Abstract
Introduction
Sickle cell disease causes chronic haemolytic anaemia, dactylitis, and painful acute crises. It also increases the risk of stroke, organ damage, bacterial infections, and complications of blood transfusion. In sub-Saharan Africa, up to a third of adults are carriers of the defective sickle cell gene, and 1% to 2% of babies are born with the disease.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: what are the effects of pharmaceutical and non-pharmaceutical interventions to prevent sickle cell crisis and other acute complications in people with sickle cell disease? What are the effects of pharmaceutical and non-pharmaceutical interventions to treat pain in people with sickle cell crisis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 38 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, antibiotic prophylaxis in children <5 years of age, antibiotic prophylaxis in children >5 years of age, aspirin, avoidance of cold environment, blood transfusion, codeine, corticosteroid (with narcotic analgesics), diflunisal, hydration, hydroxyurea, ibuprofen, ketorolac, limiting physical exercise, malaria chemoprophylaxis, morphine (controlled-release oral after initial intravenous bolus, repeated intravenous doses), oxygen, paracetamol, patient-controlled analgesia, pneumococcal vaccines, and rehydration.
Key Points
In sub-Saharan Africa, up to a third of adults are carriers of the defective sickle cell gene, and 1% to 2% of babies are born with the disease.
Sickle cell disease causes chronic haemolytic anaemia, dactylitis, and painful acute crises. It also increases the risk of stroke, organ damage, bacterial infections, and complications of blood transfusion.
We don’t know whether avoidance of cold environments, physical exercise, or rehydration can prevent crises or complications in people with sickle cell disease.
Blood transfusion (prophylactic) reduces stroke in children at increased risk of stroke, but increases the risks of iron overload, allo-immunisation, hypertensive or circulatory overload, febrile non-haemolytic reactions, allergic reactions, and haemolytic events.
Penicillin prophylaxis in children <5 years of age reduces invasive pneumococcal infections regardless of pneumococcal vaccination status. We don’t know whether penicillin prophylaxis is beneficial in older children.
Malaria chemoprophylaxis is considered useful in preventing malaria-induced crises, but we found few studies evaluating its benefit.
Polyvalent polysaccharide pneumococcal vaccine does not reduce the incidence of pneumococcal infections in people with sickle cell disease. Pneumococcal conjugate vaccines have been reported to have protective efficacy in children <2 years of age, but this protective effect has not been shown in infants with sickle cell disease.
Hydroxyurea may reduce some complications of sickle cell disease, such as painful crises compared with placebo, but long-term effects and safety are unknown.
Morphine is widely used to treat severe pain, but we found no RCT evidence comparing it with placebo in people with sickle cell crises. Controlled-release oral morphine and patient-controlled analgesia may be as effective as repeated intravenous doses of morphine. Oral morphine increases the risk of acute chest syndrome compared with intravenous administration.
High-dose corticosteroids may reduce the need for analgesia when added to intravenous morphine in people with a sickle cell crisis, but may increase the risks of adverse effects (such as infections, hypertension, and metabolic problems).
It is still unclear whether acupuncture, blood transfusion, hydration, oxygen, aspirin, codeine, diflunisal, ibuprofen, ketorolac, or paracetamol reduce pain during sickle cell crisis.
Clinical context
About this condition
Definition
Sickle cell disease refers to a group of disorders caused by inheritance of a pair of abnormal haemoglobin genes, including the sickle cell gene. It is characterised by chronic haemolytic anaemia, dactylitis, and acute episodic clinical events called "crises".[1] Vaso-occlusive (painful) crises are the most common, and because of a resistance to nitric oxide, cause tissue ischaemia. Other crises are acute chest syndrome, sequestration crisis, and aplastic crisis. A common variant of sickle cell disease, also characterised by haemolytic anaemia, occurs in people with one sickle and one thalassaemia gene. Sickle cell trait occurs in people with one sickle gene and one normal gene. People with sickle cell trait have no clinical manifestation of illness. This review covers people with sickle cell disease with or without thalassaemia.
Incidence/ Prevalence
Sickle cell disease is most common in people living in or originating from sub-Saharan Africa.[2] The disorder also affects people of Mediterranean, Caribbean, Middle-Eastern, and Asian origin. The sickle cell gene is most common in areas where malaria is endemic — sickle cell trait affects about 10% to 30% of Africa’s tropical populations.[3] Sickle cell disease affects an estimated 1% to 2% (120,000) of infants in Africa annually. About 178 babies (0.28/1000 conceptions) are affected by sickle cell disease in England annually.[4] About 60,000 people in the US[4] and 10,000 in the UK suffer from the disease.[5]
Aetiology/ Risk factors
Sickle cell disease is inherited as an autosomal recessive disorder. For a baby to be affected both parents must have the sickle cell gene. In parents with sickle cell trait the risk of having an affected baby is 1 in 4 for each pregnancy. Painful (vaso-occlusive) crisis is the most common feature of the disease, and these episodes start in infancy and early childhood.[6] Factors that precipitate or modulate the occurrence of sickle cell crisis are not fully understood, but infections, hypoxia, dehydration, acidosis, stress (such as major surgery or childbirth), and cold are believed to play some role. In tropical Africa, malaria is the most common cause of anaemic and vaso-occlusive crisis.[3] High levels of fetal haemoglobin are known to ameliorate the severity and incidence of sickle cell crisis and other complications of the disease.
Prognosis
People affected by sickle cell disease are predisposed to bacterial infections, especially those caused by encapsulated organisms such as Pneumococcus, Haemophilus influenzae, Meningococcus, and Salmonella species. Severe bacterial infections (such as pneumonia, meningitis, and septicaemia) are common causes of morbidity and mortality, especially among young children.[7] About 10% of children with sickle cell anaemia may develop a stroke, and more than 50% of these may suffer recurrent strokes.[8] Abnormal features of cerebral blood vessels, shown by transcranial Doppler scan, predict a high risk of stroke in children with sickle cell disease.[9] Frequent episodes of crisis, infections, and organ damage reduce the quality of life of people with sickle cell disease. A high rate of vaso-occlusive (painful) crisis is an index of clinical severity that correlates with early death. Life expectancy remains low, especially in communities with poor access to health services. In some parts of Africa, about 50% of children with sickle cell disease die before their first birthday.[3] The average life expectancy with sickle cell disease in the US is about 42 years for men and about 48 years for women.[10] Frequent blood transfusions could increase the risk of immune reactions and infections, such as HIV and hepatitis B or C viruses, and Chagas' disease. The need for repeated blood transfusions in people with sickle cell disease predisposes them to the risk of iron overload.[11]
Aims of intervention
To reduce mortality, the incidence and severity of sickle cell crises, and other acute complications; to prevent organ damage; to improve quality of life and increase life expectancy; to achieve effective pain relief during crises with minimal adverse effects.
Outcomes
Mortality; incidence of crisis; symptom severity pain; disease-related complications dactylitis, incidence of other acute complications (e.g., malaria, stroke, infectious complications [invasive pneumococcal infection or acute osteomyelitis]); quality of life; adverse effects of treatment (e.g., gastrointestinal bleeding owing to NSAIDs, addiction to narcotic analgesics, immune reactions, and infections caused by blood transfusions [e.g., HIV, viral hepatitis, and Chagas' disease]). Secondary outcomes include duration of crisis, days out of school or work, and requirement for blood transfusion for severe anaemia. Fetal and total haemoglobin levels are considered proxy outcomes and are not addressed in this review.
Methods
Clinical Evidence search and appraisal March 2010. The following databases were used to identify studies for this systematic review: Medline 1966 to March 2010, Embase 1980 to March 2010, and The Cochrane Database of Systematic Reviews 2010, Issue 2 (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this chapter were: published systematic reviews and RCTs in any language and containing more than 20 individuals, of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies, apart from the question on non-pharmaceutical interventions to prevent crisis and acute complications, where a minimum length of follow-up of 1 year was required. We included studies described as "open", "open label", or not blinded for this population. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. A search for published cohort studies was also undertaken for the avoidance of cold environment and limiting physical exercise interventions for the question on non-pharmaceutical interventions to prevent crisis and acute complications. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). The categorisation of the quality of the evidence (into high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table 1.
GRADE evaluation of interventions for sickle cell disease
| Important outcomes | Incidence of crises, disease-related complications, symptom severity (pain), quality of life, mortality, adverse effects | ||||||||
| Number of studies (participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of non-pharmaceutical interventions to prevent sickle cell crisis and other acute complications in people with sickle cell disease? | |||||||||
| 2 (209)[15] | Disease-related complications | Blood transfusion (prophylactic) v standard care or no treatment | 4 | 0 | 0 | 0 | +1 | High | Effect-size point added for OR <0.5 |
| 2 (209) [15] | Mortality | Blood transfusion (prophylactic) v standard care or no treatment | 4 | 0 | 0 | 0 | 0 | High | |
| What are the effects of pharmaceutical interventions to prevent sickle cell crisis and other acute complications in people with sickle cell disease? | |||||||||
| 2 (457)[18] | Disease-related complications | Penicillin v placebo (children <5 years of age) | 4 | 0 | 0 | –1 | +1 | High | Directness point deducted for differences in vaccination status of children. Effect size point added for RR <0.5 |
| 2 (215)[18] | Mortality | Penicillin v placebo (children <5 years of age) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for low event rates |
| 1 (400)[18] | Disease-related complications | Penicillin v placebo (children >5 years of age) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 2 (215)[18] | Mortality | Penicillin v placebo (children <5 years of age) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 2 (324)[21] [22] | Incidence of crises | Hydroxyurea v placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for results after crossover in one RCT. |
| 1 (299)[21] | Disease-related complications | Hydroxyurea v placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (299)[21] | Mortality | Hydroxyurea v placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (299)[21] | Quality of life | Hydroxyurea v placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (97)[27] | Incidence of crises | Malaria chemoprophylaxis v placebo | 4 | –1 | 0 | –1 | +1 | Moderate | Quality point deducted for sparse data. Directness point deducted for uncertainty about generalisability of regimens used for prophylaxis. Effect size point added for RR < 0.5 |
| 1 (97)[27] | Disease-related complications | Malaria chemoprophylaxis v placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (157)[27] | Disease-related complications | Malaria chemoprophylaxis plus antibiotic v placebo | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and randomisation/allocation flaws. Directness point deducted for uncertainty about generalisability of regimens used for prophylaxis |
| 1 (242)[28] | Disease-related complications | Polysaccharide pneumococcal vaccine v control | 4 | 0 | 0 | 0 | 0 | High | |
| What are the effects of non-pharmaceutical interventions to treat pain in people with sickle cell crisis? | |||||||||
| 1 (50)[31] | Symptom severity (pain) | Oxygen v air | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| What are the effects of pharmaceutical interventions to treat pain in people with sickle cell crisis? | |||||||||
| 1 (20) [37] | Symptom severity (pain) | Patient-controlled pethidine v intermittently administered pethidine | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and uncertainty about method of evaluating pain |
| 1 (45)[38] | Symptom severity (pain) | Patient-controlled morphine v intermittently administered morphine | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (37)[41] | Symptom severity (pain) | Diflunisal v placebo | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, and randomisation/allocation flaws |
| 1 (20)[41] [43] | Symptom severity (pain) | Ketorolac v pethidine | 4 | –2 | –1 | 0 | 0 | Very low | Quality points deducted for sparse data and randomisation/allocation flaws. Consistency point deducted for different results at different endpoints |
| 2 (39)[41] [44] [45] | Symptom severity (pain) | Ketorolac plus pethidine v placebo plus pethidine | 4 | –2 | –1 | 0 | 0 | Very low | Quality points deducted for sparse data and randomisation/allocation flaws. Consistency point deducted for assessing different outcomes and for lack of agreement between studies |
| 1 (29)[41] [46] | Symptom severity (pain) | Ketorolac plus morphine sulphate v placebo plus morphine sulphate | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and randomisation/allocation flaws |
| 2 (114)[47] [48] | Symptom severity (pain) | Dexamethasone plus morphine v placebo | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and randomisation/allocation flaws. Directness point deducted for not assessing pain reduction |
| 1 (34)[41] [49] | Symptom severity (pain) | Methylprednisolone plus morphine v placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and randomisation/allocation flaws |
| 1 (86)[50] | Symptom severity (pain) | Oral morphine v intravenous morphine | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
Type of evidence: 4 = RCT; 2 = observational. Consistency: similarity of results across studies. Directness: generalisability of population or outcomes.Effect size: based on relative risk or odds ratio.
Glossary
- Acute chest syndrome
A life-threatening complication of sickle cell disease characterised by fever, cough, chest pain, difficulty in breathing, worsening anaemia, and new pulmonary infiltrates on radiography. It is difficult to differentiate acute chest syndrome clinically from pneumonia and pulmonary infarctions.
- Aplastic crisis
Sudden cessation of the bone marrow from making new blood cells.
- CHEOPS scale (Children's Hospital of Eastern Ontario Pain scale)
A behavioural scale used to evaluate postoperative pain. It was initially validated in children aged 1–5 years, and subsequently validated in children from other populations and ages.[53] The CHEOPS scale is used to monitor the effectiveness of interventions for reducing pain and discomfort. Scores obtained from adding points from six different parameters range from 4 to 13.
- Dactylitis
Inflammation of the bones of the hands and feet, resulting in swelling, redness, and pain in the affected parts. It is common in young infants with sickle cell disease, and is precipitated by the sickle process that characterises sickle cell disease. Because it tends to occur bilaterally in the hands and feet with swelling of the dorsum, it is commonly described as sickle cell 'hand and foot syndrome'.
- Fetal haemoglobin (Hb F)
This is the predominant type of normal haemoglobin (i.e., the oxygen-carrying molecule in the human red blood cell) in the unborn child. Following birth, another type of normal haemoglobin (Hb A) replaces Hb F and remains predominant throughout life. Hb F binds oxygen more strongly than Hb A and maintains higher tissue oxygen tension than Hb A.
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Pneumococcal conjugate vaccines
Polysaccharide pneumococcal vaccines linked with proteins such as those of the outer membrane of meningococcus, tetanus, or diphtheria toxoids. The conjugate pneumococcal vaccines have been shown to be immunogenic in children younger than 2 years, and are recommended for routine use in infants beginning from the age of 2 months.[29] [52]
- Polyvalent polysaccharide pneumococcal vaccine (PPV)
This type of vaccine contains the purified capsular polysaccharides of several Streptococcus pneumoniae serotypes. Many of the polysaccharides contained in the vaccines do not induce protective immunity in children younger than 2 years. This type of pneumococcal vaccine is recommended for children aged 2 years and older affected by conditions that predispose them to an increased risk of invasive pneumococcal infection.[52]
- Sequestration crisis
Sudden pooling of blood in the spleen and liver, with the result that the person becomes anaemic and hypotensive, with the affected organ becoming remarkably enlarged and painful.
- Very low-quality evidence
Any estimate of effect is very uncertain.
NSAIDs
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Dr Martin M. Meremikwu, Department of Paediatrics, College of Medical Sciences, University of Calabar, Calabar, Nigeria.
Uduak Okomo, Medical Research Council Unit, The Gambia Unit, Fajara, The Gambia.
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