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Practice Practice Pointer

Acute painful crisis in adults with sickle cell disease

BMJ 2024; 386 doi: https://doi.org/10.1136/bmj-2023-075099 (Published 01 July 2024) Cite this as: BMJ 2024;386:e075099
  1. Kenneth S Charles, senior lecturer and consultant haematologist1,
  2. Melissa Friday, specialty trainee2,
  3. Edlin Rochford, patient author3
  1. 1Faculty of Medical Sciences, The University of the West Indies, Trinidad and Tobago
  2. 2Haematology Department, Royal Hallamshire Hospital, Sheffield, UK
  3. 3Patient author
  1. Correspondence to: K S Charles kenneth.charles{at}sta.uwi.edu

What you need to know

  • Pain in people of Asian, African, Caribbean, Latin American, or Middle Eastern ancestry could be related to acute painful crisis of sickle cell disease

  • The back and trunk are commonly affected and pain may then radiate to the limbs

  • Crises are often severe, and require strong analgesia for symptom relief

  • Consider the complication of acute chest syndrome in patients with fever and respiratory signs and symptoms

A 54 year old woman with sickle cell disease presents to the emergency department with severe back and chest pain after swimming in the sea. On examination, she is tachycardic and afebrile, and has no other clinical signs apart from pallor of the mucous membranes. She has had similar episodes of pain previously which have responded to oral analgesia and hydration at home but these interventions have been ineffective on this occasion. What is the next stage of acute management and what advice would you give her to prevent future episodes?

Sickle cell disease (SCD) is a multisystem disease that shortens life, and acute painful crisis is the hallmark of the condition. The clinical course is usually one of well compensated chronic anaemia interspersed with episodes of pain.1 With advances such as hydroxyurea therapy, chronic transfusion programmes, and stem cell transplantation, the life expectancy of patients in high income countries has risen from the mid 40s in the 1980s to the late 50s today.2 Clinicians working in primary and secondary care are therefore more likely to encounter patients with sickle cell disease and manage acute painful crises.

This article aims to help readers identify and assess patients with suspected acute painful crisis, and how to recognise and manage the complication of acute chest syndrome, optimise management in the inpatient and outpatient settings, and deliver care compassionately.

Management principles are largely similar for children and adults, however as per local protocols, consider the role of carers, impact on education, and long term complications of interventions when managing acute painful crisis in children with SCD.

What is sickle cell disease and how common is it?

SCD is a disorder of the β globin chain of haemoglobin. Red cells containing normal adult haemoglobin (HbA) are round, pliable, and able to change shape to traverse small blood vessels. They bind oxygen in the lungs and deliver it to vital tissues and organs. Patients with SCD produce haemoglobin S (HbS) in which valine replaces glutamic acid as the amino acid at position 6 of the β chain of HbA. The pathophysiology of SCD is described in box 1.

Box 1

Pathophysiology of sickle cell disease

  • Because β becomes the dominant non-α chain in the haemoglobin molecule after three months of life, clinical manifestations of SCD do not occur before this age. Before then, haemoglobin F prevents precipitation of HbS.

  • Patients with SCD have high HbS concentration, which shortens red cell survival because of their premature destruction by splenic macrophages (extravascular haemolysis). Unlike normal red cells that survive for 120 days, sickle red cells last only 10-20 days in circulation.3 This causes a reduction in haemoglobin concentration (chronic anaemia).

  • The cardiorespiratory system adapts to a low steady state haemoglobin concentration (typically 7-9 g/dL) by increasing the heart rate, stroke volume, and respiratory rate.

  • Oxygen desaturation of HbS causes it to precipitate into large aggregates called tactoids that deform the red cell from discoid and pliable to sickle shaped and rigid.3

  • In the early stages of their existence, red cells containing HbS sickle and unsickle repeatedly to cause intermittent slowing of blood flow without permanent tissue damage. But after repeated episodes of sickling and unsickling, they become irreversibly sickled cells.

  • Irreversibly sickled red cells occlude blood vessels, causing ischaemia, infarction, and widespread organ damage. Vascular occlusion by sickled cells causes interruption of blood flow into or out of tissues and is often accompanied by pain and worsening anaemia.

  • Cytokines released by tissue ischaemia activate nerve endings in deep tissues such as the bone marrow, causing pain.4

  • Ischaemia can cause avascular necrosis (death of bone tissue owing to absent blood supply) and other orthopaedic complications such as osteonecrosis, osteomyelitis, septic arthritis, and bone collapse.5

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Fig 1
Fig 1

Irreversibly sickled cell on blood film

SCD is inherited in an autosomal recessive manner. Globally, more than 300 000 children are born with SCD annually.6 The condition is commonly found in persons with ancestral links to Sub-Saharan Africa, India, the Caribbean, Latin America, and Mediterranean countries such as Turkey, Greece, and Italy. Compared with 80 million in Africa, 1.5 million in India, and 100 000 in the US, more than 14 000 people now live with SCD in the UK.7 In the Caribbean, the birth prevalence for SCD is 0.65% in Jamaica and 0.57% in Tobago.8 However, a systematic literature review of journal articles and abstracts published between 2010 and 2022 revealed a paucity of data from countries with assumed high prevalence. The global prevalence of SCD is therefore likely underestimated. However, Africa, the Middle East, India, and the Caribbean are considered SCD “hotspots.”9

What is acute painful crisis?

An acute painful crisis, also commonly referred to as vaso-occlusive crisis, is an episode of pain arising in deeper structures such as bones, joints, tendons, and muscles that is induced by sickling. The most common sites of pain onset are the back or trunk, and pain may then radiate to the limbs. In a longitudinal cohort survey of 308 adult patients with SCD in the US, the lower back and lower limbs (knee, shin, hip) were the most frequently reported pain sites.10

The frequency and severity of acute painful crises vary across patients substantially. Some patients experience them daily, weekly, or monthly from infancy, whereas others live to adulthood without experiencing severe episodes. However, acute painful crisis remains the most common reason for patients with SCD being admitted to hospital, with estimates ranging from 50% from a recent analysis of hospital episode statistics in England11 to an older estimate of 95% from a single centre US retrospective cohort study.12

Acute painful crises are typically provoked by triggers such as changes in temperature (winter/cold temperatures), fever, infection, dehydration, increased physical activity, and emotional stress, but there may be no identifiable precipitant.13 In our experience in Trinidad and Tobago, most admissions occur at night when the ambient temperature is lowest.14 Additionally, a US multisite cross sectional study of 201 adults with SCD and 330 caregivers of children with SCD showed that increased rates of admission to hospital for acute painful crisis were associated with social, environmental, and psychological factors such as depression, financial insecurity, and spirituality.15

How do patients present?

Patients with acute painful crisis may present from home to their general practitioner, hospital based clinic, or, most commonly, the emergency department. Patients with SCD admitted to hospital for another reason may also develop acute painful crisis triggered by the physical and mental effects of being in hospital.16

Pain ranges from mild to severe in intensity. It is often reported to be felt in deep tissues and is often central (chest, back, or trunk) with radiation to the limbs. Duration is usually a few hours to days, but in some cases, it may persist for weeks. Patients may recognise acute painful crisis because of a characteristic pattern that is self-identifiable as “crisis pain,” and we recommend asking whether they have experienced this type of pain before. In box 2, a patient with SCD describes her experience with acute painful crises.

Box 2

Patient perspective

It’s aptly named: crisis. It’s physically painful, frightening, and mentally debilitating. It’s sudden, crippling, and merciless. It’s confusing to others.

What does a crisis feel like? It depends on where the pain is and it can begin anywhere. I’ve had crises in my knee, hip, waist, stomach, elbow, and shoulder, one spot at a time, or in all of those at the same time.

How does a crisis begin? I have no warning. I’d go to sleep and wake up with a full blown crisis going on in my body. I’d go into an air conditioned room and come out in crippling pain. I’d go to the beach and go for a swim and I’d be lifted out of the water in pain.

Once the pain starts, it can last for days and sometimes weeks. Everything inside me and around me is in crisis. I have had friends question if I was faking my sudden change. There’s no stopping until I’m given strong medication.

Sometimes, I fall asleep pain-free and wake up screaming and unable to walk because my leg joints won’t move. Other times my stomach feels as if it is turning hard and my chest feels as if I am suffocating. Just thinking about it has me wondering, how could I have survived it so many times?

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Differentiating pain caused by acute painful crisis (irreversible sickling of cells leading to ischaemia) from that of avascular necrosis (irreversible sickled cells leading to infarction) is difficult. In our experience, pain is usually gradual and longer lasting (for more than six months continuously) in chronic avascular necrosis.

How to assess a patient with suspected crisis

Assessing a patient in suspected acute painful crisis requires balancing empathy with speed and thoroughness. Patients are often in severe discomfort and under the sedative influence of analgesia. In table 1, we outline questions to ask patients when taking a focused history, which should not delay offering pain relief. Investigations and treatment-specific information may be available on an individualised plan on their digital or paper health record. Alternatively, it may be helpful to contact their haematology team.

Table 1

Suggested questions to ask during a focused history

View this table:

A validated or locally derived pain assessment tool can help with initial pain assessment. The visual analogue tool, for example, is useful for quickly assessing the intensity, distribution, and evolution of pain to guide titration of analgesia and discharge planning. However, use of tools is limited by the multifactorial nature of pain, which means it can be experienced in the absence of physical signs such as tachycardia, making assessment largely subjective.17

Full systemic examination, and, in particular, respiratory and abdominal examinations, might elicit positive findings that suggest an alternative explanation for pain. Assess for signs and symptoms of a precipitating cause, including focal or systemic infection. Patients may be systemically unwell and are at risk of sudden decompensation. We therefore recommend regular observations of temperature, blood pressure, pulse rate, respiratory rate, and oxygen saturation, and early reassessment if there is sudden or marked deterioration.

Common differential diagnoses that may coexist, precipitate crisis, or present with features similar to crisis include arthritis, osteomyelitis, myocardial infarction, pulmonary embolism, cholecystitis, pyelonephritis, appendicitis, ruptured viscus, and peptic ulcer disease. Consider the complication of acute chest syndrome in all patients with fever, respiratory symptoms, or positive respiratory signs on examination.13

First line blood investigations include complete blood count, urea, creatinine, and electrolytes at a minimum (box 3). Depending on local protocol, this may extend to tests of liver function, C reactive protein, reticulocytes, sickle haemoglobin percentage, and blood group and save.

Box 3

Common abnormalities on blood tests in patients with sickle cell disease

  • Leucocytosis is a common finding in patients with SCD and is a predictor of disease severity and the frequency of acute painful crisis.18 It occurs as a result of haemolysis, inflammation, or tissue infarction, and can be exacerbated by infection.

  • Reduced haemoglobin is expected and is interpreted against the patient’s steady state haemoglobin to help determine whether blood transfusion is required.

  • Reactive thrombocytosis occurs in response to haemolysis, inflammation, infarction, and asplenism.

  • Renal dysfunction is common in adults with SCD.19 Non-steroidal analgesic drugs should be avoided if serum creatinine is elevated as they could cause acute papillary necrosis.

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Radiological investigations during acute painful crisis should be guided by clinical and laboratory findings. For example, a plain chest radiograph may be required to assess for pulmonary infiltrates in patients with fever, cough, chest pain, or difficulty breathing. Abdominal radiograph or ultrasound may be indicated if the patient complains of atypical abdominal pain, which may be secondary to renal or biliary tree calculi. Consider further radiological investigations, such as computed tomography or magnetic resonance imaging (guided by the multidisciplinary team), to exclude alternative diagnoses or detect complications of SCD, such as acute pulmonary embolism, abscess, osteomyelitis, or avascular necrosis.

Misdiagnosis of acute painful crisis could delay treatment, cause unnecessary pain, and prevent detection of life threatening complications. It may also undermine patient confidence and reduce the likelihood of care seeking for future episodes.20 Conversely, unnecessary and excessive treatment for acute painful crisis could lead to opiate dependence.21

What are the principles of management?

When managing acute painful crisis, oxygenation, analgesia, hydration, transfusion, and psychosocial support should be tailored to the patient’s needs (fig 2). Refer to local, national, or international SCD guidelines applicable to the area of practice. In box 4, we highlight key take-home messages for clinicians.

Fig 2
Fig 2

Principles of management for acute painful crisis. Refer to local protocol and guidelines, where available.
*Prescribe oxygen therapy if oxygen saturation is <95%13
Consider increased risk of infection and thrombosis39
No randomised controlled trials to compare fluid type and recommended route of administration22

Box 4

Tips for healthcare professionals in caring for patients who present with acute painful crisis

  • Be empathetic in your use of language and approach to identification and management—many patients have had previous interactions with multiple healthcare professionals.

  • Pain is largely subjective and cannot be assessed comprehensively using tools alone.

  • Ask about frequency of acute painful crisis and effect on activities and quality of life.

  • Ask about social circumstances—school, work, other interests—that may have triggered the episode and discuss with the patient potential strategies to avoid recurrence.

  • Do not assume drug seeking behaviour. Instead, inquire about opiate requirements and respond sensitively.

  • Assess for respiratory signs and symptoms as indicators of possible acute chest syndrome.

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Pain

Broadly, international guidelines from both high and low to middle income countries recommend self-management of mild attacks at home using acetaminophen (paracetamol), non-steroidal anti-inflammatory drugs including diclofenac and ibuprofen, or partial opioid agonists such as , tramadol, and dihyrocodeine.1323 Attendance at outpatient or hospital based settings for stronger analgesia requirements, such as regular or continuous use of opioids, is recommended if pain control is inadequate. Increasingly, patients with acute painful crisis are cared for in day case or observation units, reducing the need for hospital admission, and this is shown to be safe and cost effective.2425

Typical analgesia regimens from high income countries such as the UK and US recommend liberal opiate use and modes of delivery, including patient controlled analgesia, which require substantial resources for delivery and monitoring.1323 In low and middle income countries, such as Nigeria, India, Saudi Arabia, and in the Caribbean, guidelines follow similar principles.1426 However, delivery is often impeded by infrastructure, resources, and preferences of the health professional or patient.272829

Use of pethidine (meperidine) for analgesia remains controversial as its active metabolite norpethidine is a neurostimulant that causes seizures at high doses.30 Although its use is discouraged in high income countries, it remains widely used in several low and middle income countries.142729 Alternative opioids, such as submucosal fentanyl or oral oxycodone, are useful adjuncts or alternatives to conventional opiate therapy.31 Adjunctive use of ketamine infusions can be useful for reducing opioid requirements and overcoming opioid tolerance. This injectable dissociative anaesthetic is a non-competitive antagonist at the N-methyl-d-aspartate receptor that provides pain relief and short term memory loss.32

Some of the most common complaints from patients presenting to hospital with acute painful crisis in high income countries include unacceptable delays in receiving analgesia, inadequate dosing, inappropriate choice of analgesia, and stigmatisation of behaviour as drug seeking.33 In seeking to tackle these concerns, patients and support groups have been included in devising some national guidelines for acute painful crisis.1323 While opiate dependence and addiction are considered rare in some settings, health professionals’ concerns about them may provoke suspicion and unwillingness to prescribe and administer them.20

Fluids

Despite the proven benefit of additional hydration to treat acute painful crisis, no randomised controlled trials inform duration of hydration, route of administration, and choice of fluid. A US retrospective cohort study of 157 episodes of acute painful crisis from 49 patients admitted to hospital showed that excessive fluid administration in the first 24 hours was associated with increased development of adverse events, including new oxygen requirement, aspiration, and acute kidney injury.22 Hydration with isotonic fluid may worsen pain and precipitate acute chest syndrome by increasing intracellular HbS concentration.34 In our local practice, we prescribe intravenous 5% dextrose to induce hyponatraemia and decrease intracellular HbS concentration.14

Blood transfusion is recommended for patients whose haemoglobin concentration falls by 2 g/dL during an acute painful crisis, and exchange transfusion is recommended for those with acute chest syndrome and severe hypoxia at steady state haemoglobin concentration.35

Antibiotics

Administer antibiotics in patients in whom you suspect infection, after appropriate screening has taken place, including blood, urine, or sputum culture. Patients with SCD are susceptible to infections because of asplenia, T and B cell abnormalities, defective complement activation, leucocyte dysfunction, and infarcted tissue.36 The spleen usually removes encapsulated bacteria such as pneumococcus, therefore most treatment regimens include a cephalosporin. Furthermore, in patients with suspected acute chest crisis, consider treatment with a macrolide or quinolone because of the high frequency of infection with atypical organisms such as Mycobacterium pneumonia.37

Anticoagulation

Although SCD is a hypercoagulable state, no established recommendations are available on the use of anticoagulant prophylaxis during acute painful crisis. Both enoxaparin and direct oral anticoagulants have been used.38

Psychological support

Support patients compassionately throughout their admission to hospital, paying special attention to social or psychological factors that may have precipitated crisis, and the effect of crises on domestic, educational, and professional functioning. This may enhance your rapport with the patient and guide specific interventions.

Discuss discharge options when pain is controlled on acceptable doses of oral analgesia or improving without analgesia. Arrange for home or hospital based follow-up. Provide patients with information on how to continue to manage the current episode, and specifically13:

  • How to obtain specialist haematology support

  • How to obtain additional medication if not being prescribed at discharge

  • How to manage any potential side effects of the treatment they have received in hospital

  • How to obtain any additional psychological and social support they may need.

What is the relation between acute painful crisis and acute chest syndrome?

Acute chest syndrome is a combination of pulmonary infarction, infection, and fat embolism. It occurs as a result of sickling and ischaemia in deep tissues of the chest wall. Patients typically present with fever, acute respiratory signs and symptoms, such as cough, wheezing, dyspnoea, crepitations or chest pain, and consolidation on chest radiograph (fig 3). Acute painful crisis may precipitate or accompany acute chest syndrome,35 which is the most common cause of death in adult patients with SCD in the UK.39 In a US prospective cohort study of 1772 episodes of acute chest syndrome in 939 patients with SCD, 50% had a pain event in the two weeks preceding the event. Mortality rate was estimated to be 1% in children and 4% in adults.40

Fig 3
Fig 3

Chest radiograph of a patient with acute chest syndrome, showing bilateral consolidation in the bases

How to prevent episodes

Guidelines recommend that patients with SCD prevent acute painful crisis by avoiding known risk factors, such as cold, dehydration, and infection.41 Patients with SCD and recurrent acute painful crisis may be eligible for treatment with hydroxyurea, a ribonucleotide reductase inhibitor used as disease modifying therapy for SCD. It reduces sickling, polymerisation of HbS, and endothelial binding of red cells, and increases HbF concentration, thereby reducing incidence of acute painful crisis and acute chest crisis.42

Another medical therapy to reduce acute painful crisis is chronic transfusion to maintain HbS concentration below 30% if hydroxurea is unsuccessful.35 This option is unachievable in most low and middle income countries because of chronic blood shortage, owing to inadequate voluntary non-remunerated blood donation.4344 Low levels of blood donation in immigrant ethnic minority communities negatively affects sickle cell care in developed countries because of a shortage of suitable blood.45

Biological therapies such as crizanlizumab, L-glutamine, and the allosteric modifier voxelotor, or intensive therapy with stem cell transplantation or gene therapy may be offered to patients who live in high income countries, but cost and availability limit access in the low and middle income countries where most patients with SCD live.46

How this article was created

This practice pointer was written by a haematologist and specialty trainee with experience of managing sickle cell disease in Trinidad and Tobago and the UK. The article was coauthored by a patient with experience of the care described in the article. Personal experience was supplemented by journal articles, guidelines and documents obtained through internet searches using search terms and combinations of terms such as “sickle”, “pain”, “crisis” and “management”.

How patients were involved in the creation of this article

The patient who coauthored this article is a communications teacher with a 53 year history of sickle cell pain, a life threatening episode of acute chest syndrome, and the life transforming experience of hydroxyurea therapy. Having family members with sickle cell disease, her lived experience helped shape the paper with respect to the various interactions between patient and health service. She also reviewed the content for relevance to patients and sensitivity around communication.

Education into practice

  • In your setting, how often do patients with SCD present with acute painful crisis?

  • How might you care for a patient with SCD who presents with pain acutely?

Acknowledgments

We thank Dexter Superville, who provided figure 1, and Sanjiv Bissram, who provided figure 3.

Footnotes

  • Competing interests: The authors have no competing interests.

  • Provenance and peer review: commissioned; externally peer reviewed.

References