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Evaluation of acute pain in sickle cell disease

Evaluation of acute pain in sickle cell disease
Literature review current through: Jan 2024.
This topic last updated: Jun 30, 2023.

INTRODUCTION — Acute painful episodes are likely to be the most common reason for individuals with sickle cell disease (SCD) to seek medical attention.

When a patient with SCD presents with pain, the evaluation (to characterize the pain and uncover any associated conditions) and the treatment for the pain (analgesia and other interventions) both need to occur rapidly. A major aspect of the evaluation involves distinguishing between pain due to vaso-occlusion and pain that signifies more serious complications of disease, which often require separate evaluations and treatments in addition to analgesia.

This topic review discusses the immediate evaluation of the individual with SCD who presents with acute pain, and the testing needed to identify other SCD complications or comorbidities that require treatment.

Separate topic reviews provide detailed discussions of our approaches to providing analgesia for acute vaso-occlusive pain, chronic SCD pain management, and the role of blood transfusion in treating acute SCD complications such as stroke, acute chest syndrome, and multiorgan failure.

Analgesia for acute pain – (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Overview of acute pain management'.)

Chronic pain management – (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease".)

Transfusion for complications – (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".)

Prevention of complications – (See "Hydroxyurea use in sickle cell disease" and "Investigational therapies for sickle cell disease".)

CLINICAL ASSESSMENT OF PAIN — Patients with SCD who present with acute pain should have a rapid assessment for the possibility of other serious complications concurrently with the treatment of pain.

Features associated with acute vaso-occlusive pain — Acute vaso-occlusive pain in SCD is intense; it can begin as early as six months of age and typically lasts throughout life [1,2]. The intensity can range from mild to debilitating, and the duration can last from hours to days. Mothers with SCD have compared their intensity of acute pain to be more severe than pain associated with labor.

Common locations for vaso-occlusive pain include the back, chest, abdomen, and long bones. Infants and toddlers may present with dactylitis (pain and swelling from infarctions involving the hands and feet). Premenstrual hormonal changes may be associated with an increase in vaso-occlusive pain episodes. Neuropathic pain, which may include components of central sensitization, peripheral nerve injury, and/or hyperalgesia, increases with age and is likely underdiagnosed in individuals with SCD.

The gold standard for assessment of the pain is the patient's (or family's) report of the pain severity and similarity to or difference from previous vaso-occlusive pain episodes. There are no specific laboratory findings associated with vaso-occlusive pain.

Analgesia should not be delayed while awaiting other information such as laboratory tests, and results of laboratory testing should not be used to justify withholding of pain medication or use of a lower dose. Studies have suggested that misperceptions of health care providers can interfere significantly with adequate assessment of pain intensity, and in turn may lead to insufficient treatment. These considerations and supporting evidence are presented in more detail separately. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Clinical assessment of pain'.)

Additional information regarding pain assessment in children is also presented separately. (See "Pain in children: Approach to pain assessment and overview of management principles".)

Features that suggest an additional complication

Complications of SCD other than vaso-occlusive pain — In our experience, general features that suggest a greater likelihood of an additional complication include the following:

Patient (or family) states that the pain is atypical for their vaso-occlusive pain, in severity or location.

Abnormal vital signs.

Major changes from the baseline complete blood count (CBC) or reticulocyte count.

Leukopenia or leukocytosis may indicate infection, including acute chest syndrome.

Worsening anemia may indicate bone marrow suppression (eg, from infection), hepatic or splenic sequestration of blood, or increased hemolysis secondary to a delayed hemolytic transfusion reaction.

Increased hemoglobin concentration may indicate severe dehydration.

Decreased reticulocyte count from baseline, which usually would be elevated, may suggest bone marrow suppression. Markedly elevated reticulocyte count may suggest increased hemolysis or hepatic or splenic sequestration.

Pain associated with abdominal distention, which may indicate hepatic or splenic sequestration or acute cholecystitis.

Jaundice, which may indicate increased hemolysis or hepatobiliary disease.

Hematuria, which may indicate renal pathology.

New laboratory abnormalities such as increasing creatinine, liver function tests, lactate dehydrogenase (LDH) or coagulation abnormalities.

Any findings attributable to acute chest syndrome, which is known to be increased in individuals with acute vaso-occlusive pain. Examples include hypoxia, cough, fever, or an infiltrate on chest radiography.

Signs and symptoms attributable to specific organ systems are reviewed in the sections below. (See 'Potentially serious conditions associated with pain' below.)

Complications related to medications — Certain medications used in individuals with SCD can cause pain symptoms; this includes standard medications such as certain iron chelators as well as investigational therapies with unknown adverse drug effect (ADE) profiles or newer therapies such as L-glutamine.

As examples, the following types of medications can induce abdominal pain or discomfort:

Certain iron chelating agents such as deferasirox (brand names Exjade, Jadenu).

Certain agents that target the primary disease process such as L-glutamine or omega-3 fatty acid supplements.

A detailed medication history is important to identify these potential causes or contributing factors to pain. The patient (or family) should be asked specifically about prescribed medications, over-the-counter supplements, and clinical trial medications.

Importance of providing prompt analgesia — Analgesia remains the cornerstone of therapy for vaso-occlusive pain, and opioids are often needed for patients who present to their clinician after being unable to control the pain at home. Analgesia should not be delayed while performing additional evaluations, and triage wait time should not exceed 30 minutes. Our approach to acute pain control in SCD, including these issues, is presented in detail separately. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Overview of acute pain management'.)

POTENTIALLY SERIOUS CONDITIONS ASSOCIATED WITH PAIN

Overview of possible conditions and our approach to distinguishing among them — SCD can be associated with vaso-occlusion in almost any site, and this in turn can lead to potentially life-threatening infarction, infection, or other complications. General features that suggest an additional complication are listed above. (See 'Features that suggest an additional complication' above.)

Initially, we review the likelihood of each potential complication based on the patient's clinical presentation, as summarized in the table (table 1). In individuals with high-risk features in their history, abnormal vital signs, physical examination findings, or major changes from the baseline complete blood count (CBC), we obtain targeted laboratory tests and/or observe the patient in the hospital.

There are several high-risk features and areas of potential concern that we consider to be risk factors for complications, and we pay particular attention to the following findings in a patient with SCD having acute pain:

Comorbidities – Individuals with chronic organ dysfunction warrant early intervention and hospitalization; this includes chronic renal failure, chronic lung disease, pulmonary hypertension, cardiac dysfunction, recurrent acute chest syndrome, hypertension, and a history of neurologic disease (eg, stroke, intracranial bleeding).

Pregnancy or postoperative – Individuals who present with acute pain during pregnancy or postoperatively also warrant early intervention and close observation. These individuals are at increased risk for venous thromboembolism, acute chest syndrome, and infection. (See "Sickle cell disease: Obstetric considerations", section on 'Maternal risks'.)

Pregnancy-related mortality is also increased. In a retrospective study from the National Inpatient Sample that compared outcomes of deliveries among Black people with SCD, Black people without SCD, and non-Black controls, the mortality rate of patients with SCD was >10 times that of the Black patients without SCD and 26 times that of the non-Black patients [3,4].

A systematic review of pregnancy in individuals with SCD documented rates of pain (affecting 4 to 75 percent), acute chest syndrome (affecting 4 to 13 percent), and pulmonary thromboembolism (affecting 0.5 to 1 percent) [4]. Acute chest syndrome was the most common cause of death and was often preceded by acute pain, especially in the third trimester and postpartum. In an analysis from low- and middle-income settings, maternal death rates with SCD were 2393 and 4300 per 100,000 live births, whereas the general mortality rates in the United States is 24 per 100,000 live births, and in northern Europe, 8 per 100,000 live births.

Atypical pain – Individuals who report that their pain is atypical for their disease (eg, more severe than usual, in a different location) are more likely to have a complication or other undiagnosed comorbidity.

Vital signs – Vital signs are especially important. We repeat vital signs serially and thoroughly evaluate any abnormality such as a temperature of 38.5°C (101.3°F) or above; increased respiratory rate, oxygen desaturation by pulse oximetry, or shortness of breath; hypertension; orthostatic hypotension; or marked, persistent tachycardia.

Overall clinical picture – The overall clinical picture is important for noting features such as increased jaundice, chest pain, abdominal pain, confusion, or nonfocal neurologic symptoms.

Once the history, vital signs, and examination have been reviewed for possible complications, the need for additional laboratory testing is determined. We systematically review the possible causes of these findings and determine which require further evaluation (table 1). These are discussed in more detail in the following sections. Exclusion of possible complications does not necessarily require ordering of additional testing, but it does require conversation with the patient, a thorough review of the common potential complications, and attention to features that suggest increased risk.

Observation in the hospital may be especially helpful in identifying or systematically excluding a potentially life-threatening complication, especially if the history suggests high-risk features and initial testing (laboratory values, chest radiography) is unrevealing.

Acute systemic illness, diffuse pain, or both — Pain in multiple areas or nonspecific pain may be a sign of an acute systemic illness such as multiorgan failure, an entity known as rapidly progressive acute chest syndrome, or a hemolytic transfusion reaction (HTR). Opioid withdrawal may also cause systemic symptoms in certain individuals.

Multiorgan failure – Individuals with multiorgan failure may have a history of organ dysfunction such as chronic lung disease or chronic renal disease, although this may not always be present. Presenting findings may include especially severe, diffuse pain, along with fever, tachycardia, and tachypnea. Blood pressure can be variably high or low. Laboratory studies in multiorgan failure may show evidence of bone marrow suppression (eg, hemoglobin level below the patient's baseline; thrombocytopenia) and evidence of increased hemolysis and/or rhabdomyolysis such as increased lactate dehydrogenase (LDH), increased creatinine kinase (CK), increased creatinine, marked increase bilirubin, and increased liver enzymes. Of note, some individuals with SCD have a low creatinine at baseline, so a clinically significant increase may appear to be within the normal range. Multiorgan failure is life-threatening, and urgent hematology and/or transfusion medicine input is appropriate so that exchange transfusion can be initiated. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Multiorgan failure'.)

Rapidly progressive acute chest syndrome – A distinct phenotype of acute chest syndrome (ACS) has been identified, referred to as rapidly progressive ACS [5]. This syndrome is characterized by respiratory failure ≤24 hours after the onset of respiratory symptoms and is associated with multiorgan failure. It is distinct from ACS that has a more subacute and protracted course. In a cohort of 173 individuals (97 children and 76 adults) with SCD and at least one ACS episode, rapidly progressive ACS occurred in 16 (21 percent) of the adults and 2 (2 percent) of the children [5]. A decline in platelet count at presentation was the only predictor of developing rapidly progressive ACS (odds ratio 4.82 [95% CI 1.20-19.39]).

The typical findings of ACS are discussed in more detail below. (See 'Chest pain' below.)

Hemolytic transfusion reaction – HTRs can occur in the immediate post-transfusion period (ie, acute hemolytic transfusion reaction [AHTR]) or they may occur up to a month after transfusion due to antibody boosting from re-exposure to a red blood cell antigen (ie, delayed hemolytic transfusion reaction [DHTR]). Individuals with SCD are at increased risk of HTRs, especially DHTRs, due to the frequency of transfusions and the greater likelihood of alloimmunization. Delayed hemolytic transfusion reactions may present as an acute vaso-occlusive event. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Alloimmunization and hemolysis'.)

AHTRs are generally more clinically severe because they involve a greater degree of hemolysis and the hemolysis is mostly intravascular; intravascular hemolysis can be associated with renal failure and disseminated intravascular coagulation (DIC). However, DHTRs can also be clinically significant, especially in individuals with SCD who have ongoing compensated hemolysis at baseline. Presenting findings of AHTRs include acute back or chest pain, fever/chills, red urine, red plasma, oozing from catheter sites, and laboratory evidence of DIC (increased prothrombin time and activated partial thromboplastin time [PT and aPTT], decreased fibrinogen, increased D-dimer). DHTRs may present with painless jaundice. Both AHTRs and DHTRs are associated with laboratory evidence of hemolysis, including reduced hemoglobin compared with the patient's baseline, increased LDH, and increased bilirubin. The evaluation and management of HTRs are presented separately. (See "Approach to the patient with a suspected acute transfusion reaction".)

Opioid withdrawal – In a patient receiving opioids or who has recently had opioids discontinued, opioid withdrawal or neuropathic pain may present with diffuse pain. In opioid withdrawal, autonomic findings may be present such as tachycardia, tachypnea, restlessness, rhinorrhea, abdominal cramping, and/or diarrhea. Opioid withdrawal syndrome commonly presents as vaso-occlusive pain in patients who have been exposed to recent prolonged opioid use and have not undergone a tapering program [6]. Laboratory studies may be at the patient's baseline. Management and prevention of opioid withdrawal are presented separately. (See "Opioid withdrawal in the emergency setting" and "Opioid withdrawal in adolescents" and "Acute vaso-occlusive pain management in sickle cell disease", section on 'Tapering of opioids and discharge'.)

Jaundice — Jaundice associated with pain may be a sign of a hemolytic transfusion reaction (AHTR or DHTR) or hepatobiliary disease. (See 'Acute systemic illness, diffuse pain, or both' above and 'Abdominal pain' below.)

A markedly elevated bilirubin may be a precursor to multiorgan failure syndrome.

Headache, mental status changes, or both — Headache or neck pain in an individual with SCD may signify:

A vascular complication

Stroke

Aneurysm

Migraine

Central nervous system infection such as meningitis.

These complications may also be associated with mental status changes such as confusion and other nonfocal neurologic findings.

Stroke risk is increased in SCD (ischemic and hemorrhagic strokes), especially in those with a prior history of stroke, a history of silent cerebral infarcts, or increased transcranial Doppler velocities. Some individuals develop cerebral aneurysms with a moya-moya-like pattern. Focal or nonfocal neurologic findings may be present. There are no specific laboratory findings associated with stroke. Imaging is indicated to determine the presence, site, and features of a vascular lesion. Treatment with simple blood transfusion is appropriate for those with suspected stroke. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease".)

Individuals with SCD are at risk for infection with encapsulated organisms including meningitis, due to their functional asplenia, which occurs by early childhood. This may be especially true in those who do not have access to prophylactic penicillin but is also possible in those receiving prophylaxis. (See "Sickle cell disease in sub-Saharan Africa", section on 'Infections' and "Overview of the clinical manifestations of sickle cell disease", section on 'Infection'.)

Hypoxia is another potential contributing factor to mental status changes (eg, due to pulmonary fat embolism or acute chest syndrome).

Dental and/or craniofacial complications can cause pain in the face, neck, or head. (See "Overview of craniofacial pain".)

Chest pain — Chest pain is a common high-risk symptom; it may occur with a number of complications including:

Acute chest syndrome (ACS)

Pneumonia

Pulmonary embolism (PE)

Pulmonary fat embolism

Cardiac ischemia

Rib infarction

The history may be helpful in distinguishing among these (eg, history of deep vein thrombosis [DVT] suggests greater likelihood of PE; history of cardiac disease or pulmonary hypertension suggests increased risk of cardiac ischemia; history of coughing with abrupt pain in the chest wall suggests rib fracture). However, a high level of suspicion for the possibility of ACS should be maintained regardless of history. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)".)

A small proportion of children and approximately 20 percent of adults may develop a syndrome of rapidly progressive ACS associated with multiorgan failure. (See 'Acute systemic illness, diffuse pain, or both' above.)

Asthma or bronchospasm is a serious finding associated with increased risk of complications in an individual with acute pulmonary symptoms, and it warrants close observation and admission if bronchospasm does not resolve. Individuals with these conditions may have associated tachycardia, tachypnea, fever, and hypoxia. Many patients with chest pain and acute respiratory symptoms have had a bronchoactive pulmonary component despite the absence of a history of asthma or wheezing. Cough is more likely in children; adults with ACS may have severe chest pain without cough. Imaging (eg, chest radiography) is indicated if these diagnoses are considered; however, chest radiography may be negative initially in ACS.

PE may be difficult to diagnose initially and often occurs without antecedent diagnosis of DVT. Additional risk factors for PE include pregnancy, prolonged immobilization, obesity, history of splenectomy, and history of other thrombophilia. An elevated D-dimer is also consistent with PE, as discussed in more detail separately. (See "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis" and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)

Cardiac chest pain is increasingly recognized in individuals with SCD, especially those with frequent vaso-occlusive pain, even in the absence of large vessel coronary artery disease. Acute myocardial ischemia may present as atypical chest pain that radiates to the arm. Patients with SCD who have acute myocardial ischemic disease are often younger and without traditional risk factors, and they have a higher mortality rate than non-SCD patients with cardiac ischemia [7]. While any individual with SCD can develop myocardial ischemia, those with pulmonary hypertension, diastolic dysfunction, and corrected QT interval prolongation (QTc) are at increased risk. (See "Approach to the patient with suspected angina pectoris" and "Electrocardiogram in the diagnosis of myocardial ischemia and infarction".)

Bone infarction of a rib or the sternum typically presents as localized pain that can be elicited by pressing on the site of infarction. While individuals with rib infarction can develop ACS from hypoventilation and splinting, they are less likely to have a concomitant significant pulmonary parenchymal defect than those without rib tenderness. Individuals with rib infarction may have splinting hypoventilation, which predisposes to infection and ACS. (See "Acute and chronic bone complications of sickle cell disease".)

Abdominal pain — Abdominal pain is often a component of a vaso-occlusive pain episode, but it can also be the presentation of:

Acute surgical abdomen

Acute cholecystitis

Acute hepatic sequestration

Acute splenic sequestration or splenic infarction

Renal papillary necrosis

Urinary tract infection

Pyelonephritis

Pancreatitis

Ectopic pregnancy

Endometriosis

Pelvic inflammatory disease

Opioid-induced constipation

Hepatic or splenic sequestration are characterized by massive shifts of a large proportion of the blood volume into the liver or spleen, which can cause hemodynamic instability tachycardia and hypertension. The spleen or liver may become enlarged and tender. The hemoglobin may decrease dramatically below the patient's baseline. Hepatic sequestration may be exacerbated by underlying liver disease due to iron overload (from transfusions), hepatitis C virus infection (HCV), or other causes of liver disease. These conditions require a high index of suspicion and close monitoring, due to the massive volume shifts and organ failure. Early specialist input is advised. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Splenic sequestration crisis' and "Overview of the clinical manifestations of sickle cell disease", section on 'Hepatobiliary complications' and "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Symptomatic or severe anemia'.)

Renal and urinary tract disease in children may not be associated with specific findings attributable to the site of infarction or infection (ie, flank pain may be absent). There may be suprapubic tenderness. Adults with urinary tract infection or pyelonephritis often present with dysuria or tenderness in the back, flank, or costovertebral angle. The urinalysis may show abnormalities related to infection (eg, red blood cells, white blood cells, bacteria) or infarction (eg, red blood cells). The creatinine may be increased. (See "Sickle cell disease effects on the kidney".)

Abdominal or pelvic pain in a sexually active female also raises the possibility of ectopic pregnancy, pelvic inflammatory disease, and tubo-ovarian abscess. (See "Pelvic inflammatory disease: Clinical manifestations and diagnosis" and "Ectopic pregnancy: Clinical manifestations and diagnosis".)

Females with SCD may also have severe abdominal pain associated with the premenstrual and menstrual cycle that may mimic a vaso-occlusive crisis or initiate an event [8]. The possibility of endometriosis should be considered. Dysmenorrhea can negatively affect the quality of life of women with SCD and should be treated [9]. (See "Primary dysmenorrhea in adolescents" and "Dysmenorrhea in adult females: Clinical features and diagnosis".)

Individuals with SCD are at increased risk of gallstones and biliary disease due to chronic hemolytic anemia, which can lead to the production of heme pigment stones. Findings and evaluation are similar to individuals without SCD (eg, increased white blood cell count, increased bilirubin and/or transaminases, positive right upper quadrant ultrasound or other imaging). (See "Acute calculous cholecystitis: Clinical features and diagnosis" and "Evaluation of the adult with abdominal pain", section on 'Right upper quadrant pain'.)

There is a relatively high rate of acute pancreatitis in individuals with SCD who have a history of gallstones or gallstone surgery. In a report of 56 cases of pancreatitis in children, one-third had SCD with gallstones [10]. Many required admission to the intensive care unit (ICU), and they usually had abdominal pain with emesis and a more severe course than individuals with pancreatitis of other causes.

A diagnosis of opioid-induced constipation may be considered if opioids have been used for pain, including intermittently, especially within the previous 72 hours. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Opioid side effects'.)

Additional testing is guided by the location of the pain, other physical findings such as fever, and the CBC and urinalysis.

Pain associated with menstrual cycle — Women with SCD can have acute vaso-occlusive pain either a few days before or at the same time as their onset of the menstrual cycle. This acute vaso-occlusive pain is distinct from dysmenorrhea, and the women can distinguish the difference [8].

Optimal management of acute vaso-occlusive pain associated with the menstrual cycle (or of dysmenorrhea) in women with SCD is unknown. One option is birth control that abates the menstrual cycle. Our experience is that stopping the menstrual cycle will decrease the rates of vaso-occlusive pain associated with their menstrual cycle, dysmenorrhea, or both. The pros and cons of this strategy must be discussed with the patient. (See "Hormonal contraception for menstrual suppression".)

Extremity pain — Pain in an extremity may be due to:

Acute vaso-occlusion

Bone infarction

Avascular necrosis of a joint

Dactylitis in an infant or young child

Deep vein thrombosis (DVT)

Osteomyelitis

Not all extremity pain in SCD is related to acute vaso-occlusive pain episodes. Distinguishing the duration of the pain (acute versus chronic), location, intensity, and precipitating events may facilitate development of a working differential diagnosis. This subject is discussed in more detail separately. (See "Acute and chronic bone complications of sickle cell disease".)

If the area is associated with swelling, tenderness, or warmth, bone infarction, dactylitis, gout, and osteomyelitis are possible. Gout and dactylitis tend to affect smaller joints, whereas avascular necrosis tends to affect the hips. However, avascular necrosis of the hip may present as referred pain to the pelvis, buttocks, groin, and/or leg. Osteomyelitis may cause variable joint involvement and is significantly less common than bone infarction; the white blood cell count is often increased, and imaging may show periosteal elevation or a fluid collection. The diagnosis of osteomyelitis is often delayed. In a prospective cohort study involving 88 patients with 125 joints affected by osteonecrosis of the femoral head, presentations included pain in the spine, knee, buttocks, and groin; sometimes the examination was normal [11]. SCD patients were more likely to have bilateral disease.

DVT may present with localized tenderness without fever or warmth. Individuals with SCD have a baseline increased risk for DVT, which may be further increased in the setting of pregnancy, recent surgery, or an acute medical illness. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity" and "Deep vein thrombosis in pregnancy: Epidemiology, pathogenesis, and diagnosis".)

IMMEDIATE INTERVENTIONS — Management of acute vaso-occlusive pain, including the use of opioid analgesics, is discussed in detail separately. (See "Acute vaso-occlusive pain management in sickle cell disease".)

Certain other interventions may be considered before the cause of the pain is known, as discussed in the following sections.

Role of blood transfusion — Blood transfusion is not used to treat uncomplicated vaso-occlusive pain that is not associated with any oxygen requirement to augment a low oxygen saturation, unless accompanied by a clinically significant drop from the patient's steady-state hemoglobin level (typically, a decline of greater than 2 g/dL from baseline) along with a declining or inappropriately low reticulocyte count, indicative of bone marrow suppression. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Overview of indications'.)

However, as noted in the sections above, blood transfusion is indicated for the treatment of several of the potentially serious complications that may present with pain. Importantly, the decision to use blood transfusion is based on the presence of the complication rather than the hemoglobin level, because transfusions work by reducing the percentage of sickle hemoglobin and sickled red blood cells, not by increasing oxygen delivery. Exchange transfusion is most effective at rapidly lowering the percentage of sickle hemoglobin without causing hyperviscosity, but simple transfusion is often more rapidly available. A discussion of the indications, techniques, and other issues related to transfusion in SCD is presented separately. Early involvement of the specialist(s) with expertise in SCD and exchange transfusion is advised when one of these complications is suspected. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".)

Role of intravenous fluids — The patient's fluid status (euvolemic versus hypovolemic) is an important consideration and should be evaluated carefully and include a full assessment (ie, it should not rely on the heart rate or urine specific gravity).

The heart rate is not a reliable indicator of volume status or dehydration in children or adults with SCD [12,13].

The specific gravity of the urine may not be an indication of hypovolemia in children and adults with SCD because of hyposthenuria, a common finding related to the effects of SCD on the kidney. (See "Sickle cell disease effects on the kidney", section on 'Sickle cell nephropathy'.)

If a patient is unable to drink fluids, intravenous fluids should be strongly considered to maintain the patient in a euvolemic state. (See "Maintenance and replacement fluid therapy in adults", section on 'Maintenance fluid therapy'.)

Isotonic fluids are not used unless there is clear evidence of hypovolemia based on a history of decreased fluid intake, increased fluid loss (eg, due to gastroenteritis with diarrhea or urinary tract infection with enuresis), or both. If isotonic fluid is given, a small bolus of fluid is given and the patient's volume status is re-evaluated. As an example, a child could be given 10 mL/kg of fluid; an adult could be given 500 to 1000 mL. We do not use isotonic fluid in the absence of clear hypovolemia in children and adults presenting with acute vaso-occlusive pain. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Hydration'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias".)

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle cell disease".)

SUMMARY AND RECOMMENDATIONS

Features of vaso-occlusive pain – Vaso-occlusive pain in sickle cell disease (SCD) can begin as early as six months of age, can range from mild to debilitating, and can last from hours to days. Common locations for vaso-occlusive pain include the back, chest, abdomen, and long bones. (See 'Features associated with acute vaso-occlusive pain' above.)

Features that suggest another cause – Certain features suggest the possibility that an additional complication of SCD may be present, which may be potentially life threatening. These include the patient (or family) report that the pain is atypical; abnormal vital signs; major changes from the baseline complete blood count (CBC) or reticulocyte count; and other abnormalities on examination or initial laboratory testing, as discussed above. (See 'Features that suggest an additional complication' above.)

Rapid analgesia – Regardless of the cause of pain, appropriate analgesia should not be delayed while awaiting other information such as results of laboratory testing, and triage wait time should not exceed 30 minutes. Misperceptions among members of the health care team can interfere with adequate assessment and treatment of pain. These issues, and our approach to analgesia in SCD, are discussed in detail separately. (See 'Importance of providing prompt analgesia' above and "Acute vaso-occlusive pain management in sickle cell disease", section on 'Clinical assessment of pain'.)

Evaluation – Initially, we review the likelihood of each potential complication based on the patient's clinical presentation, as summarized in the table (table 1). In individuals with high-risk features, we obtain targeted laboratory tests and/or observe the patient in the hospital. (See 'Overview of possible conditions and our approach to distinguishing among them' above.)

Multiple or nonspecific – Pain in multiple areas or nonspecific pain may be a sign of an acute systemic illness such as multiorgan failure, rapidly progressive acute chest syndrome (ACS), or a hemolytic transfusion reaction (HTR). Opioid withdrawal may be possible in individuals who recently stopped opioid analgesics. Jaundice suggests increased hemolysis (eg, from an HTR) or hepatobiliary disease. (See 'Acute systemic illness, diffuse pain, or both' above and 'Jaundice' above.)

Headache – Headache and/or mental status changes may indicate vascular disease (stroke, intracerebral hemorrhage, aneurysm, migraine headache) or meningitis. Hypoxemia due to pulmonary complications may also cause mental status changes. (See 'Headache, mental status changes, or both' above.)

Chest – Chest pain may indicate ACS, the frequency of which is increased in individuals with vaso-occlusive pain, as well as pulmonary fat embolism, pulmonary embolism (PE), cardiac ischemia, or rib infarct. (See 'Chest pain' above.)

Abdomen – Abdominal pain may indicate splenic or hepatic sequestration, which are potentially life threatening. Other possible causes include gallstone disease, renal infarct, urinary tract infection or pyelonephritis, endometriosis, pancreatitis, and ectopic pregnancy or pelvic inflammatory disease. (See 'Abdominal pain' above.)

Extremity – Pain in an extremity may be due to vaso-occlusion, but it also may be a sign of bone infarction, avascular necrosis of a joint, dactylitis in an infant or young child, deep vein thrombosis (DVT), or, rarely, osteomyelitis. (See 'Extremity pain' above.)

Role of transfusions – Blood transfusion is not used to treat uncomplicated vaso-occlusive pain when bone marrow function is adequate. However, as noted in the sections above, blood transfusion is indicated for the treatment of several of the potentially serious complications that may present with pain. Early involvement of the specialist(s) with expertise in SCD and exchange transfusion is advised when one of these complications is suspected. Careful assessment of the patient's volume status plays an important role in determining whether to give intravenous fluids and which type of fluids to give. (See 'Immediate interventions' above and "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques" and "Acute vaso-occlusive pain management in sickle cell disease", section on 'Hydration'.)

Other manifestations of SCD – An overview of the clinical manifestations of SCD, with links to topics that discuss specific manifestations, is presented separately. (See "Overview of the clinical manifestations of sickle cell disease".)

ACKNOWLEDGMENTS

UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic review and was a founding Editor-in-Chief for UpToDate in Hematology.

The UpToDate editorial staff also acknowledges extensive contributions of Donald H Mahoney, Jr, MD, to earlier versions of this and many other topic reviews.

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