Sickle cell crisis

Sickle cell crisis is the umbrella term for the acute, life-threatening events that complicate sickle cell disease (HbS disease), the inherited haemoglobinopathy in which a single amino acid substitution in the β-globin chain allows haemoglobin to polymerise when deoxygenated. The crisis syndromes — the vaso-occlusive pain crisis, acute chest syndrome, splenic sequestration crisis and aplastic crisis — share a common mechanism (sickled erythrocytes obstructing the microvasculature, with haemolysis and ischaemia) but differ in their bedside presentation, their urgency and their specific treatment. The Fellowship candidate must recognise each syndrome from its fingerprint, deliver oxygen, hydration and prompt opioid analgesia as the universal backbone, and escalate to exchange transfusion for the severe acute chest syndrome, stroke and refractory pain.[1][2]

Definition and classification

Sickle cell disease is the autosomal recessive disorder caused by the HBB mutation (glutamate substituted by valine at the sixth position of the β-globin chain, the glu6val substitution on chromosome 11) that produces haemoglobin S. The disease encompasses several genotypes: homozygous HbSS (classic sickle cell anaemia, the most severe), and the compound heterozygotes HbSC disease, HbSβ-thalassaemia and the rarer HbS variants, which run a milder but still crisis-prone course. A "sickle cell crisis" is any acute event driven by sickling, and the emergency physician classifies the presentation by its dominant clinical syndrome, because the syndromes demand different escalation.[1]

The four acute syndromes carry the Fellowship weight. Vaso-occlusive crisis (VOC) is the acute pain crisis — the commonest presentation — in which sickled cells occlude the microvasculature of bone, marrow and viscera, producing severe ischaemic pain without an alternative cause. Acute chest syndrome (ACS) is the new pulmonary infiltrate on the chest radiograph accompanied by a respiratory symptom or sign (fever, cough, dyspnoea, pleuritic chest pain, hypoxia) — it is the leading cause of death in sickle cell disease and demands aggressive treatment.[2] Splenic sequestration crisis is the sudden trapping of blood in an enlarging spleen, producing hypovolaemic shock and a falling haemoglobin, seen in young children before functional asplenia develops. Aplastic crisis is the transient arrest of erythropoiesis, classically triggered by parvovirus B19, in which the haemoglobin falls precipitously and the reticulocyte count — normally the marrow's response to chronic haemolysis — is inappropriately low or absent. Two further acute events sit within the crisis umbrella: stroke (ischaemic, disproportionately affecting children) and priapism (a painful prolonged erection from veno-occlusion).

Epidemiology and risk factors

Sickle cell disease is the commonest severe monogenic disorder worldwide, with the gene maintained at high frequency in sub-Saharan Africa, the Mediterranean, the Middle East and parts of India where falciparum malaria is or was endemic (the heterozygote carrier, sickle cell trait, confers partial malaria protection). The sickle haplotype and genotype vary by region: HbSS is the predominant and most severe form. In Australia and New Zealand the prevalence is low in the general population but rising through migration from high-prevalence regions, and every metropolitan emergency department will see sickle cell patients; the candidate must not assume the diagnosis is absent because the local population prevalence is low.[1]

The risk of an acute crisis is driven by the triggers that promote sickling. The recognised precipitants are hypoxia (high altitude, air travel, sleep apnoea), dehydration (acidosis and increased plasma viscosity), infection (the commonest precipitant, especially respiratory infection, parvovirus B19, and in children the encapsulated organisms of functional asplenia — pneumococcus, Haemophilus, meningococcus), cold, acidosis, fever, surgery and anaesthesia, pregnancy, and psychological stress. Functional asplenia develops progressively through childhood as repeated splenic infarction autoinfarcts the organ (the "autosplenectomy" of HbSS, usually complete by age five), after which the patient is permanently at risk of overwhelming encapsulated-bacteraemia. The mortality of sickle cell disease has fallen substantially with penicillin prophylaxis, vaccination, hydroxycarbamide and transfusion programmes, but the acute chest syndrome remains the leading cause of death, and stroke remains the leading cause of neurological morbidity in children with the disease.[2]

Pathophysiology

The single molecular event is the polymerisation of deoxygenated haemoglobin S. When oxygen tension falls, the valine at position six of the β-globin chain locks into a hydrophobic pocket on an adjacent haemoglobin molecule, forming rigid polymers that elongate the red cell into the characteristic sickle shape. Sickling is initially reversible on reoxygenation, but repeated cycles produce membrane damage, intracellular dehydration and irreversibly sickled cells. Two downstream consequences dominate the clinical disease.[1]

The first is chronic haemolysis. Sickled cells are rigid and fragile, and are destroyed in the spleen and circulation; the steady-state haemoglobin of HbSS is therefore typically 60 to 90 g/L with a compensatory reticulocytosis. Free haemoglobin released by haemolysis scavenges nitric oxide, depleting the vasodilator that normally opposes pulmonary and systemic vascular tone, and this contributes over years to pulmonary hypertension, leg ulcers and the haemolysis-endothelial dysfunction phenotype. The second is vaso-occlusion. Sickled erythrocytes, along with leucocytes and platelets, adhere to an activated vascular endothelium and obstruct the microvasculature, producing ischaemia, infarction and the severe pain of the crisis, and — when this occurs in the pulmonary, cerebral or splenic circulation — the acute chest syndrome, stroke and splenic sequestration. [1]

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Clinical presentation

The clinical presentation depends on the dominant syndrome, and the emergency physician must keep all four in mind for every sickle cell patient, because one syndrome can evolve into another (a vaso-occlusive pain crisis progressing to acute chest syndrome is the classic sequence).[2]

Vaso-occlusive crisis presents with severe, acute pain, usually in the back, chest, long bones, abdomen or joints, and often at sites of previous crises. The pain is typically severe enough to be rated 7 to 10 out of 10, is reproducible, and is frequently accompanied by no objective physical findings — the absence of signs does not exclude the crisis. Tachycardia, hypertension and diaphoresis from pain and adrenergic surge are common; fever may indicate an infective trigger or evolving acute chest syndrome. Abdominal pain from mesenteric sickling can mimic an acute abdomen, and the candidate must distinguish it from surgical pathology. [1]

Acute chest syndrome presents with the new onset of respiratory symptoms — fever, cough, dyspnoea, pleuritic chest pain or wheeze — accompanied by a new pulmonary infiltrate on the chest radiograph and, frequently, hypoxia. The radiographic infiltrate may lag the symptoms by hours to days, so a normal early film does not exclude the diagnosis; a falling oxygen saturation, rising respiratory rate or increasing work of breathing in a sickle cell patient is acute chest syndrome until proven otherwise. The syndrome may be triggered by infection (bacterial, viral including SARS-CoV-2, or atypical), by fat embolism from marrow infarction, by pulmonary infarction, or by hypoventilation and atelectasis from chest-wall pain and splinting.[2]

Splenic sequestration crisis presents in a child under five (before functional asplenia develops) with sudden pallor, lethargy, irritability, abdominal pain and distension, and signs of hypovolaemic shock — tachycardia, prolonged capillary refill and hypotension. The spleen is palpably enlarged and may enlarge further over hours; the haemoglobin drops by 20 g/L or more, and the reticulocyte count is high. The crisis can be fatal within hours from hypovolaemia and severe anaemia. [1]

Aplastic crisis presents with the symptoms of acute, severe anaemia — progressive pallor, fatigue, dyspnoea on exertion, headache and, in severe cases, high-output cardiac failure — over days. There is typically a viral prodrome; parvovirus B19 is the classical trigger. The reticulocyte count is inappropriately low or absent, distinguishing the aplastic crisis from the haemolytic and sequestration crises. [1]

Stroke and priapism are the two further acute events. Stroke in sickle cell disease is predominantly ischaemic, affects children disproportionately, and may present with a focal deficit, seizures, altered conscious level, or (in the silent infarcts) only cognitive decline. Priapism — a prolonged, painful erection from veno-occlusion of the corpora cavernosa — is a urological emergency when it persists beyond four hours; stuttering priapism precedes a major event in many patients. [1]

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Differential diagnosis

The crisis syndromes each have mimics that share their presentation, and the candidate must distinguish them at the bedside — the vaso-occlusive abdominal pain from the acute abdomen, the acute chest syndrome from pneumonia and pulmonary embolism, and the aplastic anaemia from diabetic ketoacidosis and from blood loss. The history of sickle cell disease, the haemolysis pattern, the reticulocyte count and the chest radiograph are the discriminators. [1]

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Investigations and diagnostic targets

The investigations are sent in parallel with the first analgesia and oxygen; they seek the crisis syndrome, its severity and any precipitant. A full blood count shows the baseline anaemia (haemoglobin 60 to 90 g/L in HbSS); an acute fall signals sequestration, aplasia or hyperhaemolysis. The reticulocyte count is the single most discriminating test: it is high in the vaso-occlusive, sequestration and haemolytic crises (the marrow responding appropriately) and inappropriately low or absent in the aplastic crisis. A blood film shows sickled cells, target cells, and (after autosplenectomy) Howell-Jolly bodies. Haemolysis markers — raised lactate dehydrogenase, raised indirect bilirubin, low haptoglobin — confirm haemolysis. A type and screen or crossmatch is sent early because transfusion is frequently required. Blood cultures and a urine culture are sent if the patient is febrile, and a chest radiograph is mandatory to detect the new infiltrate of acute chest syndrome; the film may lag the symptoms, so a clinical suspicion with a normal early film warrants repeat imaging. Venous or arterial blood gas quantifies the hypoxia and the acidosis that drive sickling. An ECG is routine. Lipase excludes pancreatitis in the abdominal-pain presentation; β-hCG is checked in any woman of reproductive age. A haemoglobin electrophoresis quantifies the HbS fraction and confirms the genotype if it is not already documented, but it is not an emergency test.[1][3]

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Immediate management and resuscitation

The resuscitation is syndrome-specific but follows a universal backbone: oxygen, hydration, analgesia, with escalation to transfusion for the severe presentations. Secure the airway and give supplemental oxygen to maintain the oxygen saturation at or above 94 per cent — hypoxia is both a consequence of the acute chest syndrome and a driver of further sickling, so it must be corrected promptly. Establish intravenous access, attach cardiac monitoring, and send the investigations in parallel. Treat any hypovolaemia or dehydration with cautious isotonic crystalloid (0.9 per cent saline), because both over- and under-hydration harm: dehydration worsens sickling, but aggressive fluid causes pulmonary oedema that accelerates the acute chest syndrome. A rehydration rate of roughly one to one-and-a-half times maintenance is reasonable in the adult, moderated by the cardiovascular and renal status.[1]

Analgesia must be prompt. The under-treatment of sickle cell pain is the classic and most-cited failure, and the pain of a vaso-occlusive crisis is comparable to surgical pain. The first opioid should be delivered within 30 minutes of triage. The agent of choice in the haemodynamically stable adult is morphine 0.1 mg per kilogram intravenously, repeated every 15 to 20 minutes and titrated to the reported pain score, followed by a scheduled regimen or patient-controlled analgesia. Fentanyl is an alternative, particularly in the patient with renal impairment or a morphine allergy. Meperidine (pethidine) is avoided because its metabolite normeperidine accumulates, lowers the seizure threshold and causes seizures, especially in renal impairment and with repeated dosing. Paracetamol and, where renal function allows, a non-steroidal anti-inflammatory are useful adjuncts.[5][6]

The acute chest syndrome is treated on diagnosis with oxygen, broad-spectrum antibiotics (a third-generation cephalosporin such as ceftriaxone to cover pneumococcus and Haemophilus, plus a macrolide to cover atypicals, since infection is the commonest identified cause), bronchodilators if there is wheeze or a history of asthma, incentive spirometry to reverse the hypoventilation and atelectasis that drive the infiltrate, and respiratory escalation (high-flow nasal cannula or non-invasive ventilation) for hypoxia. Transfusion is the sickle-specific escalation: a simple transfusion for moderate acute chest syndrome, and an exchange transfusion for the severe syndrome (worsening hypoxia, multilobar infiltrate, rapid progression, or a falling haemoglobin), with the aim of reducing the HbS fraction below 30 per cent.[2][3]

The first hour of a suspected sickle cell crisis in one breath

Recognise the syndrome — the history of sickle cell disease, the pattern of the pain, and the respiratory status. Give oxygen to keep the saturation at or above 94 per cent; establish intravenous access; run in 0.9 per cent saline at one to one-and-a-half times maintenance (resuscitate the shocked child faster). Give morphine 0.1 mg per kilogram intravenously as the first opioid, reassess the pain score at 15 minutes and re-titrate; do not use meperidine. Send the full blood count, reticulocyte count, blood film, haemolysis markers, type and screen, blood cultures if febrile, venous gas, chest radiograph, ECG, lipase and β-hCG. If the chest radiograph shows a new infiltrate with respiratory symptoms, treat as acute chest syndrome: add ceftriaxone and a macrolide, incentive spirometry, bronchodilators if wheeze, and escalate to transfusion or exchange transfusion for worsening hypoxia. If the haemoglobin has fallen with a low reticulocyte count, isolate and transfuse for aplastic crisis; if a child is shocked with an enlarging spleen, resuscitate and transfuse urgently for splenic sequestration. Reassess the pain, the saturation and the respiratory rate at least every 30 minutes. [1]

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Definitive management — the syndrome-specific ladder

Beyond the universal backbone, each syndrome has its own escalation ladder. [1]

Vaso-occlusive crisis. The definitive therapy is opioid analgesia titrated to the pain score, hydration to correct dehydration, and the search for and treatment of any trigger (infection, dehydration, hypoxia). A patient-controlled analgesia (PCA) regimen is preferred for the established crisis in the adult: morphine 1 mg per kilogram per 24 hours as the basal demand with a 20 microgram per kilogram bolus and a 10-minute lockout is a representative regimen, adjusted to the patient's opioid history. The opioid-tolerant chronic-pain patient needs higher doses and a multimodal plan involving the pain service and haematology. Incentive spirometry every two hours while awake is prescribed for every admitted patient, because it prevents the atelectasis that precipitates acute chest syndrome. The patient is transitioned to oral analgesia once the pain is controlled, and the precipitant is treated.[5][6]

Acute chest syndrome. Oxygen, antibiotics (ceftriaxone plus a macrolide), bronchodilators, incentive spirometry and respiratory support form the backbone. Transfusion is the sickle-specific escalation. A simple transfusion is given for moderate acute chest syndrome — a falling haemoglobin, worsening hypoxia or a rising respiratory rate — aiming to raise the haemoglobin toward 100 to 110 g/L without exceeding that ceiling (a higher total haemoglobin raises viscosity and worsens vaso-occlusion). An exchange transfusion (manual or automated erythrocytapheresis) is reserved for the severe syndrome — multilobar infiltrates, rapid progression, oxygen saturation below 90 per cent despite oxygen, or a falling platelet count, worsening anaemia or neurological compromise — and aims to reduce the HbS fraction below 30 per cent while keeping the total haemoglobin below 110 g/L.[2][3]

Splenic sequestration crisis. The child is resuscitated with fluid boluses (10 to 20 mL per kilogram of 0.9 per cent saline) and transfused urgently with packed red cells to restore the circulating volume and haemoglobin. The transfusion is given cautiously because the sequestered blood can re-enter the circulation as the crisis resolves, causing a relative polycythaemia. A paediatric haematologist is involved, and after a recurrence the child is considered for chronic transfusion programme and eventual splenectomy, because recurrence is common and potentially fatal.[1]

Aplastic crisis. The patient is supported with packed red cell transfusion until the marrow recovers — typically one to two weeks — and isolated because parvovirus B19 is contagious, with particular risk to pregnant contacts (hydrops fetalis) and immunocompromised patients. The reticulocyte count is monitored for recovery. Intravenous immunoglobulin is occasionally used in the immunocompromised patient with persistent parvovirus.[1]

Stroke. An acute neurological deficit in a sickle cell patient is a stroke until proven otherwise and is treated with urgent exchange transfusion to reduce the HbS fraction below 30 per cent, ideally within hours of onset — this differs from the thrombolysis pathway of the non-sickle ischaemic stroke and is the reason the genotype must be known early. Intravenous thrombolysis and thrombectomy are considered only after consultation with stroke and haematology, because the mechanism (sickle vasculopathy and large-vessel stenosis) differs from cardioembolic stroke.[4]

Priapism. A prolonged episode beyond four hours is a urological emergency: aspiration of the corpora cavernosa with irrigation and intracavernosal phenylephrine is first-line, with exchange transfusion and urgent urology involvement for refractory cases. [1]

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Disease-modifying and preventive therapies

Beyond the acute episode, three classes of disease-modifying therapy reduce the crisis frequency, the organ damage and the mortality, and the Fellowship candidate should know the landmark evidence behind each. Hydroxycarbamide is the backbone for HbSS and HbS-beta-zero-thalassaemia; crizanlizumab and voxelotor are layered on for refractory disease; and haematopoietic stem cell transplantation is curative for selected patients.[1]

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Complications and pitfalls

Death from acute chest syndrome remains the leading cause of mortality in sickle cell disease, driven by delay in recognition and escalation; a missed or under-treated stroke causes permanent neurological deficit in a child; and the splenic sequestration crisis kills the shocked child within hours when the diagnosis is not considered. The recurring pitfalls are the inverse of the protocol. The first is under-treatment of pain — the patient labelled "drug-seeking" or given subtherapeutic doses because of unfounded opioid fear; the pain of a vaso-occlusive crisis is severe and the analgesia must be titrated to the reported score. The second is the meperidine (pethidine) prescription, still occasionally used for "sickle pain," accumulating normeperidine and causing seizures. The third is delayed recognition of acute chest syndrome, attributing hypoxia to "pain splinting" or a normal early radiograph while the infiltrate develops. The fourth is aggressive fluid resuscitation causing pulmonary oedema that accelerates the acute chest syndrome — fluids are given to correct dehydration, not to "flush" the sickle cells. The fifth is transfusion to a high total haemoglobin without reducing the HbS fraction, producing hyperviscosity and worsening vaso-occlusion; the ceiling is 110 g/L unless an exchange is reducing the HbS in parallel. The sixth is missing the aplastic crisis by treating a falling haemoglobin as "just sickle anaemia" without checking the reticulocyte count.[1][2][3]

Prognosis and disposition

The disposition is syndrome-driven. A vaso-occlusive pain crisis that is controlled with oral or simple analgesia, with no features of acute chest syndrome and an identified and treated trigger, may be managed as an outpatient with haematology follow-up and a sickle cell action plan; a crisis requiring ongoing intravenous opioids is admitted for analgesia, hydration and incentive spirometry. An acute chest syndrome is admitted — frequently to high-dependency or intensive care for the severe case, because the syndrome can deteriorate rapidly over hours. A splenic sequestration crisis is admitted to a paediatric high-dependency bed after transfusion. An aplastic crisis is admitted for transfusion support and isolation. A stroke is admitted to a stroke or intensive-care unit after exchange transfusion. The long-term outlook has improved markedly with hydroxycarbamide (which raises fetal haemoglobin and reduces crisis frequency, acute chest syndrome and mortality), penicillin prophylaxis and vaccination in the asplenic patient, chronic transfusion programmes for secondary stroke prevention, and, in selected patients, curative haematopoietic stem cell transplantation.[1][4]

Special populations

Children are the group in whom the splenic sequestration crisis and the aplastic crisis present, in whom stroke is disproportionately common, and in whom the dosing is weight-based — morphine 0.1 mg per kilogram intravenously, fluid boluses of 10 to 20 mL per kilogram, and transfusion volumes adjusted to weight. Pregnancy increases the frequency of vaso-occlusive crises and acute chest syndrome and the risk of fetal loss; prophylactic transfusion in pregnancy is debated and reserved for high-risk indications. The functionally asplenic patient (the older child and adult with HbSS, autosplenectomy complete by age five) is permanently at risk of overwhelming encapsulated bacteraemia and must receive penicillin prophylaxis and the full vaccination schedule (pneumococcal, Haemophilus influenzae type b, meningococcal, influenza, and SARS-CoV-2), and any febrile asplenic presentation is treated as a potential sepsis with empirical antibiotics. The opioid-tolerant chronic-pain patient presents a particular challenge: the baseline opioid requirement is high, the crisis pain is real, and a multimodal plan involving the pain service, haematology and the patient's own sickle cell team is essential to avoid both under-treatment and the harm of uncoordinated high-dose opioids.[1][6]

Evidence and regional guidelines

The contemporary framework rests on the NHLBI 2014 evidence-based report (Yawn and colleagues), which sets the universal backbone of oxygen, hydration and analgesia, the syndrome-specific transfusion strategy, the trigger avoidance, and the preventive use of hydroxycarbamide and penicillin prophylaxis.[1] The American Society of Hematology 2020 guidelines operationalise the transfusion strategy (Chou and colleagues) and the prevention and treatment of cerebrovascular disease (DeBaun and colleagues): exchange transfusion to reduce the HbS fraction below 30 per cent for the severe acute chest syndrome and for stroke, simple transfusion for moderate acute chest syndrome, and chronic transfusion for secondary stroke prevention.[3][4] The Vichinsky 2000 New England Journal study of the acute chest syndrome established the causes (infection, fat embolism, pulmonary infarction) and outcomes, and remains the landmark reference for the syndrome.[2] The van Beers 2007 and Telfer 2014 studies underpin the opioid analgesia approach, supporting patient-controlled analgesia and prompt titrated opioid delivery.[5][6] Regional practice is convergent: the British Society for Haematology and NHS sickle cell guidelines mirror the NHLBI and ASH approach; the Australian and New Zealand practice follows the same principles, adapted to a lower local prevalence but with the same haemoglobinopathy-transfusion standards set by the national blood authorities.

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Exam pearls

• Acute chest syndrome is the leading cause of death in sickle cell disease — any new pulmonary infiltrate with respiratory symptoms in a sickle cell patient is ACS, even if the early film is normal.
• Morphine 0.1 mg/kg intravenously, titrated every 15 to 20 minutes — the pain of a vaso-occlusive crisis is severe and surgical-grade; never under-treat it.
• The reticulocyte count discriminates the crises — high in VOC, sequestration and haemolysis; absent in the parvovirus B19 aplastic crisis. A falling haemoglobin with a low reticulocyte is aplasia until proven otherwise.
• Splenic sequestration is a disease of children under five — sudden pallor, enlarging spleen, Hb drop of 20 g/L or more, and shock; resuscitate with fluid and transfuse urgently. The older patient has autoinfarcted the spleen and cannot sequester.
• Exchange transfusion targets the HbS fraction below 30 per cent for the severe acute chest syndrome, stroke and refractory VOC; keep the total haemoglobin below 110 g/L to avoid hyperviscosity.
• Avoid meperidine (pethidine) — normeperidine accumulates and causes seizures, especially in renal impairment.
• Incentive spirometry every two hours prevents the atelectasis-driven acute chest syndrome in the admitted VOC patient.
• An acute neurological deficit in a sickle cell patient is a stroke — urgent exchange transfusion within hours, not antiplatelet therapy; the mechanism is sickle vasculopathy and large-vessel stenosis, not cardioembolism.
• Triggers to avoid: hypoxia, dehydration, infection, cold, acidosis, fever, surgery, pregnancy — prevent and treat each.
• The functionally asplenic patient needs penicillin prophylaxis, the full vaccination schedule, and empirical antibiotics for any fever.
• The molecular lesion: a single GAG-to-GTG point mutation replaces glutamic acid with valine at position six of the beta-globin chain (glu6val on chromosome 11) — one amino acid, one disease.
• HbF opposes sickling because the gamma-chain lacks the beta-6 valine and cannot enter the polymer; this is why hydroxycarbamide works (it reactivates gamma-globin) and why the high-HbF haplotypes run a milder course.
• Hydroxycarbamide is the disease-modifying backbone of HbSS — the MSH trial halved the crises and the acute chest syndrome and improved survival; offer it to every adult and child over nine months with HbSS or HbS-beta-zero-thalassaemia.
• Transcranial Doppler screens children for stroke risk (TCD velocity at or above 200 cm/s); STOP showed chronic transfusion cuts the first-stroke rate by about 90 per cent, and TWiTCH showed hydroxycarbamide can later replace the transfusion if no vasculopathy has developed.
• Crizanlizumab (anti-P-selectin) and voxelotor (HbS-polymerisation inhibitor) are newer adjuncts — crizanlizumab halves pain crises (SUSTAIN), voxelotor raises the haemoglobin (HOPE); both layer onto, not replace, hydroxycarbamide.
• The hyperhaemolysis paradox: a rapid Hb drop after a recent transfusion, with a HIGH reticulocyte count — further transfusion makes it worse. Treat with steroids and IVIG, and involve haematology before transfusing again.
• Keep the total haemoglobin at or below 110 g/L during transfusion unless an exchange is simultaneously lowering the HbS fraction — a high total Hb raises viscosity and worsens vaso-occlusion.
• Aggressive fluid is harmful, not helpful: fluids correct dehydration, they do not "flush" sickle cells; over-resuscitation causes pulmonary oedema that accelerates the acute chest syndrome.
• Priapism beyond four hours is a urological emergency — corporal aspiration with irrigation and intracavernosal phenylephrine first-line; exchange transfusion and a surgical shunt for refractory cases.
• Every fever in the asplenic sickle patient is sepsis until proven otherwise — blood cultures and empirical ceftriaxone regardless of how well the patient looks; the spleen is autoinfarcted by age five. [1]

Red flags

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References

1. [1]Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members JAMA, 2014.PMID 25203083
2. [2]Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group N Engl J Med, 2000.PMID 10861320
3. [3]Chou ST, Alsawas M, Fasano RM, et al. American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support Blood Adv, 2020.PMID 31985807
4. [4]DeBaun MR, Jordan LC, King AA, et al. American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults Blood Adv, 2020.PMID 32298430
5. [5]van Beers EJ, van Tuijn CF, Nieuwkerk PT, et al. Patient-controlled analgesia versus continuous infusion of morphine during vaso-occlusive crisis in sickle cell disease, a randomized controlled trial Am J Hematol, 2007.PMID 17617790
6. [6]Telfer P, Baheng E, Baiden S, et al. Management of the acute painful crisis in sickle cell disease- a re-evaluation of the use of opioids in adult patients Br J Haematol, 2014.PMID 24750050
7. [7]Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia N Engl J Med, 1995.PMID 7715639
8. [8]Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death N Engl J Med, 1994.PMID 7993409
9. [9]Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography N Engl J Med, 1998.PMID 9647873
10. [10]Adams RJ, Brambilla D; Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) Trial Investigators. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease N Engl J Med, 2005.PMID 16382063
11. [11]Ware RE, Davis BR, Schultz WH, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial Lancet, 2016.PMID 26670617
12. [12]Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease N Engl J Med, 2017.PMID 27959701
13. [13]Vichinsky E, Hoppe CC, Ataga KI, et al. A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease N Engl J Med, 2019.PMID 31199090