Sickle Cell Crises Management

Question 1

Sickle cell disease (SCD) is a chronic, multi-system disease that requires comprehensive care. Patterns of immigration and an increase in newborn screening mean that paediatric health care providers across Canada need to be knowledgeable about SCD. The sickling of red blood cells leads to hemolysis and vascular occlusion. What are the 6 common acute complications of SCD?

Answer 1

i) Vaso-occlusive episodes (VOE)
ii) Acute chest syndrome (ACS)
iii) Fever
iv) Splenic sequestration
v) Aplastic crises
vi) Stroke

Question 2

Sickle cell disease (SCD) is the world’s most common human genetic disease, and it affects at least 5000 individuals in Canada. This chronic, multisystem disease is best managed with comprehensive care, including prevention, anticipatory guidance, and the prompt diagnosis and treatment of acute complications. In Ontario, there are patients with SCD residing in every health region, with what % being aged 14 or less?

Answer 2

1/3

Question 3

SCD can be caused by homozygosity (i.e., possessing two identical alleles for the sickle beta-globin gene (HbS)), or by heterozygosity (possessing two different alleles for HbS and another beta-globin variant). What are the 2 other most common beta-globin variants? Note: while prevention, treatment strategies, and comprehensive care have significantly decreased mortality in children with SCD, complications continue to cause significant morbidity.

Answer 3

Beta-thalassemia or hemoglobin C

Question 4

While phenotypic severity varies among patients, acute management principles are consistent. Children who have only one sickle beta-globin gene (with one normal beta-globin gene) have the
sickle cell trait, but they do not usually exhibit clinical manifestations or require disease-specific care, apart from genetic counselling. SCD’s clinical manifestations are caused by the complex pathophysiology of deformed and fragile sickle red cells. Complications can arise from what 3
main sources?

Answer 4

i) Hemolytic anemia
ii) Pain syndromes (most commonly resulting from vaso-occlusion and ischemia-reperfusion injuries)
iii) Major organ complications due to hemolysis, vaso-occlusion or vasculopathy, or a combination of both

Question 5

All affected children should be referred to a SCD clinic. SCD clinics can help bridge distance and other barriers to care by supporting a family’s primary HCP and using video or telephone consultations. Preventive and supportive strategies should be offered. What are the 4 examples of preventive and supportive strategies for SCD outlined by the CPS?

Answer 5

i) Newborn screening
ii) Immunizations
iii) Antibiotic prophylaxis
iv) Hydroxyurea

Question 6

SCD was part of NBS in seven provinces and two territories in 2021. Name at least 3 of the 5 benefits for including SCD in NBS mentioned by the CPS.

Answer 6

i) Reduced SCD-related infant mortality rates
ii) Earlier referral
iii) Parent education
iv) Preventive strategies
v) Genetic counselling

Question 7

While the routine Canadian vaccination schedule includes partial immunization against pneumococcal disease and immunization against meningococcal type C bacterial infection, it is imperative that children with SCD receive enhanced vaccination against these encapsulated bacteria. Children with SCD should receive which specific vaccines targeting these organisms?

Answer 7

The 13-valent pneumococcal conjugate and polysaccharide vaccines against Streptococcus pneumoniae
AND
Both conjugated quadrivalent meningococcal (A,C,W,Y) and serogroup B vaccines targeting Neisseria meningitidis

Question 8

Excluding routine vaccinations, aside from enhanced vaccination against pneumococcal disease and meningococcal type C bacterial infection, name at least 3 of the 5 other examples of specific vaccinations recommended for patients with SCD.

Answer 8

i) An extra booster dose against Haemophilus influenzae type B (Hib)
ii) Immunization against hepatitis A and B
iii) Annual influenza vaccines
iv) In the context of travel, vaccination against Salmonella typhi and malaria prophylaxis should be offered

Question 9

Daily prophylactic penicillin VK or amoxicillin should be prescribed for all children with SCD in what age range? Note: the duration of prophylaxis may be extended for children who have had a surgical splenectomy or a history of invasive bacterial infections, or whose immunizations are not up to date. Cotrimoxazole or erythromycin are alternatives in cases of penicillin allergy.

Answer 9

From 2 months to 5 years of age

Question 10

Hydroxyurea is now standard of care for all patients with HbSS and HbSB thalassemia. Hydroxyurea use can significantly reduce risk for acute chest syndrome (ACS), vaso-occlusive episodes (VOE), transfusions, hospitalization, and mortality. Treatment risks and benefits should be discussed with families and the medication offered to all children above what age cut off?

Answer 10

≥9 months of age

Question 11

While experience with paediatric HbSC patients is limited, hydroxyurea should be considered for symptomatic cases. Hydroxyurea is usually held in what clinical scenario? In these case, discuss with a consulting hematologist.

Answer 11

If patients become cytopenic

Question 12

Case 1: Danielle, a 6-year-old girl with SCD, presents to the ED with a 2-day history of leg pain. She was given acetaminophen and ibuprofen at home but continues to rate her pain 9/10. On exam, she has diffuse leg tenderness without erythema, edema, or fever, and her vital signs are normal. She receives a working diagnosis of a VOE. Pain evaluation should be prompt and non-SCD-related etiologies considered. What are the 7 general principles for management of vaso-occlusive episodes (VOE) outlined by the CPS?

Answer 12

(see Table 1)

Question 13

What opioid (including route of administration) should be considered early in the setting of SCD with VOE because it can be administered quickly (which significantly reduces the time needed to provide the first opiate dose), has a rapid onset of action, and decreases the number of intravenous (IV) line insertions?

Answer 13

Intranasal (IN) fentanyl

Question 14

After a minimum observation period of 2-3h, children who achieve pain control in a VOE with oral opiates may be managed as outpatients. Parents should receive a clear, written plan of treatment and follow-up. However, if the pain proves intractable, what escalation in analgesia control should be considered?

Answer 14

A morphine bolus, with subsequent escalation to a morphine infusion with intermittent bolus

doses or patient-controlled analgesia (PCA)

Question 15

Patients with SCD experiencing a VOE with difficult to control pain should be admitted to hospital. In these cases, several principles of pain management apply, including ordering PEG 3350 to prevent opioid-related constipation. What non-opioid methods of pain control should be implemented? Note: cold packs are not applied because, due to vasoconstriction, they will worsen the VOE and can injure tissue!

Answer 15

i) Prescribe round-the-clock acetaminophen and NSAIDs
ii) Psychological supports
iii) Physical comfort measures (e.g., distraction, heat packs)

Question 16

Patients with SCD experiencing a VOE with difficult to control pain should be admitted to hospital. In these cases, several principles of pain management apply, including encourage oral hydration. Administer IV fluids to reach a TFI equivalent to maintenance volumes but not beyond. Why should HCPs avoid over-hydrating SCD patients in the setting of VOE?

Answer 16

Hyperhydration has been associated with increased risk for ACS

Question 17

Patients with SCD experiencing a VOE with difficult to control pain should be admitted to hospital. In these cases, several principles of pain management apply. Promote incentive spirometry in cases of chest, back, or abdominal pain, and encourage a seated posture and walking as soon as possible to mitigate risk for pulmonary complications. What is the target oxygen saturation in these cases? Provided this target is met, is routine supplemental oxygen recommended?

Answer 17

At least 95%.

No - due to theoretical risk for hypoventilation leading to ACS

Question 18

Patients with SCD experiencing a VOE with difficult to control pain should be admitted to hospital. Assuming an opioid infusion is required (such as with morphine), the next step is to wean the opioid infusion and transition to regular oral dosing. Educate the parents regarding pain medication at home and provide adequate doses to manage the VOE over several days following hospital discharge. Routine follow-up includes updating this child’s pain management plan. Outline the dosing of pain medications for acute VOE in children with SCD as per the CPS.

Answer 18

(see Table 2)

Question 19

What is the definition of Acute Chest Syndrome (ACS)? ACS can be caused by infection, pulmonary infarction, or fat embolism. Because these causes are difficult to differentiate, management principles are the same for all. Up to 50% of paediatric patients with ACS present during a hospital admission, most commonly for VOE. VOE patients should always be monitored for signs of ACS, as morbidity and mortality may result from this complication.

Answer 19

A new pulmonary infiltrate in the presence of fever and respiratory signs or symptoms

Question 20

ACS investigation and management should be prompt and orderly. Patients with ACS should be admitted to hospital. Maintain oxygen saturation >95%. Aside from a CXR, what are other appropriate investigations in the work up of suspected ACS? Do not wait for test results before initiating what broad-spectrum empiric antimicrobial therapy in these cases?

Question 21

Management principles for patients with ACS include to avoid over-hydration and promote incentive spirometry. Why is it important to order a crossmatch when managing these patients? Note: if a patient with ACS clinically deteriorates, consult with hematology, broaden antibiotic coverage and, based on clinical severity, consider a simple or exchange transfusion (ExT).

Answer 21

In case of possible transfusion or Exchange Transfusion (ExT) in severe cases (for which you should consult with hematology and intensive care)

Question 22

Case 2: Jared, a 3-year-old boy with SCD, presents to the ED with a sore throat and a temperature of 39.0°C. He is alert and non-toxic, has enlarged erythematous tonsils, but no other apparent focus of infection. His mother assures you that she administers his prophylactic antibiotics daily, and that his immunizations are up to date. Functional asplenia renders children with SCD particularly at risk for what kinds of invasive bacterial infections?

Answer 22

Sepsis, meningitis, or osteomyelitis

Question 23

Due to the functional asplenia in patients with SCD, all febrile episodes (defined as an oral temperature ³38.0°C or a rectal temperature ³38.5°C) in these children warrant a CBC, reticulocyte count, bilirubin, blood culture, and a type and screen if they are unwell. A key management principle for fever in SCD patients is to draw blood cultures and administer broad-spectrum antibiotics within what time frame of their presentation? Which antibiotics should be given in these cases?

Answer 23

Within 30 minutes of arrival (independent of focus for fever) - do not delay antibiotics if blood culture is not yet drawn).

IV (or IM) third-generation cephalosporin (e.g., ceftriaxone or cefotaxime). Levofloxacin could be substituted in settings of significant beta-lactam allergy.

Add vancomycin if the patient is clinically unstable.

Question 24

When treating SCD patients with fever, you must be mindful of what rare, but potentially fatal, antibiotic related complication? Note: this is why SCD patients should be observed for at least 2h following administration of these antibiotics.

Answer 24

Ceftriaxone-induced hemolytic reactions

Question 25

Investigating the source of fever in SCD patients should include a CXR, with further work-up as clinically indicated, without delaying antibiotic administration. Consider seasonal influenza (via NP swab) and treat appropriately. Children who meet low-risk criteria may be discharged home, following receipt of ceftriaxone, with follow up recommended within what time period?

Answer 25

Daily follow-up to ensure clinical stability and negative cultures

Question 26

Leukocytosis and leukopenia are both risk factors for sepsis. What is the WBC range considered acceptable to meet low-risk criteria for SCD and fever? Note: SCD patients with fever and either leukocytosis or leukopenia should receive broad-spectrum antibiotics until the blood culture is negative by 36-48h. Subsequent narrowing or discontinuation depend on focus of infection and clinical status. Once discharged home, and instruct parents to resume prophylactic antibiotics.

Answer 26

WBC 5-30 x109/L

Question 27

Case 2: 6 months later, Jared returns to the ED with pallor and abdominal pain. He is tachycardic, with normal blood pressure, and has a palpable spleen at 7cm below the costal margin (normal for him is 1cm). Jared’s mother, who was taught to palpate the spleen in clinic, fortunately noticed his enlarged spleen at home. Labs reveal a Hb 52 g/L (baseline 90 g/L), reticulocytosis, and mild thrombocytopenia, all consistent with a diagnosis of splenic sequestration (a potentially fatal complication of SCD). Splenic sequestration more commonly occurs before what age cut off? Why?

Answer 27

Age 5 years prior to auto-splenectomy (but it can happen at any age, particularly in children with HbSC and HbSB)

Question 28

Parents of kids with SCD are taught to palpate their child’s spleen at home, and HCP’s should document spleen size at each visit. If a patient with SCD has splenic sequestration, there is a strong indication for simple RBC transfusion of what volume? Why must blood transfusion volume be cautious in splenic sequestration?

Answer 28

Begin with 5-10 mL/kg of RBC

Sequestered blood can recirculate rapidly following transfusion, increasing risk for hyperviscosity (so monitor closely to ensure that the Hgb does not rise to >100-110 g/L)

Question 29

In SCD patients who experience multiple episodes of splenic sequestration, options for secondary prevention should be discussed with a paediatric hematologist. What are the 2 main options for secondary prevention of splenic sequestration in SCD patients?

Answer 29

i) Elective splenectomy
ii) Chronic transfusion therapy

Question 30

Case 3: Kya, who is 13 months old with SCD, presents with fever and fatigue. Hb is 40 g/L, with reticulocyte count of zero. What acute complication of SCD is heralded by signs of anemia and low reticulocyte count? How would you manage this patient?

Answer 30

Aplastic crisis

Send a blood culture and initiate ceftriaxone, request serology for parvovirus B19, and transfuse Kya with RBC 10-15 mL/kg (aplastic crisis is a strong indication for simple RBC transfusion). As more than one transfusion may be required, these patients should be closely monitored until reticulocytes begin to rise.

Question 31

Similar to other inherited hemolytic anemias, children with SCD are prone to aplastic crises. What is the most common etiologic agent of this condition? Note: this virus infects erythroid precursors in the bone marrow. Signs and symptoms are secondary to severe anemia, typically associated with an inappropriately low reticulocyte count, mild thrombocytopenia and leukopenia. Do SCD patients usually have recurrences of aplastic crises?

Answer 31

Parvovirus B19 (“fifth disease”)

No - due to the development of immunity against parvovirus B19, recurrences rarely occur

Question 32

SCD is the most common cause of paediatric stroke, with children between 2 and 9 years of age being at highest risk. As a result, what type of screening is recommended for SCD patients between ages 2 to 16 years old to identify high-risk patients for stroke? What is considered abnormal in this test?

Answer 32

Annual Transcranial Doppler (TCD) to screen for vasculopathies

Cerebral blood flow velocities >200cm/second

Question 33

Immediate management of stroke requires oxygen to maintain saturations >95%, IV hydration not exceeding a maintenance rate, and stat head imaging. A CT scan is ordered as a first-line diagnostic tool, but in cases of clinical suspicion for stroke and a negative CT scan, what imaging modality is indicated?

Answer 33

MRI with MR angiogram

Question 34

For SCD patients, what intervention is known to be highly effective for both primary and secondary stroke prevention? If a patient is confirmed to have a stroke, they are usually admitted to the ICU for an ExT, with the aim of decreasing HbS level to below what % cut off?

Answer 34

Prophylactic (chronic) blood transfusions

Aim for HbS <30%

Question 35

Case 3: At age 5, Kya re-presents in your ED with right-sided weakness and decreased level of consciousness. The most recent of her annual TCD assessments was abnormal. Brain imaging confirms a diagnosis of acute ischemic stroke (AIS). Is AIS more common than hemorrhagic stroke in SCD? Kya’s stat CT scan confirms a left middle cerebral artery AIS. She has persistent mild right-sided deficits, and her follow-up will include comprehensive rehabilitation services, a chronic transfusion program to prevent stroke recurrence, and collaborative management with a specialized centre.

Question 36

Along with chronic anemia, individuals with SCD have a high blood viscosity. Providing a blood transfusion in this context will further increase viscosity, raising risk for vascular complications. Also, compared with other transfusion patients, those with SCD are at increased risk for what immune-mediated complication?

Answer 36

Alloimmunization

Question 37

Clinicians must weigh the benefits and risks of blood transfusions in paediatric SCD patients. When a transfusion is indicated, liaising with the blood bank to optimize phenotypic matching and reduce risk for alloantibody development and other transfusion reactions is essential. Transfusions are considered for individuals with acute anemia and complications of SCD. Aside from the current Hgb number, what other information is instrumental in decision-making around the need for RBC transfusions?

Question 38

Decisions to transfuse SCD patients should be guided both by a child’s clinical status and the clinical context. In all situations, setting the post-transfusion target Hb to what limit mitigates risk for hyperviscosity? To prepare for surgical procedures involving general anesthesia, transfusions have been shown to reduce post-surgical risk for ACS and severe VOE. Be sure to liaise with the nearest paediatric hematologist to optimize peri-operative care in SCD patients.

Answer 38

Hgb <100g/L

Question 39

Clinical scenarios where the strength of recommendation is highest for providing a simple transfusion include acute splenic sequestration with severe anemia, and aplastic episodes. Note: simple transfusion may be administered to manage severely symptomatic ACS. Simple transfusion may also be considered in cases of severe anemia. How does the CPS define severe anemia for SCD patients?

Answer 39

Hb ≥20g/L below patient baseline OR absolute level <60g/L (when the baseline is unknown)

Question 40

Transfusion is not indicated for uncomplicated painful crisis in SCD patients. ExT, where the recipient’s blood is removed during the donor infusion, should always be carried out in consultation with a paediatric hematologist. The advantage of ExT over simple transfusion for ACS remains debatable, but ExT remains the preferred option in SCD patients with what disease complication?

Answer 40

Stroke

Question 41

According to the CPS, what are the 10 criteria that must be fulfilled for a patient with SCD and fever to be deemed low-risk? Note: in this setting, these low-risk patients can be managed on an outpatient basis.

Answer 41

i) Well-appearing, hemodynamically stable
ii) Fever <40°C
iii) Age >6 months
iv) WBC 5-30 x10 /L, PLAT >100 x10 /L and not significantly lower than baseline, Hb >60 g/L and not >20 g/L lower than baseline (admit when baseline is unknown)
v) No respiratory distress or CXR abnormality
vi) No clinical findings suggestive of meningitis, osteomyelitis, septic arthritis, ACS, splenic sequestration
vii) No history of pneumococcal sepsis or meningitis
viii) No significant pain or dehydration
ix) Initial visit for the episode
x) Safe for discharge, ability for close follow-up