Wenyi Wang (1), Anders Thorsted (1), Markus Castegren (2), Miklos Lipcsey (2), Jan Sjölin (3), Lena E. Friberg (1), Elisabet I. Nielsen (1)
Institution: (1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, (2) Department of Medical Sciences, Uppsala University, Uppsala, Sweden, (3) Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
Introduction: Sepsis is a life-threatening clinical condition resulting from exaggerated immune activation, often in response to bacterial infection, and it is the leading cause of death among those hospitalized in the intensive care unit (ICU) [1]. The progression of sepsis can be studied in mammals by the administration of endotoxin (ETX), a component in the cell membrane of Gram-negative bacteria, resulting in a systemic inflammatory response [2]. Such an immune activation has large impact on the physiological status of the individual, with clear impact on the respiratory and circulatory system, as the body is under stress [3]. The cardiovascular system plays an important role in the clinical outcome of sepsis and septic shock, with an increase of the mortality rate by 70% to 90% among septic patients with cardiovascular impairments [4]. Previously, non-linear mixed effect modelling has been applied to assess the relation between ETX exposure and immune activation as measured by the cytokine response [5]. The aim with the current project was to investigate the exposure-response relationship between infused ETX and changes to the cardiovascular system, as measured by hemodynamic outcomes.
Methods: Data was acquired from four experimental studies where ETX was administered to anesthetized piglets (n=68) [5-8]. Intravenous infusion of ETX in rates from 0.063 to 16.0 μg/kg/h were used across six-hour studies, with infusion lengths between 1 to 6 hours. Based on the recorded hemodynamic data, sub-models were built for each of the following outcomes: mean pulmonary arterial pressure (MPAP), cardiac output (CO) and heart rate (HR). In order to describe the time-courses for each of the outcomes, baselines with or without inclusion of disease progression (asymptotic) were initially established, before ETX exposure-response models (linear, Emax or sigmoidal Emax) were assessed as either direct or delayed effects.
The non-linear mixed effect model analysis was performed in NONMEM version 7.4.3 (ICON Development Solutions) using FOCE for parameter estimation.
Results: All dose groups showed an approximate doubling of MPAP from the baseline value following infusion with no change in control groups. The increase was described as an indirect effect, where an Emax model was related to the ETX concentration, with an effect compartment incorporated to account for a delay in response, resulting in similar increase across all dose groups, due to a low EC50 relative to concentrations (9.54 EU/L) and an Emax of 1.01 (a doubling effect of the baseline). The CO only decreased for the groups receiving an ETX infusion. An indirect response model described the decrease in ETX treated groups, with EC50 and Emax estimated to 5.04 EU/L (again, low compared to ETX exposure) and 0.424 (maximum reduction to 42% of the baseline CO). For HR, the piglets receiving the highest infusion rates showed an approximate doubling over the baseline value mid-way through the six-hour study period, with small increases in controls and at lower infusion rates. An asymptotic model was used to describe the general increase in HR over time, and an Emax model was coupled to the ETX exposure through an effect compartment model describing the ETX effect. All models were evaluated by visual predictive checks (VPC) stratified on the individual design arms, which demonstrated that the models could adequately describe the median of the experimental data.
Conclusions: Models were developed to describe the relationship between ETX exposure and the measured outcomes for the cardiovascular system, including MPAP, CO and HR. The developed models quantifies the changes in the variables over time after exposure to ETX to increase the understanding of the cardiovascular system response. Eventually, the models may be extrapolated to the human to assist treatment of sepsis.
References:
[1] Rello J, Valenzuela-Sánchez, Francisco, Ruiz-Rodriguez M, Moyano S. Sepsis: A Review of Advances in Management. Adv Ther. 2017 Nov;34(11):2393-2411.
[2] Goscinski G, Lipcsey M, Eriksson M, Larsson A, Tano E, Sjölin J. Endotoxin neutralization and anti-inflammatory effects of tobramycin and ceftazidime in porcine endotoxin shock. Crit Care. 2004 Feb;8(1):R35-41.
[3] Elisabetta G, Enrico L, Ornella B, Barbara V, Giuseppe M. Platelets and Multi-Organ Failure in Sepsis. Int J Mol Sci. 2017 Oct;18(10):2200.
[4] Kakihana Y, Ito T, Nakahara M, Yamaguchi K, Yasuda T. Sepsis-induced myocardial dysfunction: pathophysiology and management. J Intensive Care, 2016 Mar;4:22.
[5] Thorsted A, Bouchene S, Tano E, Castegren M, Lipcsey M, Sjölin J, Karlsson MO, Friberg LE, Nielsen EI. A non-linear mixed effect model for innate immune response: In vivo kinetics of endotoxin and its induction of the cytokines tumor necrosis factor alpha and interleukin-6. PLoS ONE. 2019 Feb 21;14(2):e0211981
[6] Lipcsey M, Larsson A, Eriksson MB, Sjölin J. Inflammatory, coagulatory and circulatory responses to logarithmic increases in the endotoxin dose in the anaesthetized pig. J Endotoxin Res. 2006;12(2):99-112.
[7] Carlsson M, Lipcsey M, Larsson A, Tano E, Rubertsson S, Eriksson M, Sjolin J. Inflammatory and circulatory effects of the reduction of endotoxin concentration in established porcine endotoxemic shock – a model of endotoxin elimination. Crit Care Med. 2009 Mar;37(3):1031-e4.
[8] Lipcsey M, Larsson A, Eriksson MB, Sjölin J. Effect of the administration rate on the biological responses to a fixed dose of endotoxin in the anesthetized pig Shock. 2008 Feb;29(2):173-80.
Reference: PAGE 28 (2019) Abstr 9143 [www.page-meeting.org/?abstract=9143]
Poster: Drug/Disease Modelling - Infection