Persistent hyperammonia and altered concentrations of urea cycle metabolites in a 5-day swine experiment of sepsis

Autonomic and vascular failures are common phenotypes of sepsis, typically characterized by tachycardia despite corrected hypotension/hypovolemia, vasopressor resistance, increased arterial stiffness and decreased peripheral vascular resistance. In a 5-day swine experiment of polymicrobial sepsis we aimed at characterizing arterial properties and autonomic mechanisms responsible for cardiovascular homeostasis regulation, with the final goal to verify whether the resuscitation therapy in agreement with standard guidelines was successful in restoring a physiological condition of hemodynamic profile, cardiovascular interactions and autonomic control. Twenty pigs were randomized to polymicrobial sepsis and protocol-based resuscitation or to prolonged mechanical ventilation and sedation without sepsis. The animals were studied at baseline, after sepsis development, and every 24 h during the 3-days resuscitation period. Beat-to-beat carotid blood pressure (BP), carotid blood flow, and central venous pressure were continuously recorded. The two-element Windkessel model was adopted to study carotid arterial compliance, systemic vascular resistance and characteristic time constant τ. Effective arterial elastance was calculated as a simple estimate of total arterial load. Cardiac baroreflex sensitivity (BRS) and low frequency (LF) spectral power of diastolic BP were computed to assess autonomic activity. Sepsis induced significant vascular and autonomic alterations, manifested as increased arterial stiffness, decreased vascular resistance and τ constant, reduced BRS and LF power, higher arterial afterload and elevated heart rate in septic pigs compared to sham animals. This compromised condition was persistent until the end of the experiment, despite achievement of recommended resuscitation goals by administered vasopressors and fluids. Vascular and autonomic alterations persist 3 days after goal-directed resuscitation in a clinically relevant sepsis model. We hypothesize that the addition of these variables to standard clinical markers may better profile patients’ response to treatment and this could drive a more tailored therapy which could have a potential impact on long-term outcomes.

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“…At the end of the experiment animals were euthanized by bolus infusion of 40 mmol of potassium chloride. Further details can be found in 26 .…”

Section: Methodsmentioning

confidence: 99%

Autonomic and circulatory alterations persist despite adequate resuscitation in a 5-day sepsis swine experiment

Carrara

Antenucci

Liu

et al. 2022

Sci Rep

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“…Effects of small increases in central venous pressure on hepatic arterial perfusion and hepatic oxygen consumption, and alterations in metabolic pathways suggested from plasma and cerebrospinal fluid samples have been reported previously [31,32] . Here we report data about the effects of repeated, acute reductions in hepatic DO 2 by portal vein occlusion on hepatic oxygen extraction capability and effects of sepsis on the HABR during prolonged resuscitation.…”

Section: Methodsmentioning

confidence: 74%

“…Systemic hemodynamics of the animals over time have been described previously [31,32] . Briefly, sepsis was associated with hyperthermia, hypotension, tachycardia and an increase in arterial lactate concentration.…”

Section: Evolution Of Signs Of Sepsis and Administered Treatmentmentioning

confidence: 99%

Hepatic blood flow regulation but not oxygen extraction capability is impaired in prolonged experimental abdominal sepsis

Liu

Köhler

Langer

et al. 2022

American Journal of Physiology-Gastrointestinal and Liver Physi

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Impaired oxygen utilization has been proposed to play a significant role in sepsis-induced liver dysfunction, but its magnitude and temporal course during prolonged resuscitation is controversial. The aim of this study is to evaluate the capability of the liver to increase oxygen extraction in sepsis during repeated acute portal vein blood flow reduction. Twenty anesthetized and mechanically ventilated pigs with hepatic hemodynamic monitoring were randomized to fecal peritonitis or controls (n=10, each). After 8-hour untreated sepsis, the animals were resuscitated for three days. The ability to increase hepatic O2 extraction was evaluated by repeated, acute decreases in hepatic oxygen delivery (DO2) via reduction of portal flow. Blood samples for liver function and liver biopsies were obtained repeatedly. While liver function tests, ATP content, and hepatic oxygen delivery (DO2) remained unaltered, there were signs of liver injury in blood samples and overt liver cell necrosis in biopsies. With acute portal vein occlusion, hepatic DO2 decreased more in septic animals compared to controls (max. decrease: 1.66±0.68 ml/min/kg in sepsis vs. 1.19±0.42 ml/min/kg in controls; Qpv reduction-sepsis interaction: p=0.028). Hepatic arterial buffer response (HABR) was impaired, but recovered after 3-day resuscitation, while hepatic oxygen extraction increased similarly during the procedures in both groups (max. increase: 0.27±0.13 in sepsis vs. 0.18±0.09 in controls; all p>0.05). Our data indicates maintained capacity of the liver to acutely increase O2 extraction, while blood flow regulation is transiently impaired with the potential to contribute to liver injury in sepsis.

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“…In these cohorts, 100% of control mice and ~93% of CLP/DCS mice survived to the experimental endpoint of 27/28 days (Figure 1A) or in combined studies assessing acute survival, 100% control mice and ~82% of CLP/DCS mice (Figure S1A). To longitudinally monitor sepsis progression in our model, we measured serum levels of CRP (a marker of inflammation found to be increased in both mouse and human sepsis studies), 33,34 and AST activity, an indicator of liver dysfunction found to be increased in both mouse and pig models of sepsis 25,33,35 (Figure 1B). Both CRP and AST were increased at CLP/DCS Day 4 (+67.90 ± 10.97% and +95.59 ± 28.66%, respectively).…”

Section: Utilization Of Cecal Ligation and Puncture And Daily Chronic...mentioning

confidence: 99%

Muscle stem cells contribute to long‐term tissue repletion following surgical sepsis

Schmitt

Dasgupta

Arneson‐Wissink

et al. 2023

J cachexia sarcopenia muscle

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Background Over the past decade, advances in sepsis identification and management have resulted in decreased sepsis mortality. This increase in survivorship has highlighted a new clinical obstacle: chronic critical illness (CCI), for which there are no effective treatment options. Up to half of sepsis survivors suffer from CCI, which can include multi-organ dysfunction, chronic inflammation, muscle wasting, physical and mental disabilities, and enhanced frailty. These symptoms prevent survivors from returning to regular day-to-day activities and are directly associated with poor quality of life. Methods Mice were subjected to cecal ligation and puncture (CLP) with daily chronic stress (DCS) as an in vivo model to study sepsis late-effects/sequelae on skeletal muscle components. Longitudinal monitoring was performed via magnetic resonance imaging, skeletal muscle and/or muscle stem cell (MuSCs) assays (e.g., post-necropsy wet muscle weights, minimum Feret diameter measurements, in vitro MuSC proliferation and differentiation, number of regenerating myofibres and numbers of Pax7-positive nuclei per myofibre), post-sepsis whole muscle metabolomics and MuSC isolation and high-content transcriptional profiling. Results We report several findings supporting the hypothesis that MuSCs/muscle regeneration are critically involved in post-sepsis muscle recovery. First, we show that genetic ablation of muscle stem cells (MuSCs) impairs post-sepsis muscle recovery (maintenance of 5-8% average lean mass loss compared with controls). Second, we observe impaired MuSCs expansion capacity and morphological defects at 26 days post-sepsis compared with control MuSCs (P < 0.001). Third, when subjected to an experimental muscle injury, sepsis-recovered mice exhibited evidence of impaired muscle regeneration compared with non-septic mice receiving the same muscle injury (CLP/DCS injured mean minimum Feret is 92.1% of control injured, P < 0.01). Fourth, we performed a longitudinal RNA sequencing study on MuSCs isolated from post-sepsis mice and found clear transcriptional differences in all post-sepsis samples compared with controls. At Day 28, CLP/DCS mice satellite cells have multiple altered metabolic pathways, such as oxidative phosphorylation, mitochondrial dysfunction, sirtuin signalling and oestrogen receptor signalling, compared with controls (P < 0.001). Conclusions Our data show that MuSCs and muscle regeneration are required for effective post-sepsis muscle recovery and that sepsis triggers morphological, functional, and transcriptional changes in MuSCs. Moving forward, we strive to leverage a more complete understanding of post-sepsis MuSC/regenerative defects to identify and test novel therapies that promote muscle recovery and improve quality of life in sepsis survivors.

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Persistent hyperammonia and altered concentrations of urea cycle metabolites in a 5-day swine experiment of sepsis

Cited by 5 publications

References 36 publications

Autonomic and circulatory alterations persist despite adequate resuscitation in a 5-day sepsis swine experiment

Autonomic and circulatory alterations persist despite adequate resuscitation in a 5-day sepsis swine experiment

Hepatic blood flow regulation but not oxygen extraction capability is impaired in prolonged experimental abdominal sepsis

Muscle stem cells contribute to long‐term tissue repletion following surgical sepsis

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