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Frithiof, Robert
Publications (9 of 9) Show all publications
Frithiof, R., Bandert, A., Larsson, A., Lipcsey, M. & Smekal, D. (2019). Central Venous Line and Dialysis Catheter Position Affects Drug Clearance during Continuous Renal Replacement Therapy in an Animal Model.. ASAIO journal (1992), 65(4), 408-413
Open this publication in new window or tab >>Central Venous Line and Dialysis Catheter Position Affects Drug Clearance during Continuous Renal Replacement Therapy in an Animal Model.
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2019 (English)In: ASAIO journal (1992), ISSN 1058-2916, E-ISSN 1538-943X, Vol. 65, no 4, p. 408-413Article in journal (Refereed) Published
Abstract [en]

In intensive care, drugs are commonly administered through central venous catheters (CVC). These catheters and central venous dialysis catheters (CVDC) are often placed in the same vessel for practical reasons. The aim of this experimental study was to investigate if the position of CVC and CVDC influences the elimination of infused drugs, during continuous renal replacement therapy (CRRT). In a randomized, cross-over model, anesthetized piglets received both a CVC and a CVDC in a jugular vein. Another CVDC was placed in a femoral vein for comparison. After baseline measurements, CRRT was performed in either of the CVDC, each CRRT-period separated by another baseline period. Hypotension was induced by peripherally given sodium nitroprusside. In the CVC, both gentamicin and noradrenaline were administered. Noradrenaline was titrated to reach a target blood pressure. When CRRT was performed using the CVDC in the same vessel as the drugs were infused, the plasma concentration of gentamicin was reduced compared with when the infusion and CVDC were in different vessels (5.66 [standard deviation (SD) ± 1.23] vs. 7.76 [SD ± 2.30] mg/L [p = 0.02]). The noradrenaline infusion rate needed to reach the target blood pressure was more than doubled (0.32 [SD ± 0.16] vs. 0.15 [SD ± 0.08] µg/kg/min [p = 0.006]). This experimental study indicates that the removal of drugs is increased if infusion is in close vicinity of the CVDC, during CRRT.

National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-353342 (URN)10.1097/MAT.0000000000000839 (DOI)000466791000022 ()29863633 (PubMedID)
Funder
Swedish Research Council, 523-2014-2569
Available from: 2018-10-18 Created: 2018-10-18 Last updated: 2019-05-29Bibliographically approved
Hanslin, K., Sjölin, J., Skorup, P., Wilske, F., Frithiof, R., Larsson, A., . . . Lipcsey, M. (2019). The impact of the systemic inflammatory response on hepatic bacterial elimination in experimental abdominal sepsis. Intensive Care Medicine Experimental, 7(1), Article ID 52.
Open this publication in new window or tab >>The impact of the systemic inflammatory response on hepatic bacterial elimination in experimental abdominal sepsis
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2019 (English)In: Intensive Care Medicine Experimental, ISSN 2197-425X, Vol. 7, no 1, article id 52Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Bacterial translocation from the gut has been suggested to induce a systemic inflammatory response syndrome (SIRS) and organ dysfunction. The liver has a pivotal role in eliminating circulating bacteria entering from the gut. We investigated whether pre-existing inflammation affects hepatic bacterial elimination.

METHODS: Fifteen anaesthetised piglets were infused with E. coli in the portal vein for 3 h. The naive group (n = 6) received the bacterial infusion without endotoxin exposure. SIRS (SIRS group, n = 6) was induced by endotoxin infusion 24 h before the bacterial infusion. For effects of anaesthesia, controls (n = 3) received saline instead of endotoxin for 24 h. Bacterial counts and endotoxin levels in the portal and hepatic veins were analysed during bacterial infusion.

RESULTS: The bacterial killing rate was higher in the naive group compared with the SIRS group (p = 0.001). The ratio of hepatic to portal venous bacterial counts, i.e. the median bacterial influx from the splanchnic circulation, was 0.06 (IQR 0.01-0.11) in the naive group and 0.71 (0.03-1.77) in the SIRS group at 3 h, and a magnitude lower in the naive group during bacteraemia (p = 0.03). Similar results were seen for hepatic endotoxin elimination. Peak log tumour necrosis factor alpha was higher in the naive 4.84 (4.77-4.89) vs. the SIRS group 3.27 (3.26-3.32) mg/L (p < 0.001).

CONCLUSIONS: Our results suggest that hepatic bacterial and endotoxin elimination is impaired in pigs with pre-existing SIRS while the inflammatory response to bacterial infusion is diminished. If similar mechanisms operate in human critical illness, the hepatic elimination of bacteria from the gut could be impaired by SIRS.

Keywords
Animal models, Bacterial translocation, Endotoxins, Escherichia coli, Mononuclear phagocyte system, Sepsis
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-392098 (URN)10.1186/s40635-019-0266-x (DOI)000483360800001 ()31456116 (PubMedID)
Funder
Swedish Society of Medicine, SLS-409831
Available from: 2019-08-29 Created: 2019-08-29 Last updated: 2019-10-18Bibliographically approved
Anderberg, S. B., Luther, T. & Frithiof, R. (2017). Physiological aspects of Toll-like receptor 4 activation in sepsis-induced acute kidney injury. Acta Physiologica, 219(3), 575-590
Open this publication in new window or tab >>Physiological aspects of Toll-like receptor 4 activation in sepsis-induced acute kidney injury
2017 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 219, no 3, p. 575-590Article, review/survey (Refereed) Published
Abstract [en]

Sepsis-induced acute kidney injury (SI-AKI) is common and associated with high mortality. Survivors are at increased risk of chronic kidney disease. The precise mechanism underlying SI-AKI is unknown, and no curative treatment exists. Toll-like receptor 4 (TLR4) activates the innate immune system in response to exogenous microbial products. The result is an inflammatory reaction aimed at clearing a potential infection. However, the consequence may also be organ dysfunction as the immune response can cause collateral damage to host tissue. The purpose of this review is to describe the basis for how ligand binding to TLR4 has the potential to cause renal dysfunction and the mechanisms by which this may take place in gram-negative sepsis. In addition, we highlight areas for future research that can further our knowledge of the pathogenesis of SI-AKI in relation to TLR4 activation. TLR4 is expressed in the kidney. Activation of TLR4 causes cytokine and chemokine release as well as renal leucocyte infiltration. It also results in endothelial and tubular dysfunction in addition to altered renal metabolism and circulation. From a physiological standpoint, inhibiting TLR4 in large animal experimental SI-AKI significantly improves renal function. Thus, current evidence indicates that TLR4 has the ability to mediate SI-AKI by a number of mechanisms. The strong experimental evidence supporting a role of TLR4 in the pathogenesis of SI-AKI in combination with the availability of pharmacological tools to target TLR4 warrants future human studies.

Place, publisher, year, edition, pages
WILEY-BLACKWELL, 2017
Keywords
acute kidney injury, AKI, renal, sepsis, TLR4, Toll-like receptor
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-320085 (URN)10.1111/apha.12798 (DOI)000393941300006 ()27602552 (PubMedID)
Funder
Swedish Research Council, 523-2014-2569
Note

De två första författarna delar förstaförfattarskapet

Available from: 2017-05-03 Created: 2017-05-03 Last updated: 2017-05-03Bibliographically approved
Nilsson, K. F., Sandin, J., Gustafsson, L. E. & Frithiof, R. (2017). The novel nitric oxide donor PDNO attenuates ovine ischemia-reperfusion induced renal failure. Intensive Care Medicine Experimental, 5, Article ID 29.
Open this publication in new window or tab >>The novel nitric oxide donor PDNO attenuates ovine ischemia-reperfusion induced renal failure
2017 (English)In: Intensive Care Medicine Experimental, ISSN 1646-2335, E-ISSN 2197-425X, Vol. 5, article id 29Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Renal ischemia-reperfusion injury is a common cause of acute kidney injury in intensive care and surgery. Recently, novel organic mononitrites of 1,2-propanediol (PDNO) were synthesized and shown to rapidly and controllably deploy nitric oxide in the circulation when administered intravenously. We hypothesized that intravenous infusion of PDNO during renal ischemia reperfusion would improve post-ischemic renal function and microcirculation.

METHODS: Sixteen sheep were anesthetized, mechanically ventilated, and surgically instrumented. The left renal artery was clamped for 90 min, and the effects of ischemia were studied for a total of 8 h. Fifteen minutes prior to the release of the clamp, intravenous infusions of PDNO (n = 8) or vehicle (1,2 propanediol + inorganic nitrite, n = 8) were initiated (180 nmol/kg/min for 30 min, thereafter 60 nmol/kg/min for the remainder of the experiment).

RESULTS: Renal artery blood flow, cortical and medullary perfusion, and diuresis and creatinine clearance decreased in the left kidney post ischemia. However, in the sheep treated with PDNO, diuresis and creatinine clearance in the left kidney were significantly higher post ischemia compared to vehicle-treated animals (1.7 ± 0.5 vs 0.7 ± 0.3 ml/kg/h, p = 0.04 and 7.5 ± 2.1 vs 1.7 ± 0.6 ml/min, p = 0.02, respectively). Left renal medullary perfusion and oxygen uptake were higher in the PDNO group (73 ± 9 vs 37 ± 5% of baseline, p = 0.004 and 2.6 ± 0.4 vs 1.6 ± 0.3 ml/min, p = 0.02, respectively). PDNO significantly increased renal oxygen consumption and reduced the oxygen utilization for sodium reabsorption (p = 0.03 for both). Mean arterial blood pressure was significantly reduced by PDNO (83 ± 3 vs 94 ± 3 mmHg, p = 0.02) but was still within normal limits. Total renal blood flow was not affected, and there were no signs of increased blood methemoglobin concentrations or tachyphylaxis.

CONCLUSIONS: The novel nitric oxide donor PDNO improved renal function after ischemia. PDNO also prevented the persistent reduction in medullary perfusion during reperfusion and improved renal oxygen utilization without severe side effects.

Keywords
AKI, Acute kidney injury, Kidney, Microcirculation, Nitrites, Renal oxygen consumption, Sheep
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-336459 (URN)10.1186/s40635-017-0143-4 (DOI)000446932200001 ()28600797 (PubMedID)
Funder
Swedish Research Council, 523-2014-2569Swedish National Space BoardSwedish Society for Medical Research (SSMF)
Available from: 2017-12-14 Created: 2017-12-14 Last updated: 2019-02-20Bibliographically approved
Lipcsey, M., Tenhunen, J., Sjölin, J., Frithiof, R., Bendel, S., Flaatten, H., . . . Rubertsson, S. (2016). Abdominal Septic Shock - Endotoxin Adsorption Treatment (ASSET) - endotoxin removal in abdominal and urogenital septic shock with the Alteco (R) LPS Adsorber: study protocol for a double-blinded, randomized placebo-controlled trial. Trials, 17, Article ID 587.
Open this publication in new window or tab >>Abdominal Septic Shock - Endotoxin Adsorption Treatment (ASSET) - endotoxin removal in abdominal and urogenital septic shock with the Alteco (R) LPS Adsorber: study protocol for a double-blinded, randomized placebo-controlled trial
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2016 (English)In: Trials, ISSN 1745-6215, E-ISSN 1745-6215, Vol. 17, article id 587Article in journal (Refereed) Published
Abstract [en]

Background: Severe sepsis and septic shock are common in intensive care and carry high mortality rates. In patients with Gram-negative infections, early and extensive removal of endotoxin may limit the inflammatory response that characterizes septic shock. The Alteco (R) LPS Adsorber (hereafter referred to cited as the lipopolysaccharide (LPS) Adsorber) can be used for endotoxin removal and attenuate the deleterious inflammatory and clinical responses seen in septic shock. Methods/design: The Abdominal Septic Shock - Endotoxin Adsorption Treatment (ASSET) trial is a pilot study investigating the feasibility and safety of LPS Adsorber therapy. This pilot, multicenter, stratified, parallel, double-blinded, randomized, phase IIa, feasibility clinical investigation will be performed in five Scandinavian intensive care units. Thirty-two subjects with early septic shock and organ failure, following adequate resuscitation, will be randomized to receive either: extracorporeal veno-venous hemoperfusion therapy with the LPS Adsorber or veno-venous hemoperfusion therapy with a placebo adsorber (without active LPS-binding peptide). Patients will be stratified by infection focus such that 20 subjects with an abdominal focus (stratum A) and 12 subjects with a urogenital focus (stratum B) will be included in a parallel design. Thereafter, an interim analysis will be performed and an additional 12 patients may be included in the study. The study is designed as adaptive a priori: the patients from this study can be included in a later phase IIb study. The aim of the study is to investigate the feasibility of LPS Adsorber therapy commenced early in the time-course of septic shock. The primary endpoint will be a characterization of all reported unanticipated serious adverse device effects and anticipated serious adverse device effects. Secondary outcomes are decrease in endotoxin plasma concentration, impact on clinical outcome measures and impact on inflammatory response by LPS Adsorber therapy, as well as detailed description of the relevant mediators bound to the LPS Adsorber. Recruitment of patients will start in September 2015. Discussion: The ASSET trial will give insight into the feasibility and safety of this LPS Adsorber therapy and preliminary data on its potential clinical effects in septic shock. Moreover, this pilot trial will provide with necessary data for designing future studies.

Keywords
Septic shock, Endotoxins, Hemoperfusion, Gram-negative bacteria
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-313532 (URN)10.1186/s13063-016-1723-4 (DOI)000390388800006 ()
Funder
Swedish Research Council, 523-2014-2569
Available from: 2017-02-01 Created: 2017-01-20 Last updated: 2017-11-29Bibliographically approved
Hanslin, K., Sjölin, J., Skorup, P., Wilske, F., Frithiof, R., Larsson, A., . . . Lipcsey, M. (2016). Pre-existing systemic inflammation attenuates bacterial clearance by the liver in porcine abdominal sepsis. Intensive Care Medicine Experimental, 3(suppl. 1), A620
Open this publication in new window or tab >>Pre-existing systemic inflammation attenuates bacterial clearance by the liver in porcine abdominal sepsis
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2016 (English)In: Intensive Care Medicine Experimental, ISSN 1646-2335, E-ISSN 2197-425X, Vol. 3, no suppl. 1, p. A620-Article in journal, Meeting abstract (Refereed) Published
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-310602 (URN)10.1186/2197-425X-3-S1-A620 (DOI)
Available from: 2016-12-16 Created: 2016-12-16 Last updated: 2017-08-16Bibliographically approved
Frithiof, R., Xing, T., McKinley, M. J., May, C. N. & Ramchandra, R. (2014). Intracarotid hypertonic sodium chloride differentially modulates sympathetic nerve activity to the heart and kidney. American Journal of Physiology. Regulatory Integrative and Comparative Physiology, 306(8), R567-R575
Open this publication in new window or tab >>Intracarotid hypertonic sodium chloride differentially modulates sympathetic nerve activity to the heart and kidney
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2014 (English)In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 306, no 8, p. R567-R575Article in journal (Refereed) Published
Abstract [en]

Frithiof R, Xing T, McKinley MJ, May CN, Ramchandra R. Intracarotid hypertonic sodium chloride differentially modulates sympathetic nerve activity to the heart and kidney. Am J Physiol Regul Integr Comp Physiol 306: R567-R575, 2014. First published February 12, 2014; doi: 10.1152/ajpregu. 00460.2013.-Hypertonic NaCl infused into the carotid arteries increases mean arterial pressure (MAP) and changes sympathetic nerve activity (SNA) via cerebral mechanisms. We hypothesized that elevated sodium levels in the blood supply to the brain would induce differential responses in renal and cardiac SNA via sensors located outside the blood-brain barrier. To investigate this hypothesis, we measured renal and cardiac SNA simultaneously in conscious sheep during intracarotid infusions of NaCl (1.2 M), sorbitol (2.4 M), or urea (2.4 M) at 1 ml/min for 4 min into each carotid. Intracarotid NaCl significantly increased MAP (91 +/- 2 to 97 +/- 3 mmHg, P < 0.05) without changing heart rate (HR). Intracarotid NaCl was associated with no change in cardiac SNA (11 +/- 5.0%), but a significant inhibition of renal SNA (-32.5 +/- 6.4%, P < 0.05). Neither intracarotid sorbitol nor urea changed MAP, HR, central venous pressure, cardiac SNA, and renal SNA. The changes in MAP and renal SNA were completely abolished by microinjection of the GABA agonist muscimol (5 mM, 500 nl each side) into the paraventricular nucleus of the hypothalamus (PVN). Infusion of intracarotid NaCl for 20 min stimulated a larger increase in water intake (1,100 +/- 75 ml) than intracarotid sorbitol (683 +/- 125 ml) or intracarotid urea (0 ml). These results demonstrate that acute increases in blood sodium levels cause a decrease in renal SNA, but no change in cardiac SNA in conscious sheep. These effects are mediated by cerebral sensors located outside the blood-brain barrier that are more responsive to changes in sodium concentration than osmolality. The renal sympathoinhibitory effects of sodium are mediated via a pathway that synapses in the PVN.

Keywords
hypertonic saline, parventricular nucleus of the hypothalamus, sodium, sympathetic nerve activity
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-225066 (URN)10.1152/ajpregu.00460.2013 (DOI)000334679100005 ()
Available from: 2014-06-23 Created: 2014-05-27 Last updated: 2018-01-11Bibliographically approved
Fenhammar, J., Rundgren, M., Hultenby, K., Forestier, J., Taavo, M., Kenne, E., . . . Frithiof, R. (2014). Renal effects of treatment with a TLR4-inhibitor in conscious septic sheep. Critical Care, 18(5), 488
Open this publication in new window or tab >>Renal effects of treatment with a TLR4-inhibitor in conscious septic sheep
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2014 (English)In: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 18, no 5, p. 488-Article in journal (Refereed) Published
Abstract [en]

Introduction: Acute kidney injury (AKI) is a common and feared complication of sepsis. The pathogenesis of sepsis-induced AKI is largely unknown, and therapeutic interventions are mainly supportive. In the present study, we tested the hypothesis that pharmacological inhibition of Toll-like receptor 4 (TLR4) would improve renal function and reduce renal damage in experimental sepsis, even after AKI had already developed. Methods: Sheep were surgically instrumented and subjected to a 36-hour intravenous infusion of live Escherichia coli. After 12 hours, they were randomized to treatment with a selective TLR4 inhibitor (TAK-242) or vehicle. Results: The E. coli caused normotensive sepsis characterized by fever, increased cardiac index, hyperlactemia, oliguria, and decreased creatinine clearance. TAK-242 significantly improved creatinine clearance and urine output. The increase in N-acetyl-beta-D-glucosaminidas, a marker of tubular damage, was attenuated. Furthermore, TAK-242 reduced the renal neutrophil accumulation and glomerular endothelial swelling caused by sepsis. These effects were independent of changes in renal artery blood flow and renal microvascular perfusion in both cortex and medulla. TAK-242 had no effect per se on the measured parameters. Conclusions: These results show that treatment with a TLR4 inhibitor is able to reverse a manifest impairment in renal function caused by sepsis. In addition, the results provide evidence that the mechanism underlying the effect of TAK-242 on renal function does not involve improved macro-circulation or micro-circulation, enhanced renal oxygen delivery, or attenuation of tubular necrosis. TLR4-mediated inflammation resulting in glomerular endothelial swelling may be an important part of the pathogenesis underlying Gram-negative septic acute kidney injury.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-231584 (URN)10.1186/s13054-014-0488-y (DOI)000351850600011 ()25182709 (PubMedID)
Available from: 2014-09-09 Created: 2014-09-09 Last updated: 2017-12-05Bibliographically approved
Frithiof, R. (2014). Toll-like receptor 4 in sepsis-induced renal failure. Paper presented at Scandinavian Physiological Society's Annual Meeting, 22–24 August 2014, Stockholm, Sweden. Acta Physiologica, 211(S696), 39-39, Article ID 7:3.
Open this publication in new window or tab >>Toll-like receptor 4 in sepsis-induced renal failure
2014 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, no S696, p. 39-39, article id 7:3Article in journal, Meeting abstract (Other academic) Published
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-247711 (URN)000349466000047 ()
Conference
Scandinavian Physiological Society's Annual Meeting, 22–24 August 2014, Stockholm, Sweden
Available from: 2015-03-24 Created: 2015-03-23 Last updated: 2018-01-11Bibliographically approved
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