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Background: The patient's individual anemia tolerance is pivotal when blood transfusions become necessary, but are not feasible for some reason. To date, the effects of neuromuscular blockade (NMB) on anemia tolerance have not been investigated. Methods: 14 anesthetized and mechanically ventilated pigs were randomly assigned to the Roc group (3.78 mg/kg rocuronium bromide followed by continuous infusion of 1 mg/kg/min, n = 7) or to the Sal group (administration of the corresponding volume of normal saline, n = 7). Subsequently, acute normovolemic anemia was induced by simultaneous exchange of whole blood for a 6% hydroxyethyl starch solution (130/0.4) until a sudden decrease of total body O2 consumption (VO2) indicated a critical limitation of O2 transport capacity. The Hb concentration quantified at this time point (Hbcrit) was the primary endpoint of the protocol. Secondary endpoints were parameters of hemodynamics, O2 transport and tissue oxygenation. Results: Hbcrit was significantly lower in the Roc group (2.4 ± 0.5 vs. 3.2 ± 0.7 g/dl) reflecting increased anemia tolerance. NMB with rocuronium bromide reduced skeletal muscular VO2 and total body O2 extraction rate. As the cardiac index increased simultaneously, total body VO2 only decreased marginally in the Roc group (change of VO2 relative to baseline -1.7 ± 0.8 vs. 3.2 ± 1.9% in the Sal group, p < 0.05). Conclusion: Deep NMB with rocuronium bromide increases the tolerance of acute normovolemic anemia. The underlying mechanism most likely involves a reduction of skeletal muscular VO2. During acellular treatment of an acute blood loss, NMB might play an adjuvant role in situations where profound stages of normovolemic anemia have to be tolerated (e.g. bridging an unexpected blood loss until blood products become available for transfusion). Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background. Utilization of an individual patient's tolerance of anaemia is a cornerstone of any restrictive transfusion policy. Whether the use of neuromuscular block (NMB) has an effect on anaemia tolerance has not been investigated. Methods. Fourteen anaesthetized and mechanically ventilated pigs were randomized to receive either rocuronium bromide 1% (Roc-group, n=7, 0.378 ml kg-1 bolus injection, 0.1 ml kg-1 min-1 continuous infusion) or the same volume of normal saline (Sal-group, n=7). Acute normovolaemic anaemia was induced by exchange of whole blood for a 6% HES-solution (130/0.4) until a sudden decrease in total body O2 consumption (VO2) indicated a critical limitation of O2 delivery to the tissues. The Hb concentration quantified at this critical time point (HbCRIT) was defined as the primary endpoint of the protocol. Secondary endpoints were parameters of central haemodynamics, O2 transport, and tissue oxygenation. Results. HbCRIT was significantly lower in the Roc-group [2.4 (0.5) vs 3.2 (0.7) g dl-1] reflecting increased tolerance of anaemia. NMB with rocuronium bromide reduced skeletal muscle O2 consumption (mVO2) and the total body O2 extraction ratio. As cardiac index increased, body O2 consumption (VO2) decreased marginally in the Roc-group [change of VO2 relative to baseline (ΔVO2) -1.7 (0.8)% vs 3.2 (1.9)% in the Sal-group, P<0.05]. Conclusions. NMB with rocuronium bromide increases the tolerance of acute normovolaemic anaemia. The underlying mechanism probably involves a reduction in skeletal muscle O2 consumption. During acellular treatment of acute blood loss, NMB might play an adjuvant role, particularly in situations where profound normovolaemic anaemia has to be tolerated, for example, bridging an acute blood loss until compatible blood products become available for transfusion. [ABSTRACT FROM AUTHOR]

Background: Elderly people are at particular high risk for postoperative delirium (POD) following spine surgery, which is associated with longer hospital stays, higher costs, risk for delayed complications, long-term care dependency, and cognitive dysfunction (POCD). It is insufficiently understood which mechanisms and risk factors contribute to the development of POD and POCD following these major but plannable surgeries., Objective: This study aims to identify modifiable risk factors in spine surgery. A better understanding thereof would help adapt medical management and surgical strategies to individual risk profiles., Methods: This is a single-center observational study jointly conducted by the departments of neurosurgery, neurology, and anesthesiology at a tertiary care hospital in Germany. All patients aged 60 years and older presenting to the neurosurgery outpatient clinic or ward for elective spine surgery are screened for eligibility. Exclusion criteria include presence of neurodegenerative or history of psychiatric disease and medication with significant central nervous system activity (eg, antidepressants, antipsychotics, sedatives). Surgical and anesthetic procedures including duration of surgery as primary end point of this study are thoroughly documented. All patients are furthermore evaluated for their preoperative cognitive abilities by a number of tests, including the Consortium to Establish a Registry for Alzheimer's Disease Plus test battery. Physical, mental, and social health and well-being are assessed using the Patient-Reported Outcome Measurement Information System Profile 29 and Hospital Anxiety and Depression Scale. Patients additionally receive preoperative cerebrovascular ultrasound and structural and functional brain imaging. The immediate postoperative period includes screening for POD using the Nursing Delirium Screening Scale and validation through Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, criteria. We furthermore investigate markers of (neuro)inflammation (eg, interleukins, C-reactive protein, tumor necrosis factor alpha). Preoperative examinations are repeated 3 months postoperatively to investigate the presence of POCD and its mechanisms. Statistical analyses will compare delirious and nondelirious patients for predictors of immediate (POD) and delayed (POCD) cognitive dysfunction., Results: This is the first study to prospectively evaluate risk factors for POD and POCD in spine surgery. Recruitment is ongoing, and data collection is estimated to be finished with the inclusion of 200 patients by mid-2020., Conclusions: The identification of mechanisms, possibly common, underlying POD and POCD would be a major step toward defining effective interventional strategies early in or even before the postoperative period, including the adaptation of surgical strategies to individual risk profiles., Trial Registration: ClinicalTrials.gov NCT03486288; https://clinicaltrials.gov/ct2/show/NCT03486288., International Registered Report Identifier (irrid): DERR1-10.2196/15488., (©Jonas Müller, Robert Fleischmann, Stephan Nowak, Antje Vogelgesang, Bettina von Sarnowski, Eiko Rathmann, Sein Schmidt, Sebastian Rehberg, Taras Usichenko, Harry Kertscho, Klaus Hahnenkamp, Agnes Flöel, Henry WS Schroeder, Jan-Uwe Müller. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 13.02.2020.)

Background: Restrictive intraoperative fluid management has been demonstrated to improve outcome of visceral and lung surgery in several studies. However, subsequent hypovolemia (HOV) may be accompanied by a decrease of anemia tolerance, resulting in increased transfusion needs. We therefore investigated the effect of volume status on anemia tolerance., Study Design and Methods: Eighteen domestic pigs of either sex (mean weight, 23.5 ± 4.8 kg) were anesthetized, ventilated, and randomized into three experimental groups: normovolemia (no intervention), HOV (blood loss of 40% of blood volume), and hypervolemia (HEV; volume infusion of 40% of blood volume). The animals were then hemodiluted until their individual critical hemoglobin concentrations (Hb crit ) were reached by the exchange of whole blood for hydroxyethyl starch (HES; 130:0.4). Subsequently, organ-specific hypoxia was assessed using pimonidazole tissue staining in relevant organs. Hemodynamic and metabolic variables were also investigated., Results: Despite significant differences in exchangeable blood volume, Hb crit was the same in all groups (2.3 g/dL, NS). During HOV, tissue hypoxia was aggravated in the myocardium, brain, and kidneys, whereas tissue oxygenation of the liver and intestine was not influenced by volume status. HEV increased tissue hypoxia in the lungs, but did not impact tissue oxygenation of other organs., Conclusions: The combination of hemorrhagic HOV with subsequent anemia leads to accentuated tissue hypoxia, revealed by a significant increase in pimonidazole binding at Hb crit , in heart, lungs, brain, and kidney. The lungs were the only organ that showed increased tissue hypoxia after pretreatment of HES infusion and subsequent anemia by normovolemic hemodilution., (© 2016 AABB.)

Background: Clonidine effectively decreases perioperative mortality by reducing sympathetic tone. However, application of clonidine might also restrict anaemia tolerance due to impairment of compensatory mechanisms. Therefore, the influence of clonidine induced, short-term sympathicolysis on anaemia tolerance was assessed in anaesthetized pigs. We measured the effect of clonidine on anaemia tolerance and of the potential for macrohemodynamic alterations to constrain the acute anaemia compensatory mechanisms., Methods: After governmental approval, 14 anaesthetized pigs of either gender (Deutsche Landrasse, weight (mean ± SD) 24.1 ± 2.4 kg) were randomly assigned to intravenous saline or clonidine treatment (bolus: 20 μg · kg -1 , continuous infusion: 15 μg · kg -1  · h -1 ). Thereafter, the animals were hemodiluted by exchange of whole blood for 6 % hydroxyethyl starch (MW 130.000/0.4) until the individual critical haemoglobin concentration (Hb crit ) was reached. Primary outcome parameters were Hb crit and the exchangeable blood volume (EBV) until Hb crit was reached., Results: Hb crit did not differ between both groups (values are median [interquartile range]: saline: 2.2 (2.0-2.5) g · dL -1 vs. clonidine: 2.1 (2.1-2.4) g · dL -1 ; n.s.). Furthermore, there was no difference in exchangeable blood volume (EBV) between both groups (saline: 88 (76-106) mL · kg -1 vs. clonidine: 92 (85-95) mL · kg -1 ; n.s.)., Conclusion: Anaemia tolerance was not affected by clonidine induced sympathicolysis. Consequently, perioperative clonidine administration probably has not to be omitted in view of acute anaemia.

Objective: Utilization of anemia tolerance reduces the need for and risks of perioperative transfusion. Recent publications indicate that the critical limit for oxygen supply might not be the same for each organ system. Therefore, we investigated the effects of acute dilutional anemia on heart, brain, kidneys, liver, small intestine, and skeletal muscle to quantify organ-specific tolerance of different levels of acute anemic hypoxia. We hypothesized that, in some organs, tissue hypoxia occurs before the critical limits of systemic oxygen supply are reached., Design: Laboratory animal experiments., Setting: Animal research laboratory at university medical school., Subjects: A total of 18 domestic pigs of either sex (average weight: 19.6 kg)., Interventions: Animals were anesthetized, ventilated, and randomized into three groups and then hemodiluted by exchange of 6% hydroxyethyl starch (130,000:0.4) for whole blood to the group-specific endpoint: Sham (no hemodilution), Hb4 (hemoglobin 4.3 g/dL), Hbcrit (2.7 g/dL). Subsequently, 10 mg/kg pimonidazole (which forms protein adducts in hypoxic cells) was injected. One hour after injection, tissue samples were collected and analyzed for pimonidazole-protein adduct quantification (dot blot) and as a surrogate for transcriptional activation during hypoxia the expression of vascular endothelial growth factor messenger RNA. Relevant hemodynamic and metabolic parameters were collected., Measurements and Main Results: Hemodynamics, metabolic parameters, or oxygen consumption did not indicate that tissue oxygenation was restricted before reaching Hbcrit. However, kidneys and skeletal muscle showed enhanced pimonidazole binding and vascular endothelial growth factor expression at Hb4. By contrast, liver oxygenation was actually improved at Hb4. Heart, brain, and liver showed no signs of tissue hypoxia at Hb4., Conclusions: Heart, brain, kidneys, liver, small intestine, and skeletal muscle experience tissue hypoxia at different degrees of acute anemia, as assessed by the pimonidazole method and vascular endothelial growth factor expression. Further studies are needed to elucidate the mechanisms that determine organ-specific anemia tolerance.

Introduction: The correction of hypovolemia with acellular fluids results in acute normovolemic anemia. Whether the choice of the infusion fluid has an impact on the maintenance of oxygen (O₂) supply during acute normovolemic anemia has not been investigated so far., Methods: Thirty-six anesthetized and mechanically ventilated pigs were hemodiluted to their physiological limit of anemia tolerance, reflected by the individual critical hemoglobin concentration (Hbcrit). Hbcrit was defined as the Hb-concentration corresponding with the onset of supply-dependency of total body O₂-consumption (VO₂). The hemodilution protocol was randomly performed with either tetrastarch (6% HES 130/0.4, TS-group, n = 9), gelatin (3.5% urea-crosslinked polygeline, GEL-group, n = 9), hetastarch (6% HES 450/0.7, HS-group, n = 9) or Ringer's solution (RS-group, n = 9). The primary endpoint was the dimension of Hbcrit, secondary endpoints were parameters of central hemodynamics, O₂ transport and tissue oxygenation., Results: In each animal, normovolemia was maintained throughout the protocol. Hbcrit was met at 3.7 ± 0.6 g/dl (RS), 3.0 ± 0.6 g/dl (HS P < 0.05 vs. RS), 2.7 ± 0.6 g/dl (GEL, P < 0.05 vs. RS) and 2.1 ± 0.4 g/dl (TS, P < 0.05 vs. GEL, HS and RS). Hemodilution with RS resulted in a significant increase of extravascular lung water index (EVLWI) and a decrease of arterial oxygen partial pressure (paO₂), and O₂ extraction ratio was increased, when animals of the TS-, GEL- and HS-groups met their individual Hbcrit., Conclusions: The choice of the intravenous fluid has an impact on the tolerance of acute normovolemic anemia induced by acellular volume replacement. Third-generation tetrastarch preparations (e.g., HES 130/0.4) appear most advantageous regarding maintenance of tissue oxygenation during progressive anemia. The underlying mechanism includes a lower degree of extravasation and favourable effects on microcirculatory function.

Aim: Ventilation with pure oxygen (hyperoxic ventilation: HV) is thought to decrease whole body oxygen consumption (VO(2)). However, the validity and impact of this phenomenon remain ambiguous; until now, under hyperoxic conditions, VO(2) has only been determined by the reverse Fick principle, a method with inherent methodological problems. The goal of this study was to determine changes of VO(2), carbon dioxide production (VCO(2)), and the respiratory quotient (RQ) during normoxic and hyperoxic ventilation, using a metabolic monitor., Methods: After providing signed informed consent and institutional acceptance, 14 healthy volunteers were asked to sequentially breathe room air, pure oxygen, and room air again. VO(2), VCO(2), RQ, and energy expenditure (EE) were determined by indirect calorimetry using a modified metabolic monitor during HV., Results: HV reduced VO(2) from 3.4 (3.0/4.0) mL/kg/min to 2.8 (2.5/3.6) mL/kg/min (P < 0.05), whereas VCO(2) remained constant (3.0 [2.6/3.6] mL/kg/min versus 3.0 [2.6/3.5] mL/kg/min, n.s.). After onset of HV, RQ increased from 0.9 (0.8/0.9) to 1.1 (1.0/1.1). Most changes during HV were immediately reversed during subsequent normoxic ventilation., Conclusion: HV not only reduces VO(2), but also increases the respiratory quotient. This might be interpreted as an indicator of the substantial metabolic changes induced by HV. However, the impact of this phenomenon requires further study.

Background: We investigated changes in heart rate variability (HRV) across different degrees of acute dilutional anemia (hemoglobin [Hb]=9, 7, 5, 4, and 3 g/dL) in a pig model., Methods: Twelve anesthetized mechanically ventilated pigs of either gender (mean body weight 27.5±5.5 kg) were hemodiluted by exchange of blood for hydroxyethyl starch (6%; 200000/0.5) from baseline values to each animal's individual critical hemoglobin concentration (Hbcrit 3.3 [2.3/3.6] g/dL). Differences in time- and frequency-domain calculations of HRV were analyzed throughout the hemodilution procedure by using short-term electrocardiogram recordings (analysis of variance+Dunn's post-hoc test)., Results: During the hemodilution procedure, the standard deviation of normal R-R intervals and the coefficient of variation changed at Hb 5.3 (4.2/5.7) g/dL. Thereafter, the high-frequency power (HF), total power of the variance, and root mean square of successive N-N interval differences changed at Hb 3.9 (3.1/4.3) g/dL. The low-frequency power (LF) and the LF/HF ratio remained unaffected by hemodilution to Hbcrit., Conclusion: Acute dilutional anemia resulted in significant changes in different time- and frequency-domain variables in HRV analysis. These changes occurred considerably earlier than did commonly recognized transfusion triggers or signs of general tissue hypoxia. Further investigation is warranted to elucidate whether these changes can be considered as indicators of imminent tissue hypoxia.

Aim of the Study: Recently it has been demonstrated that short term hyperoxic ventilation (HV) can improve glucose metabolism, reduce pulmonary and hepatic apoptosis, and improve gastrointestinal perfusion during acute sepsis. However, it is unknown whether additional O(2) improves survival. Therefore we investigated the effects of increased plasma O(2) on survival during extreme anaemia and concomitant endotoxaemia in order to quantify the efficacy of HV., Methods: Endotoxaemia (Salmonella abortus equi-LPS) was induced in 14 anesthetized pigs ventilated with room air (FiO(2)=0.21). Simultaneously, animals were haemodiluted by exchange of whole blood for 6% hydroxyethyl starch (200,000:0.5) until the individual critical hemoglobin concentration (Hb(crit)) was achieved (outermost limit of tissue oxygenation). Subsequently, animals were either ventilated with an FiO(2) of 0.21 (NOX, n=7) or an FiO(2) of 1.0 (HOX, n=7), and observed thereafter for 6 h without further intervention., Results: HV significantly prolonged survival time at Hb(crit) (NOX, 30 [27/35] min; HOX, 172 [111/235] min, p<0.05). In contrast to the NOX group, HV maintained MAP, and improved DO(2) and tissue oxygenation in the HOX group., Conclusion: The improvement of survival, oxygen transport and tissue oxygenation seems to underline the efficacy of HV during endotoxaemia and concomitant acute anaemia. Further studies are needed to transfer these results into daily clinical practice., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

We studied whether low hemoglobin concentrations during normovolemia change the myocardial electrical current (electrocardiogram) in a pig model. Normovolemic anemia was achieved by stepwise replacing blood with colloids (hydroxyethyl starch 6%). We measured the length of the PQ-, QT-, QTc, and the ST interval as well as the amplitude of the Q wave and T wave at hemoglobin concentrations of 9.5, 8.0, 5.5, 3.8, and 3.3 g·dL. Normovolemic anemia is accompanied by a gradual prolongation of the QT and QTc interval and a reduction in the amplitude of the T wave. The QRS complex is partly diminished in amplitude. Results were verified performing a time-frequency analysis on single heartbeats. During severe anemia and normovolemia, electrocardiographic changes can be detected. Further investigations are warranted to elucidate whether these changes indicate myocardial hypoxia.

Objective: To investigate the efficacy of a polyethylene glycol (PEG) modified formulation of liposome-encapsulated hemoglobin (LEH) as an oxygen-carrying blood substitute in the treatment of critical normovolemic anemia., Design and Setting: Prospective, controlled, randomized experimental study in a university research facility., Subjects: 14 anesthetized and mechanically ventilated beagle dogs., Interventions: Animals were splenectomized and hemodiluted by exchange of whole blood for iso-oncotic hetastarch (HES). Target parameter of the hemodilution protocol was the individual critical hemoglobin concentration (Hb(crit)) corresponding with the onset of O(2) supply dependency of total body O(2) consumption. At Hb(crit) animals were randomized to receive a bolus infusion (20[Symbol: see text]ml/kg) of either LEH (n = 7) or normal saline (NS; n = 7). Subsequently animals were observed without further intervention., Measurements and Results: The primary endpoint was survival time after the completion of treatment; secondary endpoints were parameters of central hemodynamics, O(2) transport and tissue oxygenation. Animals in the LEH group survived significantly longer after completion of treatment (149 +/- 109 vs. 43+/- 56 min). Immediately after treatment LEH-treated animals presented with a more stable cardiovascular condition. After 30 min tissue O(2) tension on the surface of a skeletal muscle was significantly higher in the LEH group (23+/-8 vs. 9 +/- 2 mmHg). Nevertheless, treatment with LEH did not decrease mortality within the observation period., Conclusions: In this present experimental study the infusion of a PEG-modified LEH provided adequate tissue oxygenation, hemodynamic stability, and a prolongation of survival time after critical anemia. However, these effects were sustained for only a short period of time.

The expected cost explosion in transfusion medicine increases the socio-economic significance of specific institutional transfusion programs. In this context the estimated use of the patient's physiologic tolerance represents an integral part of any blood conservation concept. The present article summarizes the mechanisms, influencing factors and limits of this natural tolerance to anemia and deduces the indication for perioperative red blood cell transfusion. The current recommendations coincide to the effect that perioperative transfusion is unnecessary up to a Hb concentration of 10 g/dl (6.21 mmol/l) even in older patients with cardiopulmonary comorbidity and is only recommended in cases of Hb <6 g/dl (<3.72 mmol/l) in otherwise healthy subjects including pregnant women and children. Critically ill patients with multiple trauma and sepsis do not seem to benefit from transfusions up to Hb concentrations >9 g/dl (>5.59 mmol/l). In cases of massive hemorrhaging and diffuse bleeding disorders the maintenance of a Hb concentration of 10 g/dl (6.21 mmol/l) seems to contribute to stabilization of coagulation.

The expected cost explosion in transfusion medicine (increasing imbalance between donors and potential recipients, treatment of transfusion-associated complications) increases the socio-economic significance of specific institutional transfusion programs. In this context the estimated use of the patient's physiologic tolerance to anemia enables 1) the tolerance of larger blood losses (loss of "diluted blood"), 2) the onset of transfusion to the time after surgical control of bleeding to be delayed and 3) the perioperative collection of autologous red blood cells. The present review article summarizes the mechanisms, influencing factors and limits of this natural tolerance to anemia and deduces the indication for perioperative red blood cell transfusion. Under strictly controlled conditions (anesthesia, normovolemia, complete muscular relaxation, hyperoxemia, mild hypothermia) extremely low hemoglobin concentrations [Hb <3 g/dl (<1.86 mmol/l)] are tolerated without transfusion by individuals with no cardiopulmonary disease. In the clinical routine these situations are limited to borderline situations e.g. unexpected massive blood losses in Jehovah's Witnesses or unexpected shortcomings in blood supply. The current recommendations coincide to the effect that perioperative red blood cell transfusion 1) is unnecessary up to a Hb concentration of 10 g/dl (6.21 mmol/l) even in older patients with cardiopulmonary comorbidity and 2) is only recommended in cases of Hb <6 g/dl (<3.72 mmol/l) in otherwise healthy subjects including pregnant women and children. Critically ill patients with multiple trauma and sepsis do not seem to benefit from transfusions up to Hb concentrations >9 g/dl (>5.59 mmol/l). In cases of massive hemorrhaging and diffuse bleeding disorders the maintenance of a Hb concentration of 10 g/dl (6.21 mmol/l) seems to contribute to stabilization of coagulation.