Transfusion thresholds and red blood cells transfusion focused on tissue oxygenation

Ripollés-Melchor, J.; García-Erce, J.A.; Vincent, V.J.L.
doi:10.1016/j.redare.2018.03.002
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Red blood cells transfusion &#40;RBC&#41; is a much-debated topic in medicine&#46; One the one hand&#44; reasonable RBC transfusion can save lives&#44; but on the other it is associated with risks that can contribute to adverse patient outcomes in some situations&#46; The challenge is to balance the risk of anaemia against the risk of transfusion&#44;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a> but many clinicians have insufficient training&#44; information&#44; or both to make this decision&#44;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a> and find it easier to simply administer transfusion according to protocols&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">3</span></a> This underscores the need to optimize not only haemoglobin &#40;Hb&#41; levels&#44; but also to improve tolerance to anaemia in any clinical setting&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a> The relationship between RBC transfusion and outcome is much more than a simple binary&#59; in addition to the volume of transfused blood products&#44; the underlying condition that leads to transfusion &#40;for example&#44; anaemia and&#47;or haemorrhage&#41; and the patient&#39;s characteristics influence outcome&#46; While treatment of anaemia by transfusion of limited volumes of RBC may be clearly beneficial under some circumstances&#44; there is a large grey area where some patients will benefit from transfusion while in others equal amounts blood products will be detrimental&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Ferraris et al&#46; illustrated this in a retrospective analysis of almost half a million postoperative patients&#44; showing that in contrast to high-risk patients&#44; low-risk patients had an 8- to 10-fold risk of adverse outcomes when they received an RBC transfusion&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a> Similarly&#44; Nielsen et al&#46; showed that in patients with abnormal tissue oxygenation or microcirculatory indices prior to transfusion&#44; these values improved after transfusion&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Transfusion thresholds are determined by the Hb value at which the benefit of RBC transfusion is expected to outweigh the risk&#46; Otherwise&#44; the tolerance of a patient to anaemia depends on the clinical condition and the presence of co-morbidities&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">6</span></a> There are two scenarios is which transfusion is less restrictive&#58; the presence of coronary artery disease&#44;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">7</span></a> and severe disease&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">8</span></a> This is frequent in both cardiac and non-cardiac surgery&#44; as well as in patients admitted to the intensive care unit &#40;ICU&#41;&#44; especially with sepsis or neurological problems&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The comparison of predefined transfusion thresholds in cardiac surgery has been studied extensively in recent years&#44; after evidence that RBC transfusion in these patients was associated with increased length of stay&#44; and higher morbidity and mortality rates and care costs&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">9</span></a> Although it is reasonable to assume that the rate of RBC transfusion should be higher in the sickest patients with the worst prognosis&#44; the Transfusion Requirements in Cardiac Surgery &#40;TRICS&#41; III trial showed that a <span class="elsevierStyleItalic">restrictive</span> RBC transfusion strategy &#40;Hb<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>7&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;dL intra-operatively or post-operatively&#41; was not inferior to a <span class="elsevierStyleItalic">liberal</span> strategy &#40;Hb<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>9&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;dL intra-operatively or post-operatively or &#60;8&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;dL in non-ICU patients&#41; in terms of mortality and major morbidity including myocardial infarction&#44; stroke&#44; or new onset of renal failure with dialysis in moderate-to-high-risk patients undergoing cardiac surgery&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">10</span></a> Interestingly&#44; a subgroup analysis based on age showed the restrictive-threshold group to be associated with a lower risk of the composite primary outcome than the liberal-threshold group in elderly patients &#40;&#62;75 years&#41; &#40;OR 0&#46;70&#59; 95&#37; CI 0&#46;54&#8211;0&#46;89&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;004&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">12</span></a> This contrasts directly with the results of a substudy<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">11</span></a> of the Transfusion Requirements After Cardiac Surgery Trial &#40;TRACS&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">12</span></a> where a <span class="elsevierStyleItalic">restrictive</span> RBC transfusion strategy was independently associated with a 2&#46;5-fold higher rate of cardiogenic shock in patients aged &#62;60 years&#59; these patients presented Hb values at the end of the surgery of less than 10<span class="elsevierStyleHsp" style=""></span>g&#47;dL &#40;9&#46;9<span class="elsevierStyleHsp" style=""></span>&#43;&#8722;<span class="elsevierStyleHsp" style=""></span>1&#46;2&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">11</span></a> which were probably insufficient to meet the physiological demands of cardiac pathology in elderly patients due to anaemia-induced tissue hypoxia&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">6</span></a> The TRICS III results also contrast to those published by Murphy et al&#46; in 2011&#44; in which it was found that a <span class="elsevierStyleItalic">restrictive</span> transfusion threshold &#40;Hb<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>7&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#41; compared with a more <span class="elsevierStyleItalic">liberal</span> transfusion threshold &#40;Hb<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>9&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#41; was associated with higher 90-day all-cause mortality &#40;4&#46;2&#37; vs 2&#46;6&#37;&#59; HR 1&#46;64&#44; CI 1&#46;00&#8211;2&#46;67&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;045&#41; in the postoperative period of non-urgent cardiac surgery&#44; despite the lack of significant differences in the number of global complications&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">13</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The Functional Outcomes in Cardiovascular patients Undergoing Surgical repair of hip fracture &#40;FOCUS&#41; trial<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">16</span></a> was designed to compare a <span class="elsevierStyleItalic">restrictive</span> vs <span class="elsevierStyleItalic">liberal</span> RBC transfusion strategy among anaemic &#40;Hb<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>g&#47;dL at recruitment&#41;&#44; relatively old &#40;&#62;50 years&#41; patients with a history of or risk factors for ischaemic heart disease who underwent surgical repair of a fractured hip&#59; In the <span class="elsevierStyleItalic">liberal</span>-strategy group&#44; <span class="elsevierStyleItalic">single-unit</span> RBC transfusions were given to restore and maintain an Hb level of over 10<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#46; In the <span class="elsevierStyleItalic">restrictive</span>-strategy group&#44; transfusions were given when Hb was &#60;8<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#46; Transfusion for symptoms of anaemia &#40;chest pain deemed to be cardiac in origin&#44; congestive heart failure&#44; and unexplained tachycardia or hypotension unresponsive to fluids&#41; was permitted in both groups&#44; which meant that transfusions were usually indicated by these symptoms in the <span class="elsevierStyleItalic">restrictive</span> group &#40;14&#37; vs 5&#37;&#41;&#46; There were no significant inter-group differences in 30-day and 60-day mortality rates&#46; In the <span class="elsevierStyleItalic">restrictive</span> group&#44; 59&#37; of patients did not receive a transfusion vs 97&#37; of the patients in the liberal group&#46; This FOCUS trial suggests that it is reasonable to withhold transfusion in the absence of symptoms of anaemia or a decline in Hb level below 8<span class="elsevierStyleHsp" style=""></span>g&#47;dL in an otherwise health patient population&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">14</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Docherty et al&#46; conducted a systematic review to compare clinical outcomes of restrictive &#40;&#60;8<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#41; or liberal transfusion strategies in patients with cardiovascular disease undergoing non-cardiac surgery&#46; The restrictive transfusion group showed a trend towards increased 30-day mortality &#40;RR 0&#46;96 &#40;95&#37; CI 0&#46;58&#8211;1&#46;59&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;87&#41;&#44; as well as a higher incidence of acute coronary syndrome &#40;RR 1&#46;78&#44; 95&#37; CI 1&#46;18&#8211;2&#46;70&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#44; compared to the more liberal transfusion group&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">15</span></a> Similarly&#44; Almeida et al&#46; found that in the postoperative period of major cancer surgery&#44; a restrictive transfusion threshold was associated with an increase in mortality and severe complications compared to a more liberal transfusion threshold &#40;19&#46;6 vs 35&#46;6&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0012&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">16</span></a> supporting the notion that in this group of patients&#44; a restrictive transfusion threshold is not the best option&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">6&#44;8</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Despite the multiple clinical trials and meta-analyses<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">7&#44;15</span></a> comparing two predefined transfusion thresholds&#44; it would seem preferable to individualize the decision to transfuse by factoring in physiological and individual clinical factors with Hb levels&#44; and thus avoiding the use of a simple laboratory value as an indication for transfusion&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">17</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Advances in the development and validation of physiological&#44; accessible&#44; practical and reliable markers to guide RBC transfusions are expected&#46; Near-infrared spectroscopy &#40;NIRS&#41; is a non-invasive technique that uses the differential absorption properties of oxyhaemoglobin and deoxyhaemoglobin to measure the tissue oxygenation status&#44; and has been used to evaluate the effect of the duration of RBC storage on tissue oxygenation response&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">18</span></a> In 2017&#44; Leal-Noval et al&#46; performed the first randomized controlled trial<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">19</span></a> to explore the utility of regional cerebral oxygen saturation &#40;rSO<span class="elsevierStyleInf">2</span>&#41; measured by NIRS compared with predefined Hb thresholds to guide RBC transfusion in adult neurocritical patients with moderate anaemia &#40;Hb values between 7 and 10<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#41;&#46; Patients were randomly assigned to Hb-guided &#40;to maintain Hb levels between 8&#46;5 and 10<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#41; or rSO<span class="elsevierStyleInf">2</span>-guided &#40;to maintain forehead rSO<span class="elsevierStyleInf">2</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>60&#37;&#41; RBC transfusion&#46; The introduction of an rSO<span class="elsevierStyleInf">2</span> cut-off into the RBC transfusion protocol reduced the number of transfused RBC units per patient &#40;mean difference&#44; 0&#46;51<span class="elsevierStyleHsp" style=""></span>U &#91;95&#37;CI &#8722;1&#46;008&#8211;0&#46;002&#93;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;04&#41;&#44; but did not reduce RBC transfusion rates&#46; In the rSO<span class="elsevierStyleInf">2</span> group&#44; RBC transfusion was associated with an increase in Hb &#40;77<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4 to 88&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#41; in parallel with an increase in rSO<span class="elsevierStyleInf">2</span> values &#40;55<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4 to 58<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#37;&#41;&#44; suggesting a direct relationship between RBC transfusion and rSO<span class="elsevierStyleInf">2</span>&#44; though not in the same proportion&#46; It would have been interesting to know if this increase occurred in all patients&#44; if it was homogeneous in all patients&#44; if it was maintained over time&#44; and if it was influenced by the storage age and volume of the transfused RBC&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Inclusion of patients with widely varying Hb levels &#40;from 7&#46;1 to 9&#46;9<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#41; makes comparison between cases impossible&#44; since patients with Hb close to 10<span class="elsevierStyleHsp" style=""></span>g&#47;dL have almost 40&#37; more erythrocyte mass&#46; Presumably&#44; the low number of patients included prevented a subgroup analysis based on Hb level at inclusion&#46; It would also have been interesting to report the rSO<span class="elsevierStyleInf">2</span> values in the Hb-guided group&#44; which would have shown whether RBC transfusion in patients with rSO<span class="elsevierStyleInf">2</span> values greater than that set in the intervention group were associated with increases in rSO<span class="elsevierStyleInf">2</span>&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Although there were no differences in mortality or hospital stay between the two transfusion strategies &#40;the study was underpowered for this outcome&#41;&#44; and despite the many limitations&#44; Leal-Noval et al&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">19</span></a> single out tissue oxygenation as the ultimate threshold for RBC transfusion&#44; and present physiological alternatives that could complement or replace arbitrary Hb thresholds to guide RBC transfusions&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Ripoll&#233;s-Melchor J&#44; Garc&#237;a-Erce JA&#44; Vincent VJL&#46; Umbrales transfusionales y transfusi&#243;n de hemat&#237;es enfocada a la microcirculaci&#243;n&#46; Rev Esp Anestesiol Reanim&#46; 2018&#59;65&#58;363&#8211;365&#46;</p>"
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