Steroid Treatment for Sickle Cell Pain Crisis

Randomized Trial of High-dose Intravenous Methylprednisolone and Steroid Taper for Vaso-occlusive Crises in Sickle Cell Disease

The painful episode is the most common problem experienced by children with sickle cell disease. Although various treatments are available during painful episodes, the medication most commonly given for pain is a pain medication such as morphine. Fluids are also used. Even with these treatments, many children still have severe pain that is difficult to control. In addition to pain medications, there are other medications that may be useful. Methylprednisolone (solumedrol) and prednisone are a group of medications called steroids that may be helpful for painful episodes. These medications are known to lower the amount of inflammation (this means swelling, tenderness, and soreness) in the body. Because this medication may help with your pain, you are being asked to be a part of this study. These types of medications are used in other illnesses such as asthma, especially during times when the illness has gotten worse.

The main purpose of this study is to see if the methylprednisolone and prednisone will lower the amount of pain and the length of hospital stay.

In addition to the pain medication you will normally receive, you will be assigned to one of 2 groups: 1) the experimental group with the active form of the medicine, or 2) a comparison group without the active form of the medicine. In either group, you will still receive all of the treatments you would normally receive for a painful episode, including pain medicines and fluids. You and your doctors will not know what group you will be assigned.

If you decide to be a part of the study the following will happen:

For the first 5 days, you will be asked to: 1) describe your current pain (0=no pain to 10=a lot of pain), worst pain (0=no pain to 10=a lot of pain), least pain (0=no pain to 10=a lot of pain), and the amount of pain relief (0=no relief to 10=complete relief); 2) describe any signs or symptoms you feel, including filling out a pain scale form each day; 3) and take the medicines for 5 days, either at home or when in the hospital. Thirty days after the study, a study researcher will call and will ask questions about your pain, any painful episodes, and any medications you had. If you are discharged home sooner than 5 days after the start of the study, research staff will call you to ask you these questions, remind you to fill out your pain forms, and remind you to take your medicine. If you are discharged home, you will be given pain scales to fill out each day at home.

Study Overview

• Status: Terminated
• Conditions: Sickle Cell Disease; Vaso-occlusive Crisis
• Intervention / Treatment: Drug: Steroid arm; Other: Placebo

Detailed Description

In the United States, 9% of African Americans have sickle cell trait and 1 in 600 has sickle cell disease. Vaso- occlusive crises in sickle cell disease remain a frequent cause of severe pain, leading to emergency room visits, hospitalizations, and dependence upon narcotics for analgesia. Current treatments for vaso-occlusive crises includes IV analgesia with narcotics, NSAIDS, and hydration. Admissions can be frequent, prolonged, and can significantly diminish quality of life.

Understanding the pathophysiology of vaso-occlusive crises helps to find possible treatments. The etiology of vaso- occlusive crises includes HbS polymerization; sickle erythrocyte polymerization; endothelial damage; and inflammation, reperfusion injury, and oxidant radical production (Steinberg et al, Hematology, 2004). For example, hydroxyurea works by increasing the amount of fetal hemoglobin (HbF) and thus inhibiting polymerization, and reduces the incidence of pain by nearly 50%. Glucocorticoids would be expected to exert effects on the endothelium and inflammation.

Vaso-occlusive crises share similar features with other inflammatory processes, including clinical symptoms of swelling, erythema, and warmth; and laboratory findings of leukocytosis and elevated ESR. It has previously been theorized that glucocorticoids, which are used in many other inflammatory disorders, could decrease the duration or severity of vaso-occlusive crises. Methylprednisolone is a corticosteroid which decreases inflammation by suppression of migration of polymorphonuclear leukocytes and reversal of increased capillary permeability (Takemoto, et al 2004). A randomized, placebo-controlled study of 2 doses of intravenous methylprednisolone for vaso-occlusive crisis showed that the duration of severe pain and the need for inpatient analgesia was decreased in patients who received methylprednisolone; however the intervention patients had more rebound attacks than those who received placebo. (Griffin et al, NEJM, 1994)

Previous studies have examined long-term administration of steroid hormones including testosterone, progesterone, and medroxyprogesterone to patients with sickle cell disease. In placebo-controlled crossover trials, patients who received steroids had fewer vaso-occlusive episodes than placebo-treated patients (Isaacs et al, Lancet,1972; DeCeulaer et al, Lancet, 1982). Initial reports of glucocorticoids for vaso-occlusive crisis include an uncontrolled report of hydrocortisone as adjunctive therapy for VOC (Araujo et al, Blood, 1990). A case report showed efficacy of dexamethasone for vaso-occlusive crisis in children (Robinson et al, Lancet, 1979). The mechanism of steroids effect is uncertain.

In acute chest syndrome, which shares many clinical features with vaso-occlusive crises, intravenous therapy with dexamethasone has been shown to reduce the length of hospital stay, prevent clinical deterioration, and reduce the need for blood transfusion (Bernini et al, Blood, 1998).

In a placebo-controlled trial of high-does methylprednisolone for VOC, patients with severe pain requiring hospital admission were randomized to receive methylprednisolone or placebo (15 mg/kg to maximum 1 gram) at admission and again 24 hours later. The duration of inpatient analgesia was significantly shorter in patients who received methylprednisolone. However, patients who received methylprednisolone were much more likely to be readmitted shortly after finishing therapy. In addition, the study was criticized because patients did not rate their pain, and very few patients received patient-controlled analgesia while hospitalized.

Since this trial was published, there have been other advances in the standard management of VOC. Ketorolac, a non-steroidal analgesic, is now a standard adjunctive therapy, and most patients are quickly placed on patient-controlled analgesia. In addition, more patients now receive chronic, preventative therapies such as hydroxyurea and chronic transfusions.

We are therefore interested in repeating and expanding upon the results obtained several years ago and in evaluating the role of steroids if given over a slightly longer period of time.

The primary objective of this study is to determine whether the use of high-dose methylprednisolone followed by steroid taper decreases the duration of hospitalization and severity of pain in VOC of sickle cell disease.

Primary Hypothesis: The experimental group treated with high-dose methylprednisolone and steroid taper plus conventional therapy will have an improvement in pain scores using a 10-point scale.

In addition, the secondary objectives were:

1. duration of inpatient admissions
2. to examine the number and type of complications and side effects (infection, hypertension, and GI bleeding)
3. to determine rate of recurrent episodes of pain within one month of treatment.
4. to determine whether the amount of analgesic used will decrease during the hospitalization, as measured by the # of days in which IV opioids were given.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Childrens Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Sickle cell and acute pain Age 8 and up English or Spanish-speaking

Exclusion Criteria:

Fever greater than 101 Acute chest syndrome or pneumonia Other SS complications (sequestration, aplastic crisis) Other explanation for pain (chronic, AVN, surgical) History of GI bleeding, HTN, or hyperglycemia/DM

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Steroid arm; Receipt of methyprednisolone pulse dose: 15mg/kg to a maximum of 1 gram; following this, the patients also received a steroid taper with oral prednisone:Day 2: Prednisone 2mg/kg PO BID Day 3: Prednisone 2mg/kg PO daily Day 4: Prednisone 1mg/kg PO daily Day 5: Prednisone 1mg/kg PO daily	Drug: Steroid arm; Day 1: Solumedrol 15 mg/kg (maximum 1 gram) Day 2: Prednisone 2mg/kg PO BID Day 3: Prednisone 2mg/kg PO daily Day 4: Prednisone 1mg/kg PO daily Day 5: Prednisone 1mg/kg PO daily; Other Names: Systemic corticosteroid receipt
Placebo Comparator: Comparison Group; Patients receiving usual care, with receipt of placebo (saline in lieu of intravenous methylprednisolone infusion or a number of placebo pills equivalent in number to what would have been received for the prednisone.	Other: Placebo; Patients received normal saline in lieu of intravenously-administered methylprednisolone and placebo pills equal in number to the steroid pills received in the steroid arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain Scores	Severity of pain using a 10-point scale ranging from 1-10, with higher numbers corresponding to worsening pain.	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Hospitalization	Length of stay (from emergency department arrival to discharge from the inpatient unit), in days, through hospitalization, up to 15 days	Through hospitalization, up to 15 days
Number of Participants With Complications and Adverse Events	To describe adverse events, including infection, hypertension, and/or GI bleeding	30 days
Number of Participants With Recurrent Episodes of Pain Within 1 Month of Treatment	Number of recurrent episodes of pain within 1 month of treatment	30 days
Number of Days Analgesia Used	# of days during which the child received parenterally-administered opioids through hospitalization, up to 15 days.	Through hospitalization, up to 15 days

Collaborators and Investigators

• Sponsor: Baylor College of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2005
• Primary Completion (Actual): June 13, 2008
• Study Completion (Actual): June 13, 2008

Study Registration Dates

• First Submitted: December 8, 2005
• First Submitted That Met QC Criteria: December 8, 2005
• First Posted (Estimate): December 9, 2005

Study Record Updates

• Last Update Posted (Actual): July 7, 2020
• Last Update Submitted That Met QC Criteria: June 22, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: vaso-occlusive crisis; Sickle cell disease; steroid treatment
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell
• Other Study ID Numbers: H-17689

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No