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Acute Normovolemic Hemodilution in the Pig Is Associated with Renal Tissue Edema, Impaired Renal Microvascular Oxygenation, and Functional Loss

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Acute Normovolemic Hemodilution in the Pig Is Associated with Renal Tissue Edema, Impaired Renal Microvascular Oxygenation, and Functional Loss PERIOPERATIVE MEDICINE Acute Normovolemic Hemodilution in the Pig Is Associated with Renal Tissue Edema, Impaired Renal Microvascular Oxygenation, and Functional Loss Franziska M. Konrad, M.D.,* Egbert G. Mik, M.D., Ph.D.,† Sander I. A. Bodmer, M.D.,‡ N. Bahar Ates, M.D.,§ Henriëtte F. E. M. Willems, M.D.,§ Karin Klingel, M.D.,|| Hilde R. H. de Geus, Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/119/2/256/261133/20130800_0-00012.pdf by guest on 29 September 2021 M.D.,# Robert Jan Stolker, M.D., Ph.D.,** Tanja Johannes, M.D., Ph.D.†† ABSTRACT What We Already Know about This Topic • As more restrictive transfusion is advanced, hemodilution and Background: The authors investigated the impact of acute its influence on acute kidney injury are of increasing impor- tance normovolemic hemodilution (ANH) on intrarenal oxygen- • Intrarenal hypoxia is likely one factor contributing to acute kid- ation and its functional short-term consequences in pigs. ney injury during the perioperative period O Methods: Renal microvascular oxygenation (µP 2) was measured in cortex, outer and inner medulla via three implanted optical fibers by oxygen-dependent quenching What This Article Tells Us That Is New of phosphorescence. Besides systemic hemodynamics, renal function, histopathology, and hypoxia-inducible factor- • Compared with colloid (hydroxyethyl starch 6% 130/0.4), nor- movolemic hemodilution with crystalloid (balanced electrolyte 1α expression were determined. ANH was performed in solution) produced greater renal hypoxia indicating the dilu- n = 18 pigs with either colloids (hydroxyethyl starch 6% ent may be a factor when evaluating hemodilution and acute 130/0.4) or crystalloids (full electrolyte solution), in three kidney injury steps from a hematocrit of 30% at baseline to a hematocrit * Resident, Department of Anesthesiology and Intensive Care Medicine, University Hospital Tübingen, Tübingen, Germany, and of 15% (H3). O Research Associate, Department of Anesthesiology, Laboratory Results: ANH with crystalloids decreased µP 2 in cortex and of Experimental Anesthesiology, Erasmus MC, University Medical outer medulla approximately by 65% (P < 0.05) and in inner Center Rotterdam, Rotterdam, The Netherlands. † Staff Anesthesi- ologist, ‡ Research Associate, § Resident, ** Professor and Chair, medulla by 30% (P < 0.05) from baseline to H3. In contrast, O †† Staff Anesthesiologist, Department of Anesthesiology, Laboratory µP 2 remained unaltered during ANH with colloids. Further- of Experimental Anesthesiology, Erasmus MC, University Medical more, renal function decreased by approximately 45% from Center Rotterdam. ‖ Professor, Department of Molecular Pathology, Institute of Pathology, University Hospital Tübingen. # Staff Inten- baseline to H3 (P < 0.05) only in the crystalloid group. Three sivist, Department of Intensive Care, Erasmus MC, University Medi- times more volume of crystalloids was administered compared cal Center Rotterdam. with the colloid group. Alterations in systemic and renal regional Received from the Department of Anesthesiology, Laboratory hemodynamics, oxygen delivery and oxygen consumption dur- of Experimental Anesthesiology, Erasmus MC, University Medi- cal Center Rotterdam, Rotterdam, The Netherlands. Submitted for ing ANH, gave no obvious explanation for the deterioration of O publication January 18, 2012. Accepted for publication March 12, µP 2 in the crystalloid group. However, ANH with crystalloids 2013. Supported in part by a grant of the ƒortüne-program (to Dr. was associated with the highest formation of renal tissue edema Johannes; No. 1717-0-0, Medical Faculty, University of Tübingen, α Tübingen, Germany) and institutional funding from the Depart- and the highest expression of hypoxia-inducible factor-1 , ment of Anesthesiology, Laboratory of Experimental Anesthesiol- which was mainly localized in distal convoluted tubules. ogy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Conclusions: ANH to a hematocrit of 15% statistically sig- The Netherlands. The authors declare no competing interests. nificantly impaired µPO and renal function in the crystalloid Address correspondence to Dr. Johannes: Department of Anes- 2 thesiology, Laboratory of Experimental Anesthesiology, Erasmus MC, University Medical Center Rotterdam, ‘s-Gravendijkwal 230, ◇ This article is featured in “This Month in Anesthesiology.” 3015 CE Rotterdam, The Netherlands. [email protected]. Please see this issue of ANESTHESIOLOGY, page 3A. This article may be accessed for personal use at no charge through ◆ This article is accompanied by an Editorial View. Please see: the Journal Web site, www.anesthesiology.org. Ince C: The great fluid debate: When will physiology prevail? Copyright © 2013, the American Society of Anesthesiologists, Inc. Lippincott ANESTHESIOLOGY 2013; 119:248–9. Williams & Wilkins. Anesthesiology 2013; 119:256-69 Anesthesiology, V 119 • No 2 256 August 2013 PERIOPERATIVE MEDICINE group. Less tissue edema formation and an unimpaired renal Materials and Methods O µP 2 in the colloid group might account for a preserved Animals renal function. The protocol of the current study was approved by the Animal Research Committee of the Erasmus MC, University Medical ORMOVOLEMIC hemodilution with crystalloid Center Rotterdam, Rotterdam, The Netherlands (DEC Nr. N or colloid solutions is a common technique to reduce EMC 2041 [EMC Nr. 129-10-01]). Animal care and han- the requirements for allogeneic blood transfusion. Hemodi- dling were performed in accordance with the national guide- lution can be the result of fluid resuscitation in emergency lines for care of laboratory animals. For the experiments 18 situations1 and of volume therapy in the daily routine.2,3 female crossbred Landrace × Yorkshire pigs, with mean body There are not much data on the influence of hemodilution weights of 30.5 ± 1 kg (mean ± standard error) were used. Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/119/2/256/261133/20130800_0-00012.pdf by guest on 29 September 2021 on renal function. In previous investigations, hemodilution Experimental Preparation has been identified as an important risk factor in the devel- After an overnight fast with free access to water, the ani- opment of acute kidney injury (AKI) for patients undergo- mals were sedated with an intramuscular injection of ket- 4,5 ing cardiopulmonary bypass. However, transposition of amine (30 mg/kg; Alfasan, Woerden, The Netherlands) data observed in cardiac surgery is quite speculative as clini- and midazolam (1 mg/kg; Roche, Mijdrecht, The Nether- cal conditions may vary in other surgical contexts. Therefore, lands). Tracheotomy was performed under continuous infu- more research into the relationship between hemodilution sion of ketamine (17 mg·kg−1·h−1) and midazolam (1.25 and the occurrence of AKI is necessary. mg·kg−1·h−1). After tracheotomy, sufentanil (8 µg·kg−1·h−1; One reason for the development of AKI after hemodilu- Janssen-Cilag, Tilburg, The Netherlands) was administered tion could be a high renal sensitivity to decreased hematocrit. as an analgesic agent. Muscle relaxation was obtained by Although under physiological circumstances the kidney’s single-dose of pancuronium bromide (0.3 mg/kg; Organon, Oss, The Netherlands) before laparotomy. oxygen delivery (DO2) exceeds its oxygen consumption by far,6 our group could demonstrate an immediate impairment Mechanical ventilation (Servo 300; Siemens-Elema, IO in renal cortical and outer medullary microvascular oxygen- Solna, Sweden) was performed standardized with an F 2 of ation and a supply dependency for oxygen, when hematocrit 30% and maintaining normocapnia (arterial carbon dioxide started to drop during acute normovolemic hemodilution tension, 40 mmHg). Central body temperature was main- tained at approximately 38°C with two heating pads under (ANH) in the rat.7 There was a correlation between renal and a heating lamp above the animal. A crystalloid solution oxygen consumption (VO ) and microvascular PO (µPO ) 2 2 2 (Sterofundin; B. Braun, Melsungen, Germany) was admin- during reduction in hematocrit, which was accompanied by istered (15 ml·kg−1·h−1) as maintenance fluid. an increase in intrarenal oxygen shunt. Therefore, our previ- Two peripheral catheters were placed in the ears for ous results demonstrated that the renal oxygen supply of the administration of fluids and anesthesia. One line (20G; kidney became critical already in an early stage of ANH. Vygon, Écouen, France) was inserted in the left internal There is more and more evidence that a disturbed intra- carotid artery for measuring arterial blood pressure and for renal oxygenation plays an important role in the develop- collection of blood samples. A pulmonary artery thermodi- ment of AKI,8 although a direct link between renal hypoxia lution catheter (Edwards 7-French; Baxter Healthcare Corp., and functional loss could not yet been identified. Recent Round Lake, IL) was positioned in the pulmonary artery via studies indicate that renal hypoxia can stimulate fibrogen- an introducer in the right jugular vein allowing the measure- esis with the consequence of glomerular and tubulointes- ment of central venous pressure (CVP), pulmonary artery, titial scarring.9 The activation of hypoxia-inducible factor and pulmonary capillary wedge pressure, central body tem- (HIF) is an oxygen-dependent mechanism to prevent renal perature, continuous cardiac output, and collection of cen- damage.10 However, increased HIF expression, caused
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