofol.

What is the potential benefit of pre-hospital extracorporeal cardiopulmonary resuscitation for patients with an out-of-hospital cardiac arrest? A predictive modelling study.

AIM: In this predictive modelling study we aimed to investigate how many patients with an out-of-hospital cardiac arrest (OHCA) would benefit from pre-hospital as opposed to in-hospital initiation of extracorporeal cardiopulmonary resuscitation (ECPR). METHODS: A temporal spatial analysis of Utstein data was performed for all adult patients with a non-traumatic OHCA attended by three emergency medical services (EMS) covering the north of the Netherlands during a one-year period. Patients were considered potentially eligible for ECPR if they had a witnessed arrest with immediate bystander CPR, an initial shockable rhythm (or signs of life during resuscitation) and could be presented in an ECPR-centre within 45 minutes of the arrest. Endpoint of interest was defined as the hypothetical number of ECPR eligible patients after 10, 15 and 20 minutes of conventional CPR and upon (hypothetical) arrival in an ECPR-centre as a fraction of the total number of OHCA patients attended by EMS. RESULTS: During the study period 622 OHCA patients were attended, of which 200 (32%) met ECPR eligibility criteria upon EMS arrival. The optimal transition point between conventional CPR and ECPR was found to be after 15 minutes. Hypothetical intra-arrest transport of all patients in whom no return of spontaneous circulation (ROSC) was obtained after that point (n = 84) would have yielded 16/622 (2.5%) patients being potentially ECPR eligible upon hospital arrival (average low-flow time 52 minutes), whereas on-scene initiation of ECPR would have resulted in 84/622 (13.5%) potential candidates (average estimated low-flow time 24 minutes before cannulation). CONCLUSION: Even in healthcare systems with relatively short transport distances to hospital, consideration should be given to pre-hospital initiation of ECPR for OHCA as it shortens low-flow time and increases the number of potentially eligible patients.

Frontal electroencephalogram based drug, sex, and age independent sedation level prediction using non-linear machine learning algorithms.

Brain monitors which track quantitative electroencephalogram (EEG) signatures to monitor sedation levels are drug and patient specific. There is a need for robust sedation level monitoring systems to accurately track sedation levels across all drug classes, sex and age groups. Forty-four quantitative features estimated from a pooled dataset of 204 EEG recordings from 66 healthy adult volunteers who received either propofol, dexmedetomidine, or sevoflurane (all with and without remifentanil) were used in a machine learning based automated system to estimate the depth of sedation. Model training and evaluation were performed using leave-one-out cross validation methodology. We trained four machine learning models to predict sedation levels and evaluated the influence of remifentanil, age, and sex on the prediction performance. The area under the receiver-operator characteristic curve (AUC) was used to assess the performance of the prediction model. The ensemble tree with bagging outperformed other machine learning models and predicted sedation levels with an AUC = 0.88 (0.81-0.90). There were significant differences in the prediction probability of the automated systems when trained and tested across different age groups and sex. The performance of the EEG based sedation level prediction system is drug, sex, and age specific. Nonlinear machine-learning models using quantitative EEG features can accurately predict sedation levels. The results obtained in this study may provide a useful reference for developing next generation EEG based sedation level prediction systems using advanced machine learning algorithms. Clinical trial registration: NCT02043938 and NCT03143972.

Comparison of haemodynamic- and electroencephalographic-monitored effects evoked by four combinations of effect-site concentrations of propofol and remifentanil, yielding a predicted tolerance to laryngoscopy of 90.

This prospective study evaluates haemodynamic and electroencephalographic effects observed when administering four combinations of effect-site concentrations of propofol (CePROP) and remifentanil (CeREMI), all yielding a single predicted probability of tolerance of laryngoscopy of 90% (PTOL = 90%) according to the Bouillon interaction model. We aimed to identify combinations of CePROP and CeREMI along a single isobole of PTOL that result in favourable hypnotic and haemodynamic conditions. This knowledge could be of advantage in the development of drug advisory monitoring technology. 80 patients (18-90 years of age, ASA I-III) were randomized into four groups and titrated towards CePROP (Schnider model, ug⋅ml-1) and CeREMI (Minto model, ng⋅ml-1) of respectively 8.6 and 1, 5.9 and 2, 3.6 and 4 and 2.0 and 8. After eleven minutes of equilibration, baseline measurements of haemodynamic endpoints and bispectral index were compared with three minutes of responsiveness measurements after laryngoscopy. Before laryngoscopy, bispectral index differed significantly (p < 0.0001) between groups in concordance with CePROP. Heart rate decreased with increasing CeREMI (p = 0.001). The haemodynamic and arousal responses evoked by laryngoscopy were not significantly different between groups, but CePROP = 3.6 µg⋅ml-1 and CeREMI = 4 ng⋅ml-1 evoked the lowest median value for ∆HR and ∆SAP after laryngoscopy. This study provides clinical insight on the haemodynamic and hypnotic consequences, when a model based predicted PTOL is used as a target for combined effect-site controlled target- controlled infusion of propofol and remifentanil. Heart rate and bispectral index were significantly different between groups despite a theoretical equipotency for PTOL, suggesting that each component of the anaesthetic state (immobility, analgesia, and hypnotic drug effect) should be considered as independent neurophysiological and pharmacological phenomena. However, claims of (in)accuracy of the predicted PTOL must be considered preliminary because larger numbers of observations are required for that goal.

A comparison of propofol-to-BIS post-operative intensive care sedation by means of target controlled infusion, Bayesian-based and predictive control methods: an observational, open-label pilot study.

PURPOSE: We evaluated the feasibility and robustness of three methods for propofol-to-bispectral index (BIS) post-operative intensive care sedation, a manually-adapted target controlled infusion protocol (HUMAN), a computer-controlled predictive control strategy (EPSAC) and a computer-controlled Bayesian rule-based optimized control strategy (BAYES). METHODS: Thirty-six patients undergoing short lasting sedation following cardiac surgery were included to receive propofol to maintain a BIS between 40 and 60. Robustness of control for all groups was analysed using prediction error and spectrographic analysis. RESULTS: Although similar time courses of measured BIS were obtained in all groups, a higher median propofol effect-site concentration (CePROP) was required in the HUMAN group compared to the BAYES and EPSAC groups. The time course analysis of the remifentanil effect-site concentration (CeREMI) revealed a significant increase in CeREMI in the EPSAC group compared to BAYES and HUMAN during the case. Although similar bias and divergence in control was found in all groups, larger control inaccuracy was observed in HUMAN versus EPSAC and BAYES. Spectrographic analysis of the system behavior shows that BAYES covers the largest spectrum of frequencies, followed by EPSAC and HUMAN. CONCLUSIONS: Both computer-based control systems are feasible to be used during ICU sedation with overall tighter control than HUMAN and even with lower required CePROP. EPSAC control required higher CeREMI than BAYES or HUMAN to maintain stable control. Clinical trial number: NCT00735631.

Safety and clinical effect of i.v. infusion of cyclopropyl-methoxycarbonyl etomidate (ABP-700), a soft analogue of etomidate, in healthy subjects.

BACKGROUND: Cyclopropyl-methoxycarbonyl metomidate, or ABP-700, is a second generation analogue of etomidate, developed to retain etomidate's beneficial haemodynamic and respiratory profile but diminishing its suppression of the adrenocortical axis. The objective of this study was to characterise the safety and efficacy of 30-min continuous infusions of ABP-700, and to assess its effect on haemodynamics and the adrenocortical response in healthy human volunteers. METHODS: Five cohorts involving 40 subjects received increasing infusion doses of ABP-700, propofol 60 µg kg-1 min-1 or placebo. Safety was evaluated through adverse event (AE) monitoring, safety laboratory tests, and arterial blood gasses. Haemodynamic and respiratory stability were assessed by continuous monitoring. Adrenocortical function was analysed by adrenocorticotropic hormone (ACTH) stimulation tests. Clinical effect was measured using the modified observer's assessment of alertness/sedation (MOAA/S) and continuous bispectral index monitoring. RESULTS: No serious AEs were reported. Haemodynamic and respiratory effects included mild dose-dependent tachycardia, slightly elevated blood pressure, and no centrally mediated apnoea. Upon stimulation with ACTH, no adrenocortical depression was observed in any subject. Involuntary muscle movements (IMM) were reported, which were more extensive with higher dosing regimens. Higher dosages of ABP-700 were associated with deeper sedation and increased likelihood of sedation. Time to onset of clinical effect was variable throughout the cohorts and recovery was swift. CONCLUSIONS: Infusions of ABP-700 showed a dose-dependent hypnotic effect, and did not cause severe hypotension, severe respiratory depression, or adrenocortical suppression. The presentation and nature of IMM is a matter of concern. CLINICAL TRIAL REGISTRATION: NTR4735.

Pharmacokinetic-pharmacodynamic model for propofol for broad application in anaesthesia and sedation.

BACKGROUND: Pharmacokinetic (PK) and pharmacodynamic (PD) models are used in target-controlled-infusion (TCI) systems to determine the optimal drug administration to achieve a desired target concentration in a central or effect-site compartment. Our aim was to develop a PK-PD model for propofol that can predict the bispectral index (BIS) for a broad population, suitable for TCI applications. METHODS: Propofol PK data were obtained from 30 previously published studies, five of which also contained BIS observations. A PK-PD model was developed using NONMEM. Weight, age, post-menstrual age (PMA), height, sex, BMI, and presence/absence of concomitant anaesthetic drugs were explored as covariates. The predictive performance was measured across young children, children, adults, elderly, and high-BMI individuals, and in simulated TCI applications. RESULTS: Overall, 15 433 propofol concentration and 28 639 BIS observations from 1033 individuals (672 males and 361 females) were analysed. The age range was from 27 weeks PMA to 88 yr, and the weight range was 0.68-160 kg. The final model uses age, PMA, weight, height, sex, and presence/absence of concomitant anaesthetic drugs as covariates. A 35-yr-old, 170 cm, 70 kg male (without concomitant anaesthetic drugs) has a V1, V2, V3, CL, Q2, Q3, and ke0 of 6.28, 25.5, 273 litres, 1.79, 1.75, 1.11 litres min-1, and 0.146 min-1, respectively. The propofol TCI administration using the model matches well with recommendations for all age groups considered for both anaesthesia and sedation. CONCLUSIONS: We developed a PK-PD model to predict the propofol concentrations and BIS for broad, diverse population. This should be useful for TCI in anaesthesia and sedation.

Phenylephrine increases cardiac output by raising cardiac preload in patients with anesthesia induced hypotension.

Induction of general anesthesia frequently induces arterial hypotension, which is often treated with a vasopressor, such as phenylephrine. As a pure α-agonist, phenylephrine is conventionally considered to solely induce arterial vasoconstriction and thus increase cardiac afterload but not cardiac preload. In specific circumstances, however, phenylephrine may also contribute to an increase in venous return and thus cardiac output (CO). The aim of this study is to describe the initial time course of the effects of phenylephrine on various hemodynamic variables and to evaluate the ability of advanced hemodynamic monitoring to quantify these changes through different hemodynamic variables. In 24 patients, after induction of anesthesia, during the period before surgical stimulus, phenylephrine 2 µg kg-1 was administered when the MAP dropped below 80% of the awake state baseline value for > 3 min. The mean arterial blood pressure (MAP), heart rate (HR), end-tidal CO2 (EtCO2), central venous pressure (CVP), stroke volume (SV), CO, pulse pressure variation (PPV), stroke volume variation (SVV) and systemic vascular resistance (SVR) were recorded continuously. The values at the moment before administration of phenylephrine and 5(T5) and 10(T10) min thereafter were compared. After phenylephrine, the mean(SD) MAP, SV, CO, CVP and EtCO2 increased by 34(13) mmHg, 11(9) mL, 1.02(0.74) L min-1, 3(2.6) mmHg and 4.0(1.6) mmHg at T5 respectively, while both dynamic preload variables decreased: PPV dropped from 20% at baseline to 9% at T5 and to 13% at T10 and SVV from 19 to 11 and 14%, respectively. Initially, the increase in MAP was perfectly aligned with the increase in SVR, until 150 s after the initial increase in MAP, when both curves started to dissociate. The dissociation of the evolution of MAP and SVR, together with the changes in PPV, CVP, EtCO2 and CO indicate that in patients with anesthesia-induced hypotension, phenylephrine increases the CO by virtue of an increase in cardiac preload.

Test of neural inertia in humans during general anaesthesia.

BACKGROUND: Neural inertia is defined as the tendency of the central nervous system to resist transitions between arousal states. This phenomenon has been observed in mice and Drosophila anaesthetized with volatile anaesthetics: the effect-site concentration required to induce anaesthesia in 50% of the population (C50) was significantly higher than the effect-site concentration for 50% of the population to recover from anaesthesia. We evaluated this phenomenon in humans using propofol or sevoflurane (both with or without remifentanil) as anaesthetic agents. METHODS: Thirty-six healthy volunteers received four sessions of anaesthesia with different drug combinations in a step-up/step-down design. Propofol or sevoflurane was administered with or without remifentanil. Serum concentrations of propofol and remifentanil were measured from arterial blood samples. Loss and return of responsiveness (LOR-ROR), response to pain (PAIN), Patient State Index (PSI) and spectral edge frequency (SEF) were modeled with NONMEM®. RESULTS: For propofol, the C50 for induction and recovery of anaesthesia was not significantly different across the different endpoints. For sevoflurane, for all endpoints except SEF, significant differences were found. For some endpoints (LOR and PAIN) the difference was significant only when sevoflurane was combined with remifentanil. CONCLUSIONS: Our results nuance earlier findings with volatile anaesthetics in mice and Drosophila. Methodological aspects of the study, such as the measured endpoint, influence the detection of neural inertia. A more thorough definition of neural inertia, with a robust methodological framework for clinical studies is required to advance our knowledge of this phenomenon. CLINICAL TRIAL REGISTRATION: NCT 02043938.

Influence of Bayesian optimization on the performance of propofol target-controlled infusion.

BACKGROUND: Target controlled infusion (TCI) systems use population-based pharmacokinetic (PK) models that do not take into account inter-individual residual variation. This study compares the bias and inaccuracy of a population-based vs a personalized TCI propofol titration using Bayesian adaptation. Haemodynamic and hypnotic stability, and the prediction probability of alternative PK models, was studied. METHODS: A double-blinded, prospective randomized controlled trial of 120 subjects undergoing cardiac surgery was conducted. Blood samples were obtained at 10, 35, 50, 65, 75 and 120 min and analysed using a point-of-care propofol blood analyser. Bayesian adaptation of the PK model was applied at 60 min in the intervention group. Median (Absolute) Performance Error (Md(A)PE) was used to evaluate the difference between bias and inaccuracy of the models. Haemodynamic (mean arterial pressure [MAP], heart rate) and hypnotic (bispectral index [BIS]) stability was studied. The predictive performance of four alternative propofol PK models was studied. RESULTS: MdPE and MdAPE did not differ between groups during the pre-adjustment period (control group: 6.3% and 16%; intervention group: 5.4% and 18%). MdPE differed in the post-adjustment period (12% vs. -0.3%), but MdAPE did not (18% vs. 15%). No difference in heart rate, MAP or BIS was found. Compared with the other models, the Eleveld propofol PK model (patients) showed the best prediction performance. CONCLUSIONS: When an accurate population-based PK model was used for propofol TCI, Bayesian adaption of the model improved bias but not precision. CLINICAL TRIAL REGISTRATION: Dutch Trial Registry NTR4518.

Dexmedetomidine pharmacokinetic-pharmacodynamic modelling in healthy volunteers: 1. Influence of arousal on bispectral index and sedation.

BACKGROUND: Dexmedetomidine, a selective α 2 -adrenoreceptor agonist, has unique characteristics, such as maintained respiratory drive and production of arousable sedation. We describe development of a pharmacokinetic-pharmacodynamic model of the sedative properties of dexmedetomidine, taking into account the effect of stimulation on its sedative properties. METHODS: In a two-period, randomized study in 18 healthy volunteers, dexmedetomidine was delivered in a step-up fashion by means of target-controlled infusion using the Dyck model. Volunteers were randomized to a session without background noise and a session with pre-recorded looped operating room background noise. Exploratory pharmacokinetic-pharmacodynamic modelling and covariate analysis were conducted in NONMEM using bispectral index (BIS) monitoring of processed EEG. RESULTS: We found that both stimulation at the time of Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale scoring and the presence or absence of ambient noise had an effect on the sedative properties of dexmedetomidine. The stimuli associated with MOAA/S scoring increased the BIS of sedated volunteers because of a transient 170% increase in the effect-site concentration necessary to reach half of the maximal effect. In contrast, volunteers deprived of ambient noise were more resistant to dexmedetomidine and required, on average, 32% higher effect-site concentrations for the same effect as subjects who were exposed to background operating room noise. CONCLUSIONS: The new pharmacokinetic-pharmacodynamic models might be used for effect-site rather than plasma concentration target-controlled infusion for dexmedetomidine in clinical practice, thereby allowing tighter control over the desired level of sedation. CLINICAL TRIAL REGISTRATION: NCT01879865.

Dexmedetomidine pharmacodynamics in healthy volunteers: 2. Haemodynamic profile.

BACKGROUND: Dexmedetomidine, a selective α 2 -adrenoreceptor agonist, has unique characteristics, with little respiratory depression and rousability during sedations. We characterized the haemodynamic properties of dexmedetomidine by developing a pharmacokinetic-pharmacodynamic (PKPD) model with a focus on changes in mean arterial blood pressure (MAP) and heart rate. METHODS: Dexmedetomidine was delivered i.v. to 18 healthy volunteers in a step-up fashion by target-controlled infusion using the Dyck model. Exploratory PKPD modelling and covariate analysis were conducted in NONMEM. RESULTS: Our model adequately describes dexmedetomidine-induced hypotension, hypertension, and bradycardia, with a greater effective concentration for the hypertensive effect. Changes in MAP were best described by a double-sigmoidal E max model with hysteresis. Covariate analysis revealed no significant covariates apart from age on the baseline MAP in the population pharmacokinetic model used to develop this PKPD model. Simulations revealed good general agreement with published descriptive studies of haemodynamics after dexmedetomedine infusion. CONCLUSIONS: The present integrated PKPD model should allow tighter control over the desired level of sedation, while limiting potential haemodynamic side-effects. CLINICAL TRIAL REGISTRATION: NCT01879865.

Propofol-based anaesthesia versus sevoflurane-based anaesthesia for living donor kidney transplantation: results of the VAPOR-1 randomized controlled trial.

BACKGROUND: Kidney transplantation is associated with harmful processes affecting the viability of the graft. One of these processes is associated with the phenomenon of ischaemia-reperfusion injury. Anaesthetic conditioning is a widely described strategy to attenuate ischaemia-reperfusion injury. We therefore conducted the Volatile Anaesthetic Protection of Renal Transplants-1 trial, a pilot project evaluating the influence of two anaesthetic regimens, propofol- vs sevoflurane-based anaesthesia, on biochemical and clinical outcomes in living donor kidney transplantation. METHODS: Sixty couples were randomly assigned to the following three groups: PROP (donor and recipient propofol), SEVO (donor and recipient sevoflurane), and PROSE (donor propofol and recipient sevoflurane). The primary outcome was renal injury reflected by urinary biomarkers. The follow-up period was 2 yr. RESULTS: Three couples were excluded, leaving 57 couples for analysis. Concentrations of kidney injury molecule-1 (KIM-1), N -acetyl-ß- d -glucosaminidase (NAG), and heart-type fatty acid binding protein (H-FABP) in the first urine upon reperfusion showed no differences. On day 2, KIM-1 concentrations were higher in SEVO [952.8 (interquartile range 311.8-1893.0) pg mmol -1 ] compared with PROP [301.2 (202.0-504.7) pg mmol -1 ]. This was the same for NAG: SEVO, 1.835 (1.162-2.457) IU mmol -1 vs PROP, 1.078 (0.819-1.713) IU mmol -1 . Concentrations of H-FABP showed no differences. Measured glomerular filtration rate at 3, 6, and 12 months showed no difference. After 2 yr, there was a difference in the acute rejection rate ( P =0.039). Post hoc testing revealed a difference between PROP (35%) and PROSE (5%; P =0.020). The difference between PROP and SEVO (11%) was not significant ( P =0.110). CONCLUSIONS: The SEVO group showed higher urinary KIM-1 and NAG concentrations in living donor kidney transplantation on the second day after transplantation. This was not reflected in inferior graft outcome. CLINICAL TRIAL REGISTRATION: NCT01248871.