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Despite current recommendations on the management of pre-operative anaemia, there is no pragmatic guidance for the diagnosis and management of anaemia and iron deficiency in surgical patients. A number of experienced researchers and clinicians took part in an expert workshop and developed the following consensus statement. After presentation of our own research data and local policies and procedures, appropriate relevant literature was reviewed and discussed. We developed a series of best-practice and evidence-based statements to advise on patient care with respect to anaemia and iron deficiency in the peri-operative period. These statements include: a diagnostic approach for anaemia and iron deficiency in surgical patients; identification of patients appropriate for treatment; and advice on practical management and follow-up. We urge anaesthetists and peri-operative physicians to embrace these recommendations, and hospital administrators to enable implementation of these concepts by allocating adequate resources., (© 2016 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists of Great Britain and Ireland.)

Background: The initial treatment of an acute blood loss with acellular fluids leads to the dilution of the red cell mass remaining in the vasculature, that is, to acute normovolemic anemia. Whether the compensation and, thus, the tolerance of acute anemia, are affected by sympathetic block induced by thoracic epidural anesthesia has not yet been investigated., Methods: Eighteen anesthetized and mechanically ventilated pigs were instrumented with thoracic epidural catheters and randomly assigned to receive an epidural injection of either 5-ml ropivacaine 0.2% (n = 9) aiming for a Th5-Th10 block or saline (n = 9) followed by continuous epidural infusion of 5 ml/h of either fluid. Subsequently, acute normovolemic anemia was induced by replacement of whole blood with 6% hydroxyethyl starch solution until a "critical" limitation of oxygen transport capacity was reached as indicated by a sudden decrease in oxygen consumption. The critical hemoglobin concentration quantified at this time point was the primary endpoint; secondary endpoints were hemodynamic and oxygen transport parameters., Results: Thoracic epidural anesthesia elicited only a moderate decrease in mean arterial pressure and cardiac index and a transient decrease in oxygen extraction ratio. During progressive anemia, the compensatory increases in cardiac index and oxygen extraction ratio were not compromised by thoracic epidural anesthesia. Critical hemoglobin concentration was reached at identical levels in both groups (ropivacaine group: 2.5 ± 0.6 g/dl, saline group: 2.5 ± 0.6 g/dl)., Conclusion: Thoracic epidural anesthesia with ropivacaine 0.2% does not decrease the tolerance to acute normovolemic anemia in healthy pigs. The hemodynamic compensation of acute anemia is fully preserved despite sympathetic block, and the critical hemoglobin concentration remains unaffected.

Background: During acellular replacement of an acute blood loss, hyperoxic ventilation (HV) increases the amount of O2 physically dissolved in the plasma and thereby improves O2 supply to the tissues. While this effect could be demonstrated for HV with inspiratory O2 fraction (FiO2) 0.6, it was unclear whether HV with pure oxygen (FiO2 1.0) would have an additional effect on the physiological limit of acute normovolemic anemia., Methods: Seven anesthetized domestic pigs were ventilated with FiO2 1.0 and subjected to an isovolemic hemodilution protocol. Blood was drawn and replaced by a 6% hydroxyethyl starch (HES) solution (130/0.4) until a sudden decrease of total body O2 consumption (VO2) indicated the onset of O2 supply dependency (primary endpoint). The corresponding hemoglobin (Hb) concentration was defined as 'critical Hb' (Hbcrit). Secondary endpoints were parameters of myocardial function, central hemodynamics, O2 transport and tissue oxygenation., Results: HV with FiO2 1.0 enabled a large blood-for-HES exchange (156 ± 28% of the circulating blood volume) until Hbcrit was met at 1.3 ± 0.3 g/dl. After termination of the hemodilution protocol, the contribution of O2 physically dissolved in the plasma to O2 delivery and VO2 had significantly increased from 11.7 ± 2 to 44.2 ± 9.7% and from 29.1 ± 4.2 to 66.2 ± 11.7%, respectively. However, at Hbcrit, cardiovascular performance was found to have severely deteriorated., Conclusion: HV with FiO2 1.0 maintains O2 supply to tissues during extensive blood-for-HES exchange. In acute situations, where profound anemia must be tolerated (e.g. bridging an acute blood loss until red blood cells become available for transfusion), O2 physically dissolved in the plasma becomes an essential source of oxygen. However, compromised cardiovascular performance might require additional treatment.

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.

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 O(2) consumption (VO(2)) indicated a critical limitation of O(2) transport capacity. The Hb concentration quantified at this time point (Hb(crit)) was the primary endpoint of the protocol. Secondary endpoints were parameters of hemodynamics, O(2) transport and tissue oxygenation., Results: Hb(crit) 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 VO(2) and total body O(2) extraction rate. As the cardiac index increased simultaneously, total body VO(2) only decreased marginally in the Roc group (change of VO(2) 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 VO(2). 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.)

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.

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.

Previously undiagnosed anaemia is common in elective orthopaedic surgical patients and is associated with increased likelihood of blood transfusion and increased perioperative morbidity and mortality. A standardized approach for the detection, evaluation, and management of anaemia in this setting has been identified as an unmet medical need. A multidisciplinary panel of physicians was convened by the Network for Advancement of Transfusion Alternatives (NATA) with the aim of developing practice guidelines for the detection, evaluation, and management of preoperative anaemia in elective orthopaedic surgery. A systematic literature review and critical evaluation of the evidence was performed, and recommendations were formulated according to the method proposed by the Grades of Recommendation Assessment, Development and Evaluation (GRADE) Working Group. We recommend that elective orthopaedic surgical patients have a haemoglobin (Hb) level determination 28 days before the scheduled surgical procedure if possible (Grade 1C). We suggest that the patient's target Hb before elective surgery be within the normal range, according to the World Health Organization criteria (Grade 2C). We recommend further laboratory testing to evaluate anaemia for nutritional deficiencies, chronic renal insufficiency, and/or chronic inflammatory disease (Grade 1C). We recommend that nutritional deficiencies be treated (Grade 1C). We suggest that erythropoiesis-stimulating agents be used for anaemic patients in whom nutritional deficiencies have been ruled out, corrected, or both (Grade 2A). Anaemia should be viewed as a serious and treatable medical condition, rather than simply an abnormal laboratory value. Implementation of anaemia management in the elective orthopaedic surgery setting will improve patient outcomes.

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.

Objective: Extreme anemia threatens myocardial oxygen supply by 1) a decline of arterial oxygen content and 2) by a decline of mean aortic pressure (MAP) and thus coronary perfusion pressure. Standard treatment of low arterial oxygen content includes ventilation with pure oxygen and the transfusion of red blood cells. However, it is unknown whether the stabilization of MAP and coronary perfusion pressure with norepinephrine as the sole therapeutic modality may also increase tolerance to extreme anemia and thus improve outcome., Design: Prospective, randomized, controlled study., Setting: Experimental animal laboratory of a university hospital., Subjects: A total of 28 anesthetized, mechanically ventilated pigs., Interventions and Measurements: In the first protocol, 14 anesthetized pigs were hemodiluted by exchange of whole blood for 6% hydroxyethyl starch (200,000:0.5) until the individual critical hemoglobin concentration was reached. For the next 6 hrs, animals were either observed without any further intervention (control group) or their MAP was maintained by adapted infusion of norepinephrine (norepinephrine group). The main outcome variable of this protocol was the 6-hr mortality in both groups. In the second protocol, 14 anesthetized pigs received hemodilution until death. In seven animals, no intervention was performed during the hemodilution procedure, whereas in the other seven animals, MAP was maintained at >60 mm Hg by adapted infusion of norepinephrine. The main outcome variable of this protocol was the maximum exchangeable blood volume until death., Main Results: MAP stabilization with norepinephrine reduced the 6-hr mortality at the critical hemoglobin concentration from 100% to 14%. Maintaining MAP by adapted norepinephrine infusion during the hemodilution procedure allowed for the exchange of 125 (110/126) (median [quartile 1/quartile 3]) mL/kg blood (163% of blood volume) in the norepinephrine group, whereas only 76 (73/91) mL/kg blood (104% of blood volume) could be exchanged in the control group., Conclusions: Application of norepinephrine can be judged a first-line intervention to bridge acute anemia via a stabilization of MAP and coronary perfusion pressure. However, due to the relevant side effects of norepinephrine, its sole long-term use during extreme anemia without concomitant transfusion of erythrocytes is not advised.

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.

Objective: To investigate the impact of prophylactic hyperoxic ventilation with Fio2 0.6 on the physiologic limit of acute normovolemic anemia., Design: Prospective, controlled, randomized experimental study., Setting: Experimental animal laboratory of a university hospital., Subjects: Fourteen anesthetized domestic pigs., Interventions: Animals were randomly ventilated with either Fio2 0.21 (group 0.21, n = 7) or Fio2 0.6 (group 0.6, n = 7), and acute anemia was induced by isovolemic blood-for-hydroxy-ethylstarch (HES) exchange using a 6% HES solution (130/0.4)., Measurements and Main Results: The blood-for-HES-exchange was continued until a sudden decrease of total body oxygen consumption indicated the onset of oxygen supply dependency (primary end point); the corresponding hemoglobin (Hb) concentration was defined as "critical" (Hb(crit)). Secondary end points were changes in myocardial function, central hemodynamics, oxygen transport, and tissue oxygenation. Compared with room air ventilation (Fio2 0.21), hyperoxic ventilation with Fio2 0.6 enabled a larger blood-for-HES-exchange (139%, 124/156) of circulating blood volume vs. 87% (68/94, p < .05), until Hb(crit) was reached (1.5 g/dL [1.4/2.1] vs. 2.4 g/dL [2.0/2.8], p < .05). At Hb 2.4 g/dL (i.e., Hb(crit) in group 0.21), animals of group 0.6 still presented with superior oxygen transport, tissue oxygenation, and hemodynamic stability. However, hemodynamic and oxygen transport variables were found deteriorated more severely at Hb 1.5 g/dL (i.e., Hb(crit) of group 0.6) compared with group 0.21 at Hb 2.4 g/dL., Conclusion: During cell-free volume replacement, hyperoxic ventilation with Fio2 0.6 generates a readily usable plasmatic oxygen reserve and thereby increases the tolerance toward acute normovolemic anemia.

Background: During acellular replacement of an acute blood loss, hyperoxic ventilation (HV) increases the amount of O2 physically dissolved in the plasma and thereby improves O2 supply to the tissues. While this effect could be demonstrated for HV with inspiratory O2 fraction (FiO2) 0.6, it was unclear whether HV with pure oxygen (FiO2 1.0) would have an additional effect on the physiological limit of acute normovolemic anemia. Methods: Seven anesthetized domestic pigs were ventilated with FiO2 1.0 and subjected to an isovolemic hemodilution protocol. Blood was drawn and replaced by a 6% hydroxyethyl starch (HES) solution (130/0.4) until a sudden decrease of total body O2 consumption (VO2) indicated the onset of O2 supply dependency (primary endpoint). The corresponding hemoglobin (Hb) concentration was defined as 'critical Hb' (Hbcrit). Secondary endpoints were parameters of myocardial function, central hemodynamics, O2 transport and tissue oxygenation. Results: HV with FiO2 1.0 enabled a large blood-for-HES exchange (156 ± 28% of the circulating blood volume) until Hbcrit was met at 1.3 ± 0.3 g/dl. After termination of the hemodilution protocol, the contribution of O2 physically dissolved in the plasma to O2 delivery and VO2 had significantly increased from 11.7 ± 2 to 44.2 ± 9.7% and from 29.1 ± 4.2 to 66.2 ± 11.7%, respectively. However, at Hbcrit, cardiovascular performance was found to have severely deteriorated. Conclusion: HV with FiO2 1.0 maintains O2 supply to tissues during extensive blood-for-HES exchange. In acute situations, where profound anemia must be tolerated (e.g. bridging an acute blood loss until red blood cells become available for transfusion), O2 physically dissolved in the plasma becomes an essential source of oxygen. However, compromised cardiovascular performance might require additional treatment. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Intraoperative surgical blood loss is initially replaced by infusion of red cell-free, cristalloidal or colloidal solutions. When normovolemia is maintained the ensuing dilutional anemia is compensated by an increase of cardiac output and of arterial oxygen extraction. In the ideal case, a surgical blood loss can entirely be ‘bridged’ without transfusion by intraoperative normovolemic hemodilution. However major blood loss results in extreme hemodilution and the transfusion of red blood cells may finally become necessary to increase arterial oxygen content and to preserve tissue oxygenation. When transfusion has to be started before surgical control of bleeding has been achieved, parts of the red blood cells transfused will get lost, thereby increasing intraoperative transfusion needs. Beside red blood cell transfusion, arterial oxygen content can be rapidly increased by ventilating the patient with 100% oxygen (hyperoxic ventilation), thus enhancing the amount of physically dissolved oxygen in plasma (hyperoxia). In experimental and clinical studies hyperoxic ventilation has emerged as a simple, safe and effective intervention to enlarge the margin of safety for hemodynamic compensation and tissue oxygenation in hemodiluted subjects experiencing major bleeding. The hyperoxia-associated microcirculatory dysregulation and impaired tissue oxygenation known to take place in the presence of a physiologic hemoglobin concentration are not encountered in hemodiluted subjects. Hyperoxic hemodilution i.e. the combination of intraoperative extreme hemodilution and hyperoxic ventilation may therefore be considered a cost-effective, safe and efficient supplement to reduce allogeneic transfusion during surgical interventions associated with high blood losses. The vast majority of the experimental and clinical investigations this new concept is based on was initiated and performed under the guidance of Prof. Konrad Messmer.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]