Guidelines on red cell transfusion in sickle cell disease Part II : indications for transfusion
2016; Wiley; Volume: 176; Issue: 2 Linguagem: Inglês
10.1111/bjh.14383
ISSN1365-2141
AutoresBernard A. Davis, Shubha Allard, Amrana Qureshi, John B. Porter, Shivan Pancham, Nay Win, Gavin Cho, Kate Ryan,
Tópico(s)Prenatal Screening and Diagnostics
ResumoRed cell transfusion has an important role in the management of sickle cell disease (SCD) in both emergency and elective settings. However, because of insufficient randomised data, it is not always clear when or how to use red cell transfusion. A companion guideline, Guidelines on red cell transfusion in sickle cell disease Part I: principles and laboratory aspects, addresses the general principles of transfusion practice in SCD (Davis et al, 2016, BJH in press). The present guideline examines current available evidence on indications for transfusion in SCD. This may not be appropriate for all clinical scenarios and clinical decisions must be based on individual patient considerations. In both guidelines, the term sickle cell disease refers to all genotypes of the disease, and sickle cell anaemia to the homozygous state (SS). The writing group was selected by the British Committee for Standards in Haematology (BCSH) General Haematology and Transfusion Task Forces with input from other experts in Haemoglobinopathy. PubMed, MEDLINE and Embase were searched systematically for publications on red cell transfusion in SCD from 1960 to May 2016 using a combination of search terms related to: (i) sickle cell (including sickle, sickle cell, sickle cell disease, sickle cell anaemia, haemoglobin SC disease, sickle cell crisis), (ii) transfusion (including transfusion, blood transfusion, red cell transfusion), (iii) transfusion indications (including aplastic crisis, parvovirus, sequestration (splenic, liver, hepatic), acute chest syndrome (ACS), stroke, silent cerebral infarcts, multi-organ failure, girdle syndrome, intrahepatic cholestasis, surgery, pregnancy, and (iv) transfusion complications (including alloimmunisation, haemolytic transfusion reactions, iron overload, viral infections). Opinions were also sought from experienced haematologists with a special interest in the care of SCD patients. The guideline was reviewed by the members of the General Haematology Task Force of the BCSH prior to being sent to a sounding board of approximately 50 UK haematologists, the BCSH and the British Society for Haematology (BSH) Committee. Comments were incorporated where appropriate. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria are specified in the BCSH guidance pack http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION/43_GRADE.html and the GRADE working group website http://www.gradeworkinggroup.org. Consideration of sickle cell patients for transfusion, particularly long-term regimens, should weigh up the potential benefits against potential risks (Grade 1C). Regular transfusion to maintain HbS <30% should be offered as initial treatment to children with SS or S/βo thalassaemia aged 2–16 years judged to be at high risk for a first stroke on the basis of Transcranial Doppler ultrasonography (TCD) (Grade 1A). Hydroxycarbamide treatment should be considered for the primary prevention of stroke in children with sickle cell anaemia and high TCD velocities but not severe Magnetic Resonance Angiography (MRA)-defined cerebral vasculopathy after an initial period of transfusions (Grade 1A). The duration of the initial period of transfusion should be tailored to the individual patient but should be for a minimum of 1 year; the transition to hydroxycarbamide should be done gradually and transfusion should be withdrawn after the hydroxycarbamide has been escalated to the maximum tolerated dose. Regular transfusion to maintain HbS <30% effectively reduces the incidence of recurrence of cerebral infarction (defined as a stroke or a new or enlarged silent cerebral infarct) in children with sickle cell anaemia and S/βo thalassaemia aged 5–15 years. Treatment options including transfusion should be discussed with families of children who are found to have silent cerebral infarcts. Transfusion should be offered to children who are identified to be at greatest risk for recurrence of infarction after discussion of its benefits and risks (Grade 1A). Long-term transfusion to maintain HbS <30% is recommended for the prevention of recurrent ischaemic stroke due to sickle cell disease in both children and adults (Grade 1B). Adults or children who present with signs or symptoms suggestive of acute ischaemic stroke should be transfused without any delay to maintain HbS <30% pending further investigation. Those with confirmed stroke due to sickle cell disease should continue regular transfusions long-term (Grade 1B). Preoperative transfusion is recommended for SS patients undergoing medium-risk surgery (e.g. abdominal, tonsillectomy, orthopaedic) (Grade 1A). Preoperative transfusion is recommended for SC patients undergoing medium-risk surgery (e.g. abdominal, tonsillectomy, orthopaedic) (Grade 1C). Transfusion is recommended for sickle cell patients of all genotypes requiring high-risk surgery (e.g. cardiovascular, brain) (Grade 1C). All sickle cell patients with other genotypes undergoing surgery should be individually assessed, taking into account previous history and complexity of surgery, and a management plan should be formulated to include the need for transfusion (Grade 1C). Particular care should be taken to ensure that all aspects of perioperative care, including oxygenation, hydration, warmth and anaesthetic and surgical technique, are optimised in all sickle cell patients undergoing surgery (Grade 1C). For patients requiring emergency surgery, the urgency and complexity of the procedure should be taken into account in the timing of perioperative transfusion. Simple transfusion should be given preoperatively if Hb 20 g/l or to Hb <50 g/l), haemodynamic compromise or concern about impending critical organ complications (Grade 1C). The benefit of transfusion to relieve established acute priapism has not been shown in randomised controlled trials. Many patients require a shunt or drainage procedure under general anaesthesia, which may require a transfusion. Such cases should be discussed with the SHT (Grade 2C). Transfusion has been shown to reduce the incidence of symptomatic avascular necrosis in children receiving regular transfusions to maintain HbS <30% for prevention of recurrence of cerebral infarction (Grade 1A). However, there is no consensus on the use of transfusion for the sole purpose of preventing this complication in routine practice. Where transfusion is considered for indications where there is insufficient evidence for its benefit (e.g. leg ulcers, pulmonary hypertension, end stage renal or liver disease, progressive sickle cell retinopathy), a full risk-benefit assessment should be carried out in liaison with the SHT and each case should be considered on its own merits (Grade 2C). The indications for red cell transfusion in SCD range from those in which transfusion can be strongly recommended to those where its use is unproven or controversial. A case-by-case detailed analysis of risk and benefit of red cell transfusion should be undertaken for unproven or controversial indications. The indications can be broadly categorised into conditions in which correction of anaemia is the main goal and those where reduction of sickle haemoglobin (HbS) may be more appropriate (see Table 1). In both categories, transfusion is either performed acutely, as part of the management of an acute complication of SCD, or electively for the prevention or management of disease complications. Elective transfusions may be one-off (e.g. preoperative) or be part of a long-term transfusion programme. The decision to transfuse any patient with SCD should be taken by senior medical staff, ideally at consultant level with the appropriate experience. Long-term elective transfusions should usually be initiated by or in consultation with a SHT. It should be recognised that the low steady state Hb in SCD is the result of the low oxygen affinity of haemoglobin S and is therefore not in itself an indication or transfusion. Acute anaemia in SCD has been defined as a fall in haemoglobin ≥20 g/l below the steady state value (Emond et al, 1985; NHLBI, 2014). Understanding the cause of the anaemia is essential for appropriate management. Causes broadly include: decreased haemoglobin production, sequestration and increased haemolysis. Initial assessment should include: history of recent transfusion, haemodynamic status, spleen and liver size, full blood count and reticulocyte count. Any decision to transfuse should take into consideration the likely cause, haemodynamic status and degree of anaemia relative to baseline. Aplastic crisis should be suspected in patients with acute exacerbation of steady state anaemia with reticulocytopenia and is usually due to infection with human erythrovirus (formerly parvovirus) B19 (Pattison et al, 1981; Serjeant et al, 1981, 1993; Goldstein et al, 1987). Anaemia is usually severe with a mean fall of approximately 40 g/l below steady state values (Goldstein et al, 1987; Serjeant et al, 2001). Simple transfusion to steady state level is usually all that is required to maintain the oxygen carrying capacity of blood (Goldstein et al, 1987; Serjeant et al, 1993; Smith-Whitley et al, 2004). Spontaneous resumption of erythropoiesis tends to occur within 7–10 days of aplasia (Anderson et al, 1985), restoring the Hb to the steady state value. Most patients will be close to spontaneous marrow recovery at the time of clinical presentation with development of reticulocytosis and recovery of Hb occurring 80 g/l) should be avoided due to the risk of hyperviscosity when sequestered red cells return to the circulation (Kinney et al, 1990; Wanko & Telen, 2005; Josephson et al, 2007; Quirolo, 2010; NHLBI 2014). All patients with previous splenic sequestration should be discussed with the SHT. There is a high recurrence rate (Emond et al, 1985; Brousse et al, 2012) and splenectomy is advised in patients who have recurrent episodes (two or more). Splenectomy is not associated with an increased long-term risk of bacteraemic episodes or death (Wright et al, 1999). Regular transfusion to maintain HbS 20 g/l or Hb < 50 g/l), haemodynamic compromise or concern about impending critical organ complications (see below). An acute decline in Hb due to haemolysis is common in acute sickle complications, such as ACS (Howard et al, 2015) and acute multi-organ failure syndrome (Hassell et al, 1994). The role of transfusion in these two syndromes is described in sections Acute chest syndrome (ACS) and Acute multi-organ failure syndrome. Urgent transfusion is indicated for acute blood loss. Severe anaemia during hydroxycarbamide therapy requiring transfusion is usually due to an acute intercurrent illness, such as acute splenic sequestration, aplastic crisis or ACS rather than the myelosuppressive effects of the drug (Scott et al, 1996; Kinney et al, 1999; Wang et al, 2001; Gulbis et al, 2005; Hankins et al, 2005a). The effects of myelosuppression are usually reversible rapidly upon reduction of the dose or temporary cessation of hydroxycarbamide but full recovery may not occur for several weeks (Wang et al, 2001; Hankins et al, 2005a). In patients with sickle cell nephropathy, a slow decline of haemoglobin concentration occurs as the renal disease progresses and the anaemia may be severe enough to compromise cardiovascular function (Serjeant & Serjeant, 2001). Simple transfusion to steady state haemoglobin concentration is indicated for patients with acute exacerbation of anaemia as a result of aplastic crisis or sequestration crisis (Grade 1B). Over-transfusion (to Hb > 80 g/l) should be avoided in sequestration crises because of the risk of hyperviscosity due to the re-entry of sequestered red cells into the circulation. Transfusion is not recommended in uncomplicated vaso-occlusive crisis but should be considered if there is worsening anaemia, haemodynamic compromise or concern about impending critical organ complications (Grade 1C). Transfusion for other causes of acute anaemia requires individual assessment and should be discussed with the SHT (Grade 1C). Transfusion to reduce the %HbS is indicated where there is evidence of acute critical organ complications, especially ACS and ischaemic stroke. ACS usually develops during a painful crisis and should be suspected in patients presenting with fever and/or respiratory symptoms, together with clinical signs of lung consolidation (Howard et al, 2015). Early recognition of ACS and intervention with blood transfusion can be life-saving. ACS can develop rapidly and progress to acute respiratory failure within a few hours. It is advisable to plan to have blood available if early signs of ACS occur, even if other measures subsequently render transfusion unnecessary. Both simple and exchange transfusion rapidly improved oxygenation with similar efficacy in non-randomised studies (Vichinsky et al, 2000; Turner et al, 2009). A simple transfusion aiming for a target Hb 100–110 g/l is effective in preventing progression to acute respiratory failure in SS patients with mild ACS if it is given early in the illness (Emre et al, 1995) and should be considered in patients with a PaO2 < 9·0 kPa on room air, but may also be needed at less severe degrees of hypoxaemia, depending on the individual patient's history and clinical features, or if the patient's oxygen requirements are increasing (Howard et al, 2015). Exchange transfusion is recommended in patients with features of severe ACS, those who fail to respond to initial simple transfusion, or patients with a higher Hb (>90 g/l) where there is little leeway for simple transfusion (Emre et al, 1995; Vichinsky et al, 1997; NHLBI 2014; Howard et al, 2015). There is no evidence as to the optimal %HbS target post-exchange transfusion. In practice, a target of <30–40% is often used, but clinicians should be guided by the clinical response (Howard et al, 2015). Guidelines for the diagnosis and management of ACS are available from the BCSH (Howard et al, 2015). The value of transfusion and the comparative effects of exchange versus simple transfusion in acute ischaemic stroke have not been evaluated in randomised trials. Emergency exchange transfusion to reduce HbS to <30% is recommended for acute ischaemic stroke (RCP, 2004; Sickle Cell Society 2008; NHLBI 2014). Initial simple transfusion should be given if the stroke has occurred in the context of severe acute anaemia (e.g. in aplastic crisis) (RCP 2004). Although there are no controlled trials on the effect of transfusion on the stroke itself, red cell transfusion may potentially minimise morbidity and mortality by improving perfusion and oxygenation to the brain, thereby preventing extension of an infarct. There is evidence from a retrospective cohort study that exchange transfusion for a first overt stroke at the time of stroke presentation is associated with a lower risk of a subsequent stroke compared to simple transfusion (Hulbert et al, 2006). It is important to avoid hypovolaemia during the procedure and to keep the post-transfusion Hb at a target of 100 g/l, as a high haematocrit associated with hyperviscosity may worsen the neurological insult. Current pathways for acute stroke care in the UK require adult patients with suspected stroke to be admitted directly to specialist stroke units (hyperacute stroke units) (NICE, 2008). National Health Service (NHS) Trusts must ensure that governance arrangements are in place to provide specialist haemoglobinopathy care for SCD patients with suspected stroke who are admitted to hyperacute stroke units, so that emergency exchange transfusion can be provided in a timely manner. Although this model of care has not been developed for paediatrics, NHS Trusts must develop local protocols with the collaboration of their SHT so that SCD children with acute stroke can receive appropriate care, including timely exchange transfusion and specialist neurology advice (RCP 2004; Dick, 2010). There are currently no data to support the use of red cell transfusion either in the acute management of haemorrhagic stroke or to prevent its recurrence and it is recommended that specialist advice should be sought for individual cases. This is a severe life-threatening syndrome that may complicate a severe painful crisis. It is particularly likely to occur in patients with otherwise mild SCD and a relatively high haemoglobin concentration. The patient presents with multi-organ failure with associated fever, rapid decrements in Hb and platelet count, non-focal encephalopathy and rhabdomyolysis. The syndrome usually responds to aggressive exchange transfusion (Hassell et al, 1994). This is a rare severe sequestration syndrome characterised by simultaneous or consecutive sickling and sequestration in the mesenteric vascular bed, liver and lungs (Brozovic et al, 1987). Preceding pain in the abdomen, lumbar spine and limbs is common. Sickling in the abdomen can present with tenderness and rigidity, mimicking peritonitis and progressing to ileus, with a silent distended abdomen and dilated loops of bowel on X-ray. ACS frequently develops due to splinting of the chest wall. Acute exchange blood transfusion is indicated. Severe sepsis often engenders a vicious circle of tissue hypoxia, acidosis and sickling. An exchange transfusion or simple transfusion may be useful in correcting anaemia, improving microvascular blood flow, tissue oxygenation and the patient's overall clinical condition (Ohene-Frempong, 2001). This is a rare and little understood complication that presents with extreme hyperbilirubinaemia (mainly conjugated) (Banerjee et al, 2001; Gardner et al, 2014), marked elevation of the alkaline phosphatase and variable rises in transaminase levels. There is a high mortality from liver failure or bleeding. There is no established treatment but exchange transfusion appears to be beneficial (Shao & Orringer, 1995). The treatment of priority in acute fulminant priapism is penile aspiration/irrigation followed by the intracavernosal injection of sympathomimetic drugs if aspiration fails to resolve the problem (Montague et al, 2003). This initial urological intervention should not be delayed while a transfusion is arranged. Neither simple nor exchange transfusion have been evaluated for acute management of priapism in randomised controlled trials. Small case series and literature reviews provide no evidence of amelioration of pain or duration of priapism once this has been established (McCarthy et al, 2000; Merritt et al, 2006). Surgical management is indicated if initial urological measures are not effective (Montague et al, 2003). Shunt procedures for the relief of acute priapism require a general anaesthetic so that the patient may benefit from transfusion, as with other surgical procedures (Howard et al, 2013). If patients do not respond to initial shunt procedures there may be benefit from exchange transfusion to decrease %HbS. Local hospitals should develop referral pathways so that patients requiring specialist surgery are transferred promptly to tertiary centres. Such patients must be discussed with the SHT with regards to possible transfusion preoperatively. Transfusion is recommended in cases of acute chest syndrome with hypoxia. Transfusion may be given by simple or exchange transfusion depending on clinical severity under the guidance of the SHT (Grade 1B). Adults or children with signs or symptoms suggestive of acute ischaemic stroke should be transfused to sickle haemoglobin (HbS) <30% pending further investigation. Those with confirmed stroke due to sickle cell disease should continue regular transfusions indefinitely (Grade 1B). Transfusion should be considered in the unwell patient with acute multi-organ failure, mesenteric syndrome (Grade 1C) and patients with severe sepsis (Grade 2C). Such cases should be discussed with the SHT. The benefit of transfusion to relieve established acute priapism has not been shown in randomised controlled trials. Many patients require a shunt or drainage procedure under general anaesthesia, which may require a transfusion. Such cases should be discussed with the SHT (Grade 2C). The best data to support chronic transfusion programmes are for the primary prevention of stroke (Adams et al, 1998; Adams & Brambilla, 2005) and secondary prevention of silent cerebral infarcts in paediatric populations (DeBaun et al, 2014). There is also good evidence for the effectiveness of transfusions in preventing recurrent stroke in children (Pegelow et al, 1995; Scothorn et al, 2002). Chronic exchange transfusion has been utilised for a wide variety of indications, including prevention of recurrent vaso-occlusive crises and recurrent chest syndrome. In many of these circumstances there is also evidence of benefit of hydroxycarbamide therapy (Charache et al, 1995; Thornburg et al, 2012) and chronic transfusion should only be contemplated where hydroxycarbamide is ineffective or contra-indicated. Where chronic transfusion is initiated outside the context of paediatric stroke, the parameters to assess efficacy should be clearly documented and the risks and benefits for the patient regularly reviewed. Outcomes of chronic transfusion programmes should be regularly audited across centres. Decisions to initiate chronic transfusion should be made by the SHT. Long-term red cell transfusion is the mainstay of treatment for the primary and secondary prevention of stroke due to SCD. Evidence for the efficacy of transfusion for primary stroke prevention is available only for children but the principles may be relevant for adult patients (over 16 years). Regular red cell transfusion to maintain HbS level <30% is indicated for the primary prevention of stroke in children (2–16 years) with SS or S/βo thalassaemia with time averaged mean TCD velocities of ≥200 cm/s in the internal carotid or middle cerebral artery (Stroke Prevention Trial in Sickle Cell Anemia study – STOP) (Adams et al, 1998). Regular red cell transfusion reduced the risk of an initial stroke by 92% (Adams et al, 1998), This was confirmed in the Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP2) Trial, where children whose transfusions were discontinued were more likely to have a stroke or to revert to abnormal TCD velocities than those who continued on regular transfusion (Adams & Brambilla, 2005). The role of hydroxycarbamide in maintaining normal TCD velocities in children without severe cerebral vasculopathy or prior transient ischaemic attack (TIA) who have received transfusions for at least 1 year (mean 4 years) for primary stroke prevention has recently been investigated in the TCD With Transfusions Changing to Hydroxyurea (TWiTCH) trial (Ware et al, 2016). In this randomised trial, hydroxycarbamide at maximum tolerated dose (alternative group) was compared to standard transfusions (standard group) after patients randomised to hydroxycarbamide had been slowly weaned off transfusions over 4–9 months. This trial showed that hydroxycarbamide is non-inferior to transfusions for the maintenance of TCD velocities and can be used as a substitute to help prevent primary stroke after discontinuation of initial transfusion therapy. Transfusion to maintain HbS <30% should be offered to children at high risk of stroke following Transcranial Doppler (TCD) screening. Transfusion is the recommended initial treatment to prevent stroke in such children (Grade 1A). Hydroxycarbamide treatment should be considered for the primary prevention of stroke in children with high TCD velocities but not severe MRA-defined cerebral vasculopathy after an initial period of transfusion of at least 1 year (Grade 1A). The duration of the initial period of transfusion should be tailored to the individual patient; the transition to hydroxycarbamide should be done gradually and transfusion should be withdrawn after the hydroxycarbamide has been escalated to the maximum tolerated dose. The role of transfusion in the management of children with sickle cell anaemia aged 5–15 years (median 10 years) w
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