Overview of Complications Seen in Pediatric Sickle Cell Disease Patients and How to Manage Them in the Emergency Department

It is estimated there are around 100,000 individuals living in the United States with sickle cell disease (SCD).

The majority are of African ancestry with a minority being Hispanic, Middle Eastern, or Asian Indian descent. In addition, there are estimated to be 3.5 million people in the U.S. who are heterozygous carriers.¹

Patients with SCD predominantly have sickle hemoglobin present in their red blood cells because of the amino acid substitution of valine for glutamic acid at the 6^th position on the beta-globin chain. This substitution causes the red blood cells to develop a sickle shape and become inflexible in deoxygenated conditions, leading to increased blood viscosity as well as abnormal interactions with other cells in systemic circulation. Patients with sickle cell disease are predisposed to a variety of complications.¹

Things to ask every patient with sickle cell disease
Any patient with a history of SCD should be asked what their typical pain crisis looks like and how their current pain varies. When obtaining a review of systems, it is important to ask if the patient has recently had a fever. Knowing the patient’s transfusion history and baseline hemoglobin level will help guide clinical decision-making.²

PEARL: Of note, patients with SCD (hemoglobin SS disease much less common HbSβ0-thalassemia) typically present earlier and with more severe symptoms.¹

Clinical Cases to Highlight Complications of SCD

Pain
A 16-year-old male presents to the ED for acute pain crisis. He has a history of Hemoglobin SS disease.

He is on hydroxyurea for suppression therapy. He reports his current home pain regimen of first line ibuprofen and second line oxycodone have not controlled his current pain episode. He typically has severe bilateral lower extremity pain with his previous crises. Today he is presenting for similar symptoms.

Acute pain crisis (APC) is pain caused by vaso-occlusion and can involve any body system. Fever and leukocytosis frequently occur with APC and warrant an infectious investigation if present, given SCD patients’ high susceptibility to pathogens.

Established pain protocols
The National Heart, Lung and Blood Institute (NHLBI) have established guidelines for the management of APC. They recommend initiation of analgesia within 60 minutes of registration or 30 minutes of triage to the ED.⁴ The use of IV opioid is considered first line for APC pain management. NSAIDs should be used in conjunction with opioid therapy. The use of APC patient-management protocols are recommended to give a standardized approach for providers in the same hospital system.² Studies show the protocols decrease time to delivery of pain medication, decrease frequency of ED visits, result in fewer hospital days, and increase utilization of patients’ primary provider for follow-up services.⁴

Pain management strategies that need further investigation
Akinsola et al. found that use of intranasal fentanyl decreased the time to first parenteral opioid in the emergency department, but overall did not show significant decrease in overall pain scores or admission rates. The investigators concluded intranasal fentanyl may be a useful temporizing measure for pain control until IV access can be established.⁵

Things to avoid: The use of supplemental oxygen is not recommended unless oxygen saturations are less than 92%.² Euvolemia should be maintained. The use of normal saline boluses has not been shown to reduce pain scores or admission rates.⁶ Excessive hydration can lead to atelectasis, hyperchloremic metabolic acidosis and pulmonary edema.² Ketamine infusions are currently being utilized and investigated as a pain control option. Hagedorn et al performed a literature review which showed ketamine was useful in reducing pain scores, but not enough data is currently available for specific clinical recommendations.⁷

Discharge can be considered if pain is adequately controlled. Patients should be discharged home with an oral equivalent of the IV pain regimen provided while in the ED. If adequate pain control cannot be achieved the patient should be admitted for further management.²

Fever
A 2-year-old female with history of hemoglobin SS disease presents with fever of 102⁰F at home.

Family has been intermittently compliant with home penicillin prophylaxis. Family reports no recent cough, congestion, or other URI symptoms, and no sick contacts. Toddler is non-toxic on exam with no focal findings.

Fever in infants < 60 days: Proceed to complete full work-up per institutional guidelines. Use of Rochester criteria or home institution algorithm can help guide limited workup with discharge versus full workup with antibiotics and admission. All infants under 29 days of age warrant a CBC, CMP, CRP (or other inflammatory marker), blood culture, UA with urine culture and lumbar puncture. Providers should consider viral testing (to include HSV) and CXR on a case-by-case basis.⁸

PEARL: The NHLBI recommend oral penicillin prophylaxis until 5 years of age in all children with hemoglobin SS disease.³

Fever in infants > 60 days through 5 years: Children under age 5 with SCD should be on daily prophylactic penicillin. Compliance with this regimen should be elicited during the H&P to help risk stratify these children. Vaccination history is also an important component since these children are at increased risk for bacterial infections.¹⁰ Given their increased risk for Streptococcus pneumoniae infections along with Haemophilus influenzae, Neisseria meningitides, and Salmonellae infections, all children under 5 with hemoglobin SS disease should receive antibiotics that cover pneumococcus such as ceftriaxone (50-75 mg/kg/dose every 24 hours).^9,13

PEARL: Urine culture should be obtained in any febrile pediatric patient with SCD complaining of urinary symptoms.³

Fever in children over 5 years: Any child presenting with a fever of 101.3 ⁰ F warrants prompt evaluation to include history and physical, CBC and blood culture. If urinary symptoms are present a urine culture should also be obtained. Most patients with SCD who lack high risk criteria can be managed as an outpatient after administration of IV ceftriaxone. Patients are considered high risk if: white blood cell could greater than 30,000 or less than 5,000, fever is greater than or equal to103.1⁰ F or they are ill-appearing.³

PEARL: Any SCD patient presenting with a fever ≥103.1⁰ F who are ill-appearing warrant hospital admission with IV antibiotics.¹

Pulmonary
A 6-year-old male with history of SCD presents with fever, cough and difficulty breathing. He is tachypneic with course breath sounds on exam.

Acute chest syndrome (ACS) has a classic triad of fever, hypoxia, and a new infiltrate on chest x-ray. Any SCD patient presenting with respiratory symptoms accompanied by chest pain and are hypoxic should alert the provider to consider ACS in the differential diagnosis. Children with SCD can also have pulmonary acute pain crisis. In pulmonary APC children present with a constellation of chest pain, fever, and shortness of breath like that seen in ACS but do not have an infiltrate on CXR and are not hypoxic. Pain should be managed aggressively in these patients since splitting can lead to atelectasis and pneumonia. Patients diagnosed with ACS should be admitted for close monitoring and symptom management. Antibiotics for community acquired pneumonia should be started and aggressive pulmonary toilet should be utilized.²

PEARL: SCD patients presenting with chest pain, hypoxia and respiratory distress who lack fever or specific chest x-ray findings should warrant consideration of obtaining a CT to evaluate for pulmonary embolism.¹⁰

Neurologic
A 16-year-old female with history of hemoglobin SS disease presents with new-onset slurred speech and right-sided weakness.

She was in her normal state of health until she started experiencing these symptoms at school earlier today. EMS was called and she was transported to your department. She has no recent history of head trauma and is non-toxic on exam. Vital signs are within normal limits. Physical exam exhibits an aphasic teenager who is cooperative but anxious on exam. She has 3/5 strength in her upper and lower right extremities. Normal strength on the left. Cranial nerves are grossly intact, she has no ataxia or abnormal cerebellar testing. Her blood glucose is 70 by POC glucometer.

Stroke: Stroke and silent cerebral infarcts are the most common permanent sequelae of SCD in children and adults. Acute stroke evaluation should be considered in any SCD patient presenting with severe headache, altered level of consciousness, seizures, speech problems, and/or paralysis. A neurology consult should be obtained as well as head CT and MRI as well as MRA when available.³ ASH guidelines recommend blood transfusion to achieve a hemoglobin of 10 g/dL or exchange transfusion in any child with SCD presenting with acute neurological deficits including TIA. The decision to transfuse should not solely rely on MRI results but the entire clinical picture.¹¹

Subarachnoid hemorrhage: Children with SCD are at increased risk for cerebral aneurysms which can rupture and result in subarachnoid hemorrhage. Aneurysms are more commonly found in posterior or vestibular circulation when compared to the general population. This diagnosis should be considered in any patient presenting with sudden severe headache, nausea, vomiting, symptoms of meningeal irritation, photophobia or other visual changes, behavior changes or loss of consciousness. If neurosurgical intervention is required, it is recommended to give a blood transfusion to prevent anesthesia complications.¹⁰

PEARL: Consider cerebral venous sinus thrombosis in symptomatic patient with SCD and negative neuroimaging.¹²

Ophthalmologic
A 15-year-old male presents with decreased vision in his right eye.

On exam there is a fluid level appreciated in his anterior chamber. The right eye is also injected and actively tearing on exam. He endorses significant pain from the right eye. Upon review of history, he was recently in a fist fight at school where he did receive a blow to the face.

Acute glaucoma after eye injury: Patients who sustain direct or blunt force trauma to the eye orbit are at risk hyphema. The accumulation of blood in the anterior chamber allows for sickling and the blockage of trabecular meshwork which can lead to the development of acute closed angle glaucoma. Patients present with a painful red eye and may have obvious blood on inspection or with slit lamp examination.¹³ Urgent ophthalmology consultation should be obtained.

Central Retinal artery occlusion: Presents with sudden painless vision loss in one or both eyes. No specific therapy has been characterized for management, but goal should be to optimize oxygen delivery and blood flow to prevent further ischemia while obtaining an ophthalmology consult. Most individuals affected by this will only have partial if any vision recovery.¹⁰

Orbital wall infarct: Typically, a younger patient, due to increased marrow space in facial bones, will present with eye pain, periorbital edema, proptosis, visual acuity changes, fever and/or headache. Symptomatology overlaps with presentation of periorbital or orbital cellulitis and orbital abscess. Imaging should be obtained by CT or MRI. Treatment is supportive with IV hydration and pain control and ophthalmology consultation.¹⁰

Gastrointestinal
A 10-year-old male with SCD presents with new-onset right upper quadrant pain. He has had nausea and non-bilious non-bloody emesis.

He denies any diarrhea or urinary symptoms. He is tender to palpation in the right upper quadrant without rebound or guarding.

Children with SCD can have any of the common etiologies of abdominal pain such as constipation, reflux, or acute gastroenteritis but they also are at risk for multiple other abdominal pathologies. In the setting of new onset abdominal pain, the clinician must consider: cholelithiasis, cholecystitis, acute intrahepatic cholestasis, acute sickle hepatic crisis and acute hepatic sequestration.² Children with SCD are also at increased risk of pica which in rare instance can lead to ingestion of nonfood items that accumulate and cause a bezoar.¹⁴ In addition to a thorough history and physical exam initial studies should include a CBC, liver function test, coagulation studies (PT, PTT, INR). Further evaluation with imaging should include an ultrasound or CT.² Children with SCD are at increased risk of gallbladder and hepatic pathologies due to the increased hemolysis leading to the formation of pigmented gallstones and hepatic congestion. Below is a review of some of the hepatic complications:

Acute intrahepatic cholestasis: Sickled red blood cells can cause vascular stasis in the hepatic sinusoids. Patients can present with isolated hyperbilirubinemia, RUQ pain with or without other liver function derangements. Renal failure and coagulopathies can be present in severe cases. Consultation of hematology should be considered for possible exchange transfusion.²

Acute sickle hepatic crisis: Patients present like cholecystitis to include RUQ pain, fever, leukocytosis and transaminitis in addition to hepatomegaly. Management is conservative with pain control and possible blood transfusion.²

Acute hepatic sequestration can occur with acute sickle hepatic crisis. Includes the symptomatology mentioned as well as an acute drop in hemoglobin and hematocrit with a reticulocytotic. Treatment should include consultation with hematology for simple versus exchange transfusion.²

Genitourinary
An 8-year-old male with history of SCD presents for an erection lasting greater than 4 hours.

Priapism: Ischemic priapism is the most common form of priapism encountered in SCD patients. It is due to the low flow or venous occlusion. Patients present with rigid, painful corpus cavernosa. Ischemic priapism is a medical emergency and can be distinguished from non-ischemic priapism with a corpus cavernosum venous blood gas. The blood gas typical shows an acidosis with pH < 7.25, PO2 < 30 and PCO2 of > 60. Treatment involves needle aspiration of blood from the cavernosa followed by intercavernosal injection of a sympathomimetic such as phenylephrine. Urology consultation is recommended for providers unfamiliar with this procedure.²

Sickle cell nephropathy and renal infarct: Depending on which part of the kidney is affected by the occlusion will determine clinical presentation. IF the renal medulla is involved the patient will present with flank pain and costovertebral angle tenderness on exam.² If there is papillary necrosis the patient will present with painful gross or microscopic hematuria.¹⁴ Either presentation can result in renal dysfunction which should be managed with IVF hydration. Serial examination of renal function is recommended.²

Hematologic
A 3-year-old female with history of hemoglobin SS disease presents for pallor, difficulty breathing and fatigue.

Per family patient had been in her normal state of health but when she woke up this morning mom felt she looked very pale. She has shown less interest in play and has only wanted to rest today. She also appears to be breathing harder than usual. On exam she has a palpable spleen 5cm below the costal margin. She is tachycardic and tachypneic.

Splenic sequestration: Defined by a drop in hemoglobin greater than or equal to 2g/dL below patient’s baseline and acute increase in spleen size with an elevated reticulocyte count. Patients typically present with abdominal pain and/or fullness pallor and lethargy. They will have splenomegaly on exam with tachycardia and potentially other signs of hypovolemic shock. Treatment is with blood transfusion.¹⁴

Aplastic crisis: Infection with parvovirus B19 can induce transient red cell aplasia. Due to the shortened lifespan of red blood cells in SCD patients they are at increased risk for significant drops in hemoglobin. Patients can present with a viral syndrome of gradual onset of pallor, fatigue, and headache. In extreme cases patients may present in hypovolemic shock. This clinical presentation can be differentiated from splenic sequestration with normal spleen size and low reticulocyte count. Treatment is slow blood transfusion.¹⁰

Summary
Patients with SCD presenting to the ED are at risk for unique complications but can also have garden-variety diagnoses. It is important for the clinician to take into consideration the entire clinical picture and obtain appropriate diagnostics based on recommended practice guidelines.

References

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. Journal of the American Medical Association. 2014;312(10):1034-1048.
2. Simon E, Long B, Koyfman A. Emergency Medicine Management of Sickle Cell Disease Complications: An Evidence- Based Update. The Journal of Emergency Medicine. 2016;51(4):370-381. doi:10.1016/j.jemermed.2016.05.042
3. Buchanan G, Yawn B. Evidence Based Management of Sickle Cell Disease. National Heart Lung and Blood Institute. https://www.nhlbi.nih.gov/sites/default/files/media/docs/sickle-cell-disease-report%20020816_0.pdf. Published 2014. Accessed December 16, 2020.
4. Muslu CS, Kopetsky M, Nimmer M, Visotcky A, Fraser R, Brousseau DC. The association between timely opioid administration and hospitalization in children with sickle cell disease presenting to the emergency department in acute pain. Pediatric Blood and Cancer. 2020. doi:10.1002/pbc.28268
5. Akinsola B, Hagborn R, Zitmtrovich A, et al. Impact of intranasal fentanyl in nurse initiated protocols for sickle cell vaso‐occlusive pain episodes in a pediatric emergency department. American Journal of Hematology. 2018. doi:10.1002/ajh.25144
6. Carden MA, Brousseau DC, et al. Normal Saline Bolus Use in Pediatric Emergency Departments is Associated with Worse Pain Control in Children with Sickle Cell Anemia and Vaso-occlusive Pain. American Journal of Hematology. 2019;94(6):689-696. doi:10.1002/ajh.25471
7. Hagedorn JM, Monico EC. Ketamine Infusion for Pain Control in Acute Pediatric Sickle Cell Painful Crises. Pediatric Emergency Care. 2019;35(1):78-79. www.pec-online.com. Accessed December 16, 2020.
8. Jaskiewicz JA, McCarthy CA, et al. Febrile Infants at Low Risk for Serious Bacterial Infection- An Appraisal of the Rochester Criteria and Implementation for Management. Pediatrics. 1994;94(3):390-396. www.aappublications.org/news. Accessed December 16, 2020.
9. Inusa BPD, Hsu LL, et al. Sickle Cell Disease—Genetics, Pathophysiology, Clinical Presentation and Treatment. International Journal of Neonatal Screening. 2019;5(2). doi:10.3390/ijns5020020
10. Brandow AM, Liem R. Sickle Cell Disease in the Emergency Department: Atypical Complications and Management. Clinical Pediatric Emergency Medicine. 2011;12(3). doi:10.1016/j.cpem.2011.07.003
11. DeBaun MR, Jordan LC, et al. American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults. Blood Advances. 2020;4(8):1554-1588. doi:10.1182/bloodadvances.2019001142
12. Hines PC, McKnight TP, et al. Central Nervous System Events in Children with Sickle Cell Disease Presenting Acutely with Headache. The Journal of Pediatrics. 2011;159(3). www.jpeds.com. Accessed December 16, 2020.
13. Izsack, E. and Strunk, C., 2020. Sickle Cell Disease. [podcast] Peds RAP. Available at: <https://www.hippoed.com/peds/rap/episode/pedsnovember/sicklecell> [Accessed 16 December 2020].
14. Rhodes MM, Bates DG. Abdominal Pain in Children with Sickle Cell Disease. Journal Clinical Gastroenterology. 2014;48(2):99-105. www.jcpe.com. Accessed December 16, 2020.