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Systematic review highlights high risk of bias of clinical prediction models for blood transfusion in patients undergoing elective surgery
Dhiman P, Ma J, Gibbs VN, Rampotas A, Kamal H, Arshad SS, Kirtley S, Doree C, Murphy MF, Collins GS, et al
Journal of clinical epidemiology. 2023
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Editor's Choice
Abstract
BACKGROUND Blood transfusion can be a lifesaving intervention after perioperative blood loss. Many prediction models have been developed to identify patients most likely to require blood transfusion during elective surgery, but it is unclear whether any are suitable for clinical practice. STUDY DESIGN AND SETTING We conducted a systematic review, searching MEDLINE, Embase, PubMed, The Cochrane Library, Transfusion Evidence Library, Scopus, and Web of Science databases for studies reporting the development or validation of a blood transfusion prediction model in elective surgery patients between 01/01/2000 to 30/06/2021. We extracted study characteristics, discrimination performance (c-statistics) of final models and data which we used to perform risk of bias assessment using the Prediction model Risk Of Bias ASsessment Tool (PROBAST). RESULTS We reviewed 66 studies (72 developed and 48 externally validated models). Pooled c-statistics of externally validated models ranged from 0.67 to 0.78. Most developed and validated models were at high risk of bias due to handling of predictors, validation methods, and too small sample sizes. CONCLUSION Most blood transfusion prediction models are at high risk of bias and suffer from poor reporting and methodological quality, which must be addressed before they can be safely used in clinical practice.
PICO Summary
Population
Patients undergoing elective surgery (66 studies).
Intervention
Blood transfusion prediction models used perioperatively.
Comparison
Outcome
This systematic review appraised 120 prediction models developed or validated for predicting blood transfusion in elective surgery (72 developed and 48 externally validated models). Pooled c-statistics of externally validated models ranged from 0.67 to 0.78. Most developed and validated models were at high risk of bias due to handling of predictors, validation methods, and too small sample sizes.
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Practice review: Evidence-based and effective management of anaemia in palliative care patients
Neoh K, Page A, Chin-Yee N, Doree C, Bennett MI
Palliative medicine. 2022;:2692163221081967
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Abstract
BACKGROUND Anaemia is a common sequela of advanced disease and is associated with significant symptom burden. No specific guidance exists for the investigation and management of anaemia in palliative care patients. AIM: We aim to offer a pragmatic overview of the approaches to investigate and manage anaemia in advanced disease, based on guidelines and evidence in disease specific patient groups, including cancer, heart failure and chronic kidney disease. DESIGN Scoping review methodology was used to determine the strength of evidence supporting the investigation and management of anaemia in patients with advanced disease. DATA SOURCES A search for guidelines was performed in 2020. National or international guidelines were examined if they described the investigation or management of anaemia in adult patients with health conditions seen by palliative care services written within the last 5 years in the English language. Searches of MEDLINE, the Cochrane library and WHO guidance were made in 2019 to identify key publications that provided additional primary data. RESULTS Evidence supports patient-centred investigation of anaemia, results of which should guide targeted intervention. Blanket use of blood transfusion should be avoided, with evidence supporting a more restrictive approach to transfusion. Routine use of oral iron and erythropoetin stimulating agents (ESAs) are not recommended. Insufficient evidence exists to determine the effectiveness of IV iron in this patient group. CONCLUSION We advocate early consideration and investigation of anaemia, guided by symptom burden and patient preferences. Correction of reversible causes should be the mainstay of treatment, with a restrictive approach to blood transfusion. Research is required to evaluate the efficacy of IV iron in these patients.
PICO Summary
Population
Palliative care patients (6 guidelines).
Intervention
Scoping review methodology was used to determine the strength of evidence supporting the investigation and management of anaemia.
Comparison
Outcome
Evidence supported patient-centred investigation of anaemia. There was insufficient evidence to determine the effectiveness of intravenous iron in this patient group.
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Assessing efficacy and safety of replacement fluids in therapeutic plasma exchange: A systematic scoping review of outcome measures used
Kohli R, Geneen LJ, Brunskill SJ, Doree C, Estcourt L, Chee SEJ, Al-Bader R, Sin WYC, MacCallum P, Green L
Journal of clinical apheresis. 2022
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Abstract
OBJECTIVE The aim of this systematic scoping review is to identify and categorize the outcome measures that have been reported in clinical studies, where therapeutic plasma exchange (TPE) has been used as an intervention in any clinical settings, excluding thrombotic thrombocytopenic purpura (TTP). METHODS We searched electronic databases using a predefined search strategy from inception to October 9, 2020. Two reviewers independently screened and extracted data. RESULTS We included 42 studies (37 RCTs and 5 prospective cohort studies) grouped into six main categories (neurology, immunology, renal, rheumatology, hematology, and dermatology). Primary outcomes were defined in eight studies (19%, 8/42) and were categorized as efficacy (five studies) or patient reported outcomes (three studies). A power calculation was reported in six studies (75%, 6/8): five neurology studies (mainly patient reported outcomes) and a single immunological study (efficacy outcome). Disease-specific efficacy outcomes were dependent on the clinical setting of the population receiving TPE. Most of the trials (43%, 18/42) were undertaken in patients with neurology conditions where clear, disease-specific, clinical outcome measures were used, including neurological disability scales (11/18, 61%), change in neurological examination (9/18, 50%), and functional improvement scores (7/18, 39%). For other conditions, the reporting of disease-specific outcomes was poorly reported. Safety outcomes were mainly related to replacement fluid type rather than being disease-specific. The most common outcome reported was hypotension (19%, 8/42), and this was primarily in patients exchanged with albumin. CONCLUSION Future clinical studies to determine which fluid replacement option is most efficacious and safe should use disease-specific outcomes, as a trial in one therapeutic area may not necessarily translate to another therapeutic area. Patient reported outcomes are not universally reported for all disease areas. Safety measures focused primarily on fluid safety.
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Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review
Piechotta V, Chai KL, Valk SJ, Doree C, Monsef I, Wood EM, Lamikanra A, Kimber C, McQuilten Z, So-Osman C, et al
Cochrane Database Syst Rev. 2020;7:Cd013600
Abstract
BACKGROUND Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with viral respiratory diseases, and are currently being investigated in trials as potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding the benefits and risks is required. OBJECTIVES To continually assess, as more evidence becomes available, whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in treatment of people with COVID-19. SEARCH METHODS We searched the World Health Organization (WHO) COVID-19 Global Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, Centers for Disease Control and Prevention COVID-19 Research Article Database and trial registries to identify completed and ongoing studies on 4 June 2020. SELECTION CRITERIA We followed standard Cochrane methodology. We included studies evaluating convalescent plasma or hyperimmune immunoglobulin for people with COVID-19, irrespective of study design, disease severity, age, gender or ethnicity. We excluded studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)) and studies evaluating standard immunoglobulin. DATA COLLECTION AND ANALYSIS We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane 'Risk of bias' tool for randomised controlled trials (RCTs), the Risk of Bias in Non-randomised Studies - of Interventions (ROBINS-I) tool for controlled non-randomised studies of interventions (NRSIs), and the assessment criteria for observational studies, provided by Cochrane Childhood Cancer for non-controlled NRSIs. MAIN RESULTS This is the first living update of our review. We included 20 studies (1 RCT, 3 controlled NRSIs, 16 non-controlled NRSIs) with 5443 participants, of whom 5211 received convalescent plasma, and identified a further 98 ongoing studies evaluating convalescent plasma or hyperimmune immunoglobulin, of which 50 are randomised. We did not identify any completed studies evaluating hyperimmune immunoglobulin. Overall risk of bias of included studies was high, due to study design, type of participants, and other previous or concurrent treatments. Effectiveness of convalescent plasma for people with COVID-19 We included results from four controlled studies (1 RCT (stopped early) with 103 participants, of whom 52 received convalescent plasma; and 3 controlled NRSIs with 236 participants, of whom 55 received convalescent plasma) to assess effectiveness of convalescent plasma. Control groups received standard care at time of treatment without convalescent plasma. All-cause mortality at hospital discharge (1 controlled NRSI, 21 participants) We are very uncertain whether convalescent plasma has any effect on all-cause mortality at hospital discharge (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.61 to 1.31; very low-certainty evidence). Time to death (1 RCT, 103 participants; 1 controlled NRSI, 195 participants) We are very uncertain whether convalescent plasma prolongs time to death (RCT: hazard ratio (HR) 0.74, 95% CI 0.30 to 1.82; controlled NRSI HR 0.46, 95% CI 0.22 to 0.96; very low-certainty evidence). Improvement of clinical symptoms, assessed by need for respiratory support (1 RCT, 103 participants; 1 controlled NRSI, 195 participants) We are very uncertain whether convalescent plasma has any effect on improvement of clinical symptoms at seven days (RCT: RR 0.98, 95% CI 0.30 to 3.19), 14 days (RCT: RR 1.85, 95% CI 0.91 to 3.77; controlled NRSI RR 1.08, 95% CI 0.91 to 1.29), and 28 days (RCT: RR 1.20, 95% CI 0.80 to 1.81; very low-certainty evidence). Quality of life No studies reported this outcome. Safety of convalescent plasma for people with COVID-19 We included results from 1 RCT, 3 controlled NRSIs and 10 non-controlled NRSIs assessing safety of convalescent plasma. Reporting of adverse events and serious adverse events was variable. The controlled studies reported on adverse e ents and serious adverse events only in participants receiving convalescent plasma. The duration of follow-up varied. Some, but not all, studies included death as a serious adverse event. Grade 3 or 4 adverse events (13 studies, 201 participants) The studies did not report the grade of adverse events. Thirteen studies (201 participants) reported on adverse events of possible grade 3 or 4 severity. The majority of these adverse events were allergic or respiratory events. We are very uncertain whether or not convalescent plasma therapy affects the risk of moderate to severe adverse events (very low-certainty evidence). Serious adverse events (14 studies, 5201 participants) Fourteen studies (5201 participants) reported on serious adverse events. The majority of participants were from one non-controlled NRSI (5000 participants), which reported only on serious adverse events limited to the first four hours after convalescent plasma transfusion. This study included death as a serious adverse event; they reported 15 deaths, four of which they classified as potentially, probably or definitely related to transfusion. Other serious adverse events reported in all studies were predominantly allergic or respiratory in nature, including anaphylaxis, transfusion-associated dyspnoea, and transfusion-related acute lung injury (TRALI). We are very uncertain whether or not convalescent plasma affects the number of serious adverse events. AUTHORS' CONCLUSIONS We are very uncertain whether convalescent plasma is beneficial for people admitted to hospital with COVID-19. For safety outcomes we also included non-controlled NRSIs. There was limited information regarding adverse events. Of the controlled studies, none reported on this outcome in the control group. There is only very low-certainty evidence for safety of convalescent plasma for COVID-19. While major efforts to conduct research on COVID-19 are being made, problems with recruiting the anticipated number of participants into these studies are conceivable. The early termination of the first RCT investigating convalescent plasma, and the multitude of studies registered in the past months illustrate this. It is therefore necessary to critically assess the design of these registered studies, and well-designed studies should be prioritised. Other considerations for these studies are the need to report outcomes for all study arms in the same way, and the importance of maintaining comparability in terms of co-interventions administered in all study arms. There are 98 ongoing studies evaluating convalescent plasma and hyperimmune immunoglobulin, of which 50 are RCTs. This is the first living update of the review, and we will continue to update this review periodically. These updates may show different results to those reported here.
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Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a rapid review
Valk SJ, Piechotta V, Chai KL, Doree C, Monsef I, Wood EM, Lamikanra A, Kimber C, McQuilten Z, So-Osman C, et al
The Cochrane Database of Systematic Reviews. 2020;5:Cd013600
Abstract
BACKGROUND Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with respiratory virus diseases, and are currently being investigated in trials as a potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding the benefits and risks is required. OBJECTIVES To assess whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in the treatment of people with COVID-19. SEARCH METHODS The protocol was pre-published with the Center for Open Science and can be accessed here: osf.io/dwf53 We searched the World Health Organization (WHO) COVID-19 Global Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, Centers for Disease Control and Prevention COVID-19 Research Article Database and trials registries to identify ongoing studies and results of completed studies on 23 April 2020 for case-series, cohort, prospectively planned, and randomised controlled trials (RCTs). SELECTION CRITERIA We followed standard Cochrane methodology and performed all steps regarding study selection in duplicate by two independent review authors (in contrast to the recommendations of the Cochrane Rapid Reviews Methods Group). We included studies evaluating convalescent plasma or hyperimmune immunoglobulin for people with COVID-19, irrespective of disease severity, age, gender or ethnicity. We excluded studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)) and studies evaluating standard immunoglobulins. DATA COLLECTION AND ANALYSIS We followed recommendations of the Cochrane Rapid Reviews Methods Group regarding data extraction and assessment. To assess bias in included studies, we used the assessment criteria tool for observational studies, provided by Cochrane Childhood Cancer. We rated the certainty of evidence using the GRADE approach for the following outcomes: all-cause mortality at hospital discharge, improvement of clinical symptoms (7, 15, and 30 days after transfusion), grade 3 and 4 adverse events, and serious adverse events. MAIN RESULTS We included eight studies (seven case-series, one prospectively planned, single-arm intervention study) with 32 participants, and identified a further 48 ongoing studies evaluating convalescent plasma (47 studies) or hyperimmune immunoglobulin (one study), of which 22 are randomised. Overall risk of bias of the eight included studies was high, due to: study design; small number of participants; poor reporting within studies; and varied type of participants with different severities of disease, comorbidities, and types of previous or concurrent treatments, including antivirals, antifungals or antibiotics, corticosteroids, hydroxychloroquine and respiratory support. We rated all outcomes as very low certainty, and we were unable to summarise numerical data in any meaningful way. As we identified case-series studies only, we reported results narratively. Effectiveness of convalescent plasma for people with COVID-19 The following reported outcomes could all be related to the underlying natural history of the disease or other concomitant treatment, rather than convalescent plasma. All-cause mortality at hospital discharge All studies reported mortality. All participants were alive at the end of the reporting period, but not all participants had been discharged from hospital by the end of the study (15 participants discharged, 6 still hospitalised, 11 unclear). Follow-up ranged from 3 days to 37 days post-transfusion. We do not know whether convalescent plasma therapy affects mortality (very low-certainty evidence). Improvement of clinical symptoms (assessed by respiratory support) Six studies, including 28 participants, reported the level of respiratory support required; most participants required respiratory support at baseline. All studies reported improvement in clinical symptoms in at least some participants. We do not know whether convalescent plasma improves clinic l symptoms (very low-certainty evidence). Time to discharge from hospital Six studies reported time to discharge from hospital for at least some participants, which ranged from four to 35 days after convalescent plasma therapy. Admission on the intensive care unit (ICU) Six studies included patients who were critically ill. At final follow-up the majority of these patients were no longer on the ICU or no longer required mechanical ventilation. Length of stay on the ICU Only one study (1 participant) reported length of stay on the ICU. The individual was discharged from the ICU 11 days after plasma transfusion. Safety of convalescent plasma for people with COVID-19 Grade 3 or 4 adverse events The studies did not report the grade of adverse events after convalescent plasma transfusion. Two studies reported data relating to participants who had experienced adverse events, that were presumably grade 3 or 4. One case study reported a participant who had moderate fever (38.9 degrees C). Another study (3 participants) reported a case of severe anaphylactic shock. Four studies reported the absence of moderate or severe adverse events (19 participants). We are very uncertain whether or not convalescent plasma therapy affects the risk of moderate to severe adverse events (very low-certainty evidence). Serious adverse events One study (3 participants) reported one serious adverse event. As described above, this individual had severe anaphylactic shock after receiving convalescent plasma. Six studies reported that no serious adverse events occurred. We are very uncertain whether or not convalescent plasma therapy affects the risk of serious adverse events (very low-certainty evidence). AUTHORS' CONCLUSIONS We identified eight studies (seven case-series and one prospectively planned single-arm intervention study) with a total of 32 participants (range 1 to 10). Most studies assessed the risks of the intervention; reporting two adverse events (potentially grade 3 or 4), one of which was a serious adverse event. We are very uncertain whether convalescent plasma is effective for people admitted to hospital with COVID-19 as studies reported results inconsistently, making it difficult to compare results and to draw conclusions. We identified very low-certainty evidence on the effectiveness and safety of convalescent plasma therapy for people with COVID-19; all studies were at high risk of bias and reporting quality was low. No RCTs or controlled non-randomised studies evaluating benefits and harms of convalescent plasma have been completed. There are 47 ongoing studies evaluating convalescent plasma, of which 22 are RCTs, and one trial evaluating hyperimmune immunoglobulin. We will update this review as a living systematic review, based on monthly searches in the above mentioned databases and registries. These updates are likely to show different results to those reported here.
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Effects of the COVID-19 pandemic on supply and use of blood for transfusion
Stanworth SJ, New HV, Apelseth TO, Brunskill S, Cardigan R, Doree C, Germain M, Goldman M, Massey E, Prati D, et al
Lancet Haematol. 2020
Abstract
The COVID-19 pandemic has major implications for blood transfusion. There are uncertain patterns of demand, and transfusion institutions need to plan for reductions in donations and loss of crucial staff because of sickness and public health restrictions. We systematically searched for relevant studies addressing the transfusion chain-from donor, through collection and processing, to patients-to provide a synthesis of the published literature and guidance during times of potential or actual shortage. A reduction in donor numbers has largely been matched by reductions in demand for transfusion. Contingency planning includes prioritisation policies for patients in the event of predicted shortage. A range of strategies maintain ongoing equitable access to blood for transfusion during the pandemic, in addition to providing new therapies such as convalescent plasma. Sharing experience and developing expert consensus on the basis of evolving publications will help transfusion services and hospitals in countries at different stages in the pandemic.
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Interventions for preventing silent cerebral infarcts in people with sickle cell disease
Estcourt LJ, Kimber C, Hopewell S, Trivella M, Doree C, Abboud MR
Cochrane Database Syst Rev. 2020;4:Cd012389
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Abstract
BACKGROUND Sickle cell disease (SCD) is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Silent cerebral infarcts are the commonest neurological complication in children and probably adults with SCD. Silent cerebral infarcts also affect academic performance, increase cognitive deficits and may lower intelligence quotient. OBJECTIVES To assess the effectiveness of interventions to reduce or prevent silent cerebral infarcts in people with SCD. SEARCH METHODS We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 14 November 2019. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register: 07 October 2019. SELECTION CRITERIA Randomised controlled trials comparing interventions to prevent silent cerebral infarcts in people with SCD. There were no restrictions by outcomes examined, language or publication status. DATA COLLECTION AND ANALYSIS We used standard Cochrane methodological procedures. MAIN RESULTS We included five trials (660 children or adolescents) published between 1998 and 2016. Four of the five trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of SCD. One trial focused on preventing silent cerebral infarcts or stroke; three trials were for primary stroke prevention and one trial dealt with secondary stroke prevention. Three trials compared the use of regular long-term red blood cell transfusions to standard care. Two of these trials included children with no previous long-term transfusions: one in children with normal transcranial doppler (TCD) velocities; and one in children with abnormal TCD velocities. The third trial included children and adolescents on long-term transfusion. Two trials compared the drug hydroxyurea and phlebotomy to long-term transfusions and iron chelation therapy: one in primary prevention (children), and one in secondary prevention (children and adolescents). The quality of the evidence was moderate to very low across different outcomes according to GRADE methodology. This was due to trials being at high risk of bias because they were unblinded; indirectness (available evidence was only for children with HbSS); and imprecise outcome estimates. Long-term red blood cell transfusions versus standard care Children with no previous long-term transfusions and higher risk of stroke (abnormal TCD velocities or previous history of silent cerebral infarcts) Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, risk ratio (RR) 0.11 (95% confidence interval (CI) 0.02 to 0.86) (one trial, 124 participants, low-quality evidence); but make little or no difference to the incidence of silent cerebral infarcts in children with previous silent cerebral infarcts on magnetic resonance imaging and normal or conditional TCDs, RR 0.70 (95% CI 0.23 to 2.13) (one trial, 196 participants, low-quality evidence). No deaths were reported in either trial. Long-term red blood cell transfusions may reduce the incidence of: acute chest syndrome, RR 0.24 (95% CI 0.12 to 0.49) (two trials, 326 participants, low-quality evidence); and painful crisis, RR 0.63 (95% CI 0.42 to 0.95) (two trials, 326 participants, low-quality evidence); and probably reduces the incidence of clinical stroke, RR 0.12 (95% CI 0.03 to 0.49) (two trials, 326 participants, moderate-quality evidence). Long-term red blood cell transfusions may improve quality of life in children with previous silent cerebral infarcts (difference estimate -0.54; 95% confidence interval -0.92 to -0.17; one trial; 166 participants), but may have no effect on cognitive function (least squares means: 1.7, 95% CI -1.1 to 4.4) (one trial, 166 participants, low-quality evidence). Transfusions continued versus transfusions halted: children and adolescents with normalised TCD velocities (79 participants; one trial) Continuing red blood cell transfusions may reduce the incidence of silent cerebral infarcts, RR 0.29 (95% CI 0.09 to 0.97 (low-quality evidence). We are very uncertain whether continuing red blood cell transfusions has any effect on all-cause mortality, Peto odds ratio (OR) 8.00 (95% CI 0.16 to 404.12); or clinical stroke, RR 0.22 (95% CI 0.01 to 4.35) (very low-quality evidence). The trial did not report: comparative numbers for SCD-related adverse events; quality of life; or cognitive function. Hydroxyurea and phlebotomy versus transfusions and chelation Primary prevention, children (121 participants; one trial) We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts (no infarcts); all-cause mortality (no deaths); risk of stroke (no strokes); or SCD-related complications, RR 1.52 (95% CI 0.58 to 4.02) (very low-quality evidence). Secondary prevention, children and adolescents with a history of stroke (133 participants; one trial) We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts, Peto OR 7.28 (95% CI 0.14 to 366.91); all-cause mortality, Peto OR 1.02 (95%CI 0.06 to 16.41); or clinical stroke, RR 14.78 (95% CI 0.86 to 253.66) (very low-quality evidence). Switching to hydroxyurea and phlebotomy may increase the risk of SCD-related complications, RR 3.10 (95% CI 1.42 to 6.75) (low-quality evidence). Neither trial reported on quality of life or cognitive function. AUTHORS' CONCLUSIONS We identified no trials for preventing silent cerebral infarcts in adults, or in children who do not have HbSS SCD. Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, but may have little or no effect on children with normal TCD velocities. In children who are at higher risk of stroke and have not had previous long-term transfusions, long-term red blood cell transfusions probably reduce the risk of stroke, and other SCD-related complications (acute chest syndrome and painful crises). In children and adolescents at high risk of stroke whose TCD velocities have normalised, continuing red blood cell transfusions may reduce the risk of silent cerebral infarcts. No treatment duration threshold has been established for stopping transfusions. Switching to hydroxyurea with phlebotomy may increase the risk of silent cerebral infarcts and SCD-related serious adverse events in secondary stroke prevention. All other evidence in this review is of very low-quality.
PICO Summary
Population
Children or adolescents with sickle cell disease (SCD), five trials (n=660).
Intervention
Long-term red blood cell transfusions.
Comparison
Standard care or halting transfusions, or hydroxyurea and phlebotomy.
Outcome
Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal transcranial doppler (TCD) velocities; but make little or no difference to the incidence of silent cerebral infarcts in children with previous silent cerebral infarcts on magnetic resonance imaging and normal or conditional TCDs. Long-term red blood cell transfusions may improve quality of life in children with previous silent cerebral infarcts, but may have no effect on cognitive function. Continuing red blood cell transfusions may reduce the incidence of silent cerebral infarcts. It is uncertain whether switching to hydroxyurea and phlebotomy has any effect on silent cerebral infarcts (no infarcts); all-cause mortality (no deaths); risk of stroke (no strokes); or SCD-related complications. For children and adolescents with a history of stroke it was uncertain whether switching to hydroxyurea and phlebotomy has any effect on silent cerebral infarcts all-cause mortality or clinical stroke. Switching to hydroxyurea and phlebotomy may increase the risk of SCD-related complications.
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8.
Preoperative blood transfusions for sickle cell disease
Estcourt LJ, Kimber C, Trivella M, Doree C, Hopewell S
Cochrane Database Syst Rev. 2020;7:Cd003149
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Abstract
BACKGROUND Sickle cell disease (SCD) is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Surgical interventions are more common in people with SCD, and occur at much younger ages than in the general population. Blood transfusions are frequently used prior to surgery and several regimens are used but there is no consensus over the best method or the necessity of transfusion in specific surgical cases. This is an update of a Cochrane Review. OBJECTIVES To determine whether there is evidence that preoperative blood transfusion in people with SCD undergoing elective or emergency surgery reduces mortality and perioperative or sickle cell-related serious adverse events. To compare the effectiveness of different transfusion regimens (aggressive or conservative) if preoperative transfusions are indicated in people with SCD. SEARCH METHODS We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 28 January 2020 We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register: 19 September 2019. SELECTION CRITERIA All randomised controlled trials and quasi-randomised controlled trials comparing preoperative blood transfusion regimens to different regimens or no transfusion in people with SCD undergoing elective or emergency surgery. There was no restriction by outcomes examined, language or publication status. DATA COLLECTION AND ANALYSIS Two authors independently assessed trial eligibility and the risk of bias and extracted data. MAIN RESULTS Three trials with 990 participants were eligible for inclusion in the review. There were no ongoing trials identified. These trials were conducted between 1988 and 2011. The majority of people included had haemoglobin (Hb) SS SCD. The majority of surgical procedures were considered low or intermediate risk for developing sickle cell-related complications. Aggressive versus simple red blood cell transfusions One trial (551 participants) compared an aggressive transfusion regimen (decreasing sickle haemoglobin to less than 30%) to a simple transfusion regimen (increasing haemoglobin to 100 g/L). This trial re-randomised\ participants and therefore quantitative analysis was only possible on two subsets of data: participants undergoing cholecystectomy (230 participants); and participants undergoing tonsillectomy or adenoidectomy surgeries (107 participants). Data were not combined as we do not know if any participant received both surgeries. Overall, the quality of the evidence was very low across different outcomes according to GRADE methodology. This was due to the trial being at high risk of bias primarily due to lack of blinding, indirectness and the outcome estimates being imprecise. Cholecystectomy subgroup results are reported in the abstract. Results for both subgroups were similar. There was no difference in all-cause mortality between people receiving aggressive transfusions and those receiving conservative transfusions. No deaths occurred in either subgroup. There were no differences between the aggressive transfusion group and conservative transfusion group in the number of people developing: * an acute chest syndrome, risk ratio (RR) 0.84 (95% confidence interval (CI) 0.38 to 1.84) (one trial, 230 participants, very low-quality evidence); * vaso-occlusive crisis, risk ratio 0.30 (95% CI 0.09 to 1.04) (one trial, 230 participants, very low quality evidence); * serious infection, risk ratio 1.75 (95% CI 0.59 to 5.18) (one trial, 230 participants, very low-quality evidence); * any perioperative complications, RR 0.75 (95% CI 0.36 to 1.55) (one trial, 230 participants, very low-quality evidence); * a transfusion-related complication, RR 1.85 (95% CI 0.89 to 3.88) (one trial, 230 participants, very low-quality evidence). Preoperative transfusion versus no preoperative transfusion Two trials (434 participants) compared a preoperative transfusion plus standard care to a group receiving standard care. Overall, the quality of the evidence was low to very low across different outcomes according to GRADE methodology. This was due to the trials being at high risk of bias due to lack of blinding, and outcome estimates being imprecise. One trial was stopped early because more people in the no transfusion arm developed an acute chest syndrome. There was no difference in all-cause mortality between people receiving preoperative transfusions and those receiving no preoperative transfusions (two trials, 434 participants, no deaths occurred). There was significant heterogeneity between the two trials in the number of people developing an acute chest syndrome, a meta-analysis was therefore not performed. One trial showed a reduced number of people developing acute chest syndrome between people receiving preoperative transfusions and those receiving no preoperative transfusions, risk ratio 0.11 (95% confidence interval 0.01 to 0.80) (65 participants), whereas the other trial did not, RR 4.81 (95% CI 0.23 to 99.61) (369 participants). There were no differences between the preoperative transfusion groups and the groups without preoperative transfusion in the number of people developing: * a vaso-occlusive crisis, Peto odds ratio (OR) 1.91 (95% confidence interval 0.61 to 6.04) (two trials, 434 participants, very low-quality evidence). * a serious infection, Peto OR 1.29 (95% CI 0.29 to 5.71) (two trials, 434 participants, very low-quality evidence); * any perioperative complications, RR 0.24 (95% CI 0.03 to 2.05) (one trial, 65 participants, low-quality evidence). There was an increase in the number of people developing circulatory overload in those receiving preoperative transfusions compared to those not receiving preoperative transfusions in one of the two trials, and no events were seen in the other trial (no meta-analysis performed). AUTHORS' CONCLUSIONS There is insufficient evidence from randomised trials to determine whether conservative preoperative blood transfusion is as effective as aggressive preoperative blood transfusion in preventing sickle-related or surgery-related complications in people with HbSS disease. There is very low quality evidence that preoperative blood transfusion may prevent development of acute chest syndrome. Due to lack of evidence this review cannot comment on management for people with HbSC or HbSbeta(+) disease or for those with high baseline haemoglobin concentrations.
PICO Summary
Population
Patients with sickle cell disease (SCD) undergoing elective or emergency surgery (3 studies, n= 990).
Intervention
Aggressive transfusion regime prior to surgery.
Comparison
Conservative transfusion regime or no transfusion prior to surgery.
Outcome
There was no difference between the aggressive and the conservative transfusion regimens before surgery in preventing surgical or sickle‐related complications immediately after surgery. There was no difference in all‐cause mortality between patients receiving preoperative transfusions and those receiving no preoperative transfusions. There was significant heterogeneity between the two trials in the number of people developing an acute chest syndrome, however there was no difference between giving a blood transfusion before surgery compared to not giving a blood transfusion before surgery in preventing any other sickle‐related or surgical complications immediately after surgery.
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9.
Prophylactic plasma transfusion for patients without inherited bleeding disorders or anticoagulant use undergoing non-cardiac surgery or invasive procedures
Huber J, Stanworth SJ, Doree C, Fortin PM, Trivella M, Brunskill SJ, Hopewell S, Wilkinson KL, Estcourt LJ
The Cochrane database of systematic reviews. 2019;11:Cd012745
Abstract
BACKGROUND In the absence of bleeding, plasma is commonly transfused to people prophylactically to prevent bleeding. In this context, it is transfused before operative or invasive procedures (such as liver biopsy or chest drainage tube insertion) in those considered at increased risk of bleeding, typically defined by abnormalities of laboratory tests of coagulation. As plasma contains procoagulant factors, plasma transfusion may reduce perioperative bleeding risk. This outcome has clinical importance given that perioperative bleeding and blood transfusion have been associated with increased morbidity and mortality. Plasma is expensive, and some countries have experienced issues with blood product shortages, donor pool reliability, and incomplete screening for transmissible infections. Thus, although the benefit of prophylactic plasma transfusion has not been well established, plasma transfusion does carry potentially life-threatening risks. OBJECTIVES To determine the clinical effectiveness and safety of prophylactic plasma transfusion for people with coagulation test abnormalities (in the absence of inherited bleeding disorders or use of anticoagulant medication) requiring non-cardiac surgery or invasive procedures. SEARCH METHODS We searched for randomised controlled trials (RCTs), without language or publication status restrictions in: Cochrane Central Register of Controlled Trials (CENTRAL; 2017 Issue 7); Ovid MEDLINE (from 1946); Ovid Embase (from 1974); Cumulative Index to Nursing and Allied Health Literature (CINAHL; EBSCOHost) (from 1937); PubMed (e-publications and in-process citations ahead of print only); Transfusion Evidence Library (from 1950); Latin American Caribbean Health Sciences Literature (LILACS) (from 1982); Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) (Thomson Reuters, from 1990); ClinicalTrials.gov; and World Health Organization (WHO) International Clinical Trials Registry Search Platform (ICTRP) to 28 January 2019. SELECTION CRITERIA We included RCTs comparing: prophylactic plasma transfusion to placebo, intravenous fluid, or no intervention; prophylactic plasma transfusion to alternative pro-haemostatic agents; or different haemostatic thresholds for prophylactic plasma transfusion. We included participants of any age, and we excluded trials incorporating individuals with previous active bleeding, with inherited bleeding disorders, or taking anticoagulant medication before enrolment. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. MAIN RESULTS We included five trials in this review, all were conducted in high-income countries. Three additional trials are ongoing. One trial compared fresh frozen plasma (FFP) transfusion with no transfusion given. One trial compared FFP or platelet transfusion or both with neither FFP nor platelet transfusion given. One trial compared FFP transfusion with administration of alternative pro-haemostatic agents (factors II, IX, and X followed by VII). One trial compared the use of different transfusion triggers using the international normalised ratio measurement. One trial compared the use of a thromboelastographic-guided transfusion trigger using standard laboratory measurements of coagulation. Four trials enrolled only adults, whereas the fifth trial did not specify participant age. Four trials included only minor procedures that could be performed by the bedside. Only one trial included some participants undergoing major surgical operations. Two trials included only participants in intensive care. Two trials included only participants with liver disease. Three trials did not recruit sufficient participants to meet their pre-calculated sample size. Overall, the quality of evidence was low to very low across different outcomes according to GRADE methodology, due to risk of bias, indirectness, and imprecision. One trial was stopped after recruiting two participants, therefore this review's findings are based on the remaining four trials (234 participants). When plasma transfusion was compared with no transfusion given, we are very uncertain whether there was a difference in 30-day mortality (1 trial comparing FFP or platelet transfusion or both with neither FFP nor platelet transfusion, 72 participants; risk ratio (RR) 0.38, 95% confidence interval (CI) 0.13 to 1.10; very low-quality evidence). We are very uncertain whether there was a difference in major bleeding within 24 hours (1 trial comparing FFP transfusion vs no transfusion, 76 participants; RR 0.33, 95% CI 0.01 to 7.93; very low-quality evidence; 1 trial comparing FFP or platelet transfusion or both with neither FFP nor platelet transfusion, 72 participants; RR 1.59, 95% CI 0.28 to 8.93; very low-quality evidence). We are very uncertain whether there was a difference in the number of blood product transfusions per person (1 trial, 76 participants; study authors reported no difference; very low-quality evidence) or in the number of people requiring transfusion (1 trial comparing FFP or platelet transfusion or both with neither FFP nor platelet transfusion, 72 participants; study authors reported no blood transfusion given; very low-quality evidence) or in the risk of transfusion-related adverse events (acute lung injury) (1 trial, 76 participants; study authors reported no difference; very low-quality evidence). When plasma transfusion was compared with other pro-haemostatic agents, we are very uncertain whether there was a difference in major bleeding (1 trial; 21 participants; no events; very low-quality evidence) or in transfusion-related adverse events (febrile or allergic reactions) (1 trial, 21 participants; RR 9.82, 95% CI 0.59 to 162.24; very low-quality evidence). When different triggers for FFP transfusion were compared, the number of people requiring transfusion may have been reduced (for overall blood products) when a thromboelastographic-guided transfusion trigger was compared with standard laboratory tests (1 trial, 60 participants; RR 0.18, 95% CI 0.08 to 0.39; low-quality evidence). We are very uncertain whether there was a difference in major bleeding (1 trial, 60 participants; RR 0.33, 95% CI 0.01 to 7.87; very low-quality evidence) or in transfusion-related adverse events (allergic reactions) (1 trial; 60 participants; RR 0.33, 95% CI 0.01 to 7.87; very low-quality evidence). Only one trial reported 30-day mortality. No trials reported procedure-related harmful events (excluding bleeding) or quality of life. AUTHORS' CONCLUSIONS Review findings show uncertainty for the utility and safety of prophylactic FFP use. This is due to predominantly very low-quality evidence that is available for its use over a range of clinically important outcomes, together with lack of confidence in the wider applicability of study findings, given the paucity or absence of study data in settings such as major body cavity surgery, extensive soft tissue surgery, orthopaedic surgery, or neurosurgery. Therefore, from the limited RCT evidence, we can neither support nor oppose the use of prophylactic FFP in clinical practice.
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10.
Transfusion of red blood cells stored for shorter versus longer duration for all conditions
Shah A, Brunskill SJ, Desborough MJ, Doree C, Trivella M, Stanworth SJ
The Cochrane Database of Systematic Reviews. 2018;12:CD010801.
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Abstract
BACKGROUND Red blood cell (RBC) transfusion is a common treatment for anaemia in many conditions. The safety and efficacy of transfusing RBC units that have been stored for different durations before a transfusion is a current concern. The duration of storage for a RBC unit can be up to 42 days. If evidence from randomised controlled trials (RCT) were to indicate that clinical outcomes are affected by storage duration, the implications for inventory management and clinical practice would be significant. OBJECTIVES To assess the effects of using red blood cells (RBCs) stored for a shorter versus a longer duration, or versus RBCs stored for standard practice duration, in people requiring a RBC transfusion. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, PubMed (for epublications), LILACS, Transfusion Evidence Library, Web of Science CPCI-S and four international clinical trial registries on 20 November 2017. SELECTION CRITERIA We included RCTs that compared transfusion of RBCs of shorter versus longer storage duration, or versus standard practice storage duration. DATA COLLECTION AND ANALYSIS We used standard Cochrane methods. MAIN RESULTS We included 22 trials (42,835 participants) in this review.The GRADE quality of evidence ranged from very low to moderate for our primary outcome of in-hospital and short-term mortality reported at different time points.Transfusion of RBCs of shorter versus longer storage duration Eleven trials (2249 participants) compared transfusion of RBCs of shorter versus longer storage duration. Two trials enrolled low birth weight neonates, two enrolled children with severe anaemia secondary to malaria or sickle cell disease, and eight enrolled adults across a range of clinical settings (intensive care, cardiac surgery, major elective surgery, hospitalised in-patients, haematology outpatients). We judged only two trials to be at low risk of bias across all domains; most trials had an unclear risk for multiple domains.Transfusion of RBCs of shorter versus longer storage duration probably leads to little or no difference in mortality at seven-day follow-up (risk ratio (RR) 1.42, 95% confidence interval (CI) 0.66 to 3.06; 1 trial, 3098 participants; moderate quality evidence) or 30-day follow-up (RR 0.85, 95%CI 0.50 to 1.45; 2 trials, 1121 participants; moderate quality evidence) in adults undergoing major elective cardiac or non-cardiac surgery.For neonates, no studies reported on the primary outcome of in-hospital or short-term mortality. At 40 weeks gestational age, the effect of RBCs of shorter versus longer storage duration on the risk of death was uncertain, as the quality of evidence is very low (RR 0.90, 95% CI 0.41 to 1.85; 1 trial, 52 participants).The effect of RBCs of shorter versus longer storage duration on the risk of death in children with severe anaemia was also uncertain within 24 hours of transfusion (RR 1.50, 95% CI 0.43 to 5.25; 2 trials, 364 participants; very low quality evidence), or at 30-day follow-up (RR 1.40, 95% CI 0.45 to 4.31; 1 trial, 290 participants; low quality evidence).Only one trial, in children with severe anaemia (290 participants), reported adverse transfusion reactions. Only one child in each arm experienced an adverse reaction within 24 hours of transfusion.Transfusion of RBCs of shorter versus standard practice storage duration Eleven trials (40,588 participants) compared transfusion of RBCs of shorter versus standard practice storage duration. Three trials enrolled critically ill term neonates; two of these enrolled very low birth weight neonates. There were no trials in children. Eight trials enrolled critically ill and non-critically ill adults, with most being hospitalised. We judged four trials to be at low risk of bias across all domains with the others having an unclear risk of bias across multiple domains.Transfusion of RBCs of shorter versus standard practice storage duration probably leads to little or no difference in adult in-hospital mortality (RR 1.05, 95% CI 0.97 to 1.14; 4 trials, 25,704 participants; moderate quality evidence), ICU mortality (RR 1.06, 95% CI 0.98 to 1.15; 3 trials, 13,066 participants; moderate quality evidence), or 30-day mortality (RR 1.04, 95% CI 0.96 to 1.13; 4 trials, 7510 participants;moderate quality evidence).Two of the three trials that enrolled neonates reported that there were no adverse transfusion reactions. One trial reported an isolated case of cytomegalovirus infection in participants assigned to the standard practice storage duration group. Two trials in critically ill adults reported data on transfusion reactions: one observed no difference in acute transfusion reactions between arms (RR 0.67, 95% CI 0.19 to 2.36, 2413 participants), but the other observed more febrile nonhaemolytic reactions in the shorter storage duration arm (RR 1.48, 95% CI 1.13 to 1.95, 4919 participants).Trial sequential analysis showed that we may now have sufficient evidence to reject a 5% relative risk increase or decrease of death within 30 days when transfusing RBCs of shorter versus longer storage duration across all patient groups. AUTHORS' CONCLUSIONS The effect of storage duration on clinically important outcomes has now been investigated in large, high quality RCTs, predominantly in adults. There appears to be no evidence of an effect on mortality that is related to length of storage of transfused RBCs. However, the quality of evidence in neonates and children is low. The current practice in blood banks of using the oldest available RBCs can be continued safely. Additional RCTs are not required, but research using alternative study designs, should focus on particular subgroups (e.g. those requiring multiple RBC units) and on factors affecting RBC quality.
PICO Summary
Population
Adults, children, and neonates requiring a red blood cell (RBC) transfusion (22 randomised controlled trials, n= 42,835).
Intervention
Transfusion of RBCs of shorter storage duration.
Comparison
Transfusion of RBCs of longer storage duration; Standard practice storage duration.
Outcome
Transfusion of RBCs of shorter vs. longer storage duration (11 trials, n= 2,249) probably led to little or no difference in mortality at seven-day follow-up (risk ratio (RR) 1.42, 95% confidence interval (CI) 0.66 to 3.06; 1 trial, n= 3,098) or 30-day follow-up (RR 0.85, 95%CI 0.50 to 1.45; 2 trials, n= 1,121) in adults undergoing major elective cardiac or non-cardiac surgery. At 40 weeks gestational age, the effect on the risk of death was uncertain (RR 0.90, 95% CI 0.41 to 1.85; 1 trial, n= 52). The effect of RBCs of shorter vs. longer storage duration on the risk of death in children with severe anaemia was also uncertain within 24 hours of transfusion (RR 1.50, 95% CI 0.43 to 5.25; 2 trials, n= 364), or at 30-day follow-up (RR 1.40, 95% CI 0.45 to 4.31; 1 trial, n= 290). Only one trial, in children with severe anaemia (n= 290), reported adverse transfusion reactions. Only one child in each arm experienced an adverse reaction within 24 hours of transfusion. Transfusion of RBCs of shorter vs. standard practice storage duration (11 trials, n= 40,588) probably led to little or no difference in adult in-hospital mortality (RR 1.05, 95% CI 0.97 to 1.14; 4 trials, n= 25,704), ICU mortality (RR 1.06, 95% CI 0.98 to 1.15; 3 trials, n= 13,066), or 30-day mortality (RR 1.04, 95% CI 0.96 to 1.13; 4 trials, n= 7,510). Two of the three trials that enrolled neonates reported that there were no adverse transfusion reactions. One trial reported an isolated case of cytomegalovirus infection in participants assigned to the standard practice storage duration group. Two trials in critically ill adults reported data on transfusion reactions: one observed no difference in acute transfusion reactions between arms (RR 0.67, 95% CI 0.19 to 2.36, n= 2,413), but the other observed more febrile non-haemolytic reactions in the shorter storage duration arm (RR 1.48, 95% CI 1.13 to 1.95, n= 4,919). Trial sequential analysis showed that we may now have sufficient evidence to reject a 5% relative risk increase or decrease of death within 30 days when transfusing RBCs of shorter vs. longer storage duration across all patient groups.