Frequently Asked Questions (FAQs) - Questions submitted to the Web site by clinicians

Major Topics: Sickle Cell Disease , Bone Marrow and Stem Cell Transplant, Sickle Cell Trait and G6PD, Students and Teachers,  Physicians, Nurses and Health Care Providers, Sickle Cell Newborn Screening 

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IV Fluids 

Question - Why do you use D5W as your IV hydration fluid of choice?

Answer - The use of hypotonic solutions is evidenced based and the evidence comes form the 60, 70, and 80s. The principles are well established and there is unlikely to be further basic or clinical research on the issue. The principle is simple and based on the biochemistry of sickle hemoglobin polymerization and physiology. The rate of hemoglobin polymerization (sickling) is strongly dependent on the concentration of hemoglobin in the solution. This is exponential with the rate changing with the 25^th to 35^th power of the hemoglobin concentration. This means that sickling of intact sickle cells is very dependent on the concentration of hemoglobin within the red cell (MCHC).

Because the red cell is an ideal osmometer, the concentration of water inside the red cell is determined by the concentration of water outside the red cell. Most think in terms of the concentration of sodium and potassium which varies in the opposite direction. That is, when the concentration of sodium goes down outside the red cell, water goes into the red cell and the concentration of hemoglobin in the red cell (MCHC) goes down. The bottom line is that small changes in sodium concentration outside the red cell cause reduction in MCHC which markedly reduces the sickling of the red cells when the intracellular hemoglobin is Hb S. There are many articles that address this in hemoglobin solution, sickle red cells, and in clinical responses in patients. This is as evidenced based as anything we do in medicine.

There are many other very important considerations. Almost all adults and most children with sickle cell anemia have renal tubular damage which prevents them from retaining free water. They cannot concentrate their urine so the loose large volumes of free water in the kidneys every day. The kidneys handle sodium normally and because of the anemia, they then to hold on to sodium they take in. When the patient becomes ill, they often decrease their intake of fluids and become free water dehydrated which greatly increases the sickling of their red cells and the potential for complications. Your doctors can verify this in their patients because the sodium level will be 145 or higher when they come in crisis and 130 to 135 is ideal for reducing sickling without side effects.

The third problem is the misconception about blood volume. Normal saline is used is a rehydrating solution because most dehydrated patients have reduced blood volume. Because of the chronic life-long anemia, the blood volume in sickle cell patients in normal or increased. This has been measured but the studies are old. Administration of normal saline is potentially very dangerous in sickle cell patients during complications. Their plasma volume is increased, they have high cardiac demand from the anemia, and we are administering opiates that decrease cardiac output. Sodium will be retained and normal saline may precipitate heart failure.

Very young children and individuals with Hb SC and Sbeta thalassemia may have less renal damage and be better able to retain water. Individuals with renal disease also may become hyponatremic with D5W. The best solutions for them are d5w ¼ normal or 1/3 normal saline. I feel the best approach is to use one of the three and monitor the serum sodium, rather than to give a physiologically inappropriate replacement fluid (normal saline).

There is no large clinical trial that directly addresses the issue. The first reference is Guy et al In vitro and In vivo effect of hypotonic saline on the sickle phenomenon. Amer J Med Sci 266:267-277, 1973. It is also addressed indirectly in the article by Rosa et al in New Engl J Med 303:1138-1143, 1980. I don't think there will be further studies because people either believe the dogma and would consider it
unimportant and unethical or such a small benefit off low cost so it is not important enough to spend the money required to test the hypothesis. There are recent attempts to capitalize on this effect by chronically decreasing the MCHC: chlotrimazole, Magnesium, and others. The studies on this are in process.

In Children - It is true that sickle cell patients with pain usually do not have dehydration of the whole body. However, as you know, sickle erythrocytes are usually slightly dehydrated because of abnormal membrane transport. This erythrocyte dehydration is bad because sickle hemoglobin polymerization is very sensitive to intracellular hydration status (polymer formation kinetics depend on Mean Cell Hemoglobin Concentration raised to the exponent 30). Therefore, our strategy is to try to slightly overhydrate the whole body in order to also slightly overhydrate the sickle erythrocytes. We also try to use hypotonic solution, because the therapy is water not sodium. The preferred solutions are 5%Dextrose 0.2 NaCl or 5%Dextrose for children and adults.

We use IV hydration at 1.5 times the daily maintenance requirements at the start of pain treatment in the emergency department and the hospital.  After a day or two, we then decrease to just the maintenance requirement rate.

The only caveat is overhydration during sickle acute chest syndrome. Overhydration will probably cause any regions of pneumonitis to develop
pulmonary edema. For patients with infiltrate on chest roentgenogram, our
strategy is to start with IV hydration at maintenance.

All of these practices are our preferences, based on theory and experience
and because we have IV hydration readily available. We admit that they
have not been tested with formal clinical trials. I have heard from
colleagues in Jamaica, Cuba, and Ghana that they do not use IV hydration
for sickle pain management for reasons of economics.

Life Expectancy

Question: What is the average life expectancy for  some one with sickle cell disease?

Answer: Median survival of individuals of all ages with sickle cell disease based on genotype and sex (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 330(23): 1639-1644 (1994). 

Sex and Genotype Median Survival
Males with Hb SS  - 42 years
Females with Hb SS - 48 years
Males with Hb SC - 60 years
Females with Hb SC - 68 years

Note that this was reported in 1994. Now in 2002 many new advances with the medication hydrea, the new pneumoccocal vaccine Prevnar, stroke prevention with TCD, and cures with bone marrow transplants the life expectancy is increasing.

 Splenic Sequestration

Question: I am caring for a 1 9/12 y old girl with sickle cell anemia, and now with splenic sequestration. Is chronic transfusion still the treatment of choice in this age group?

Answer: generally, yes. There does not appear to be a consensus of expert practice, but three general approaches. Some experts proceed to splenectomy at this age, others wait to allow a bit of additional maturation of the immune system before splenectomy, and others are trying to find ways to preserve some spleen immune function by performing partial splenectomy.

At our center we would put such a patient on monthly transfusion if there has been one life-threatening splenic sequestration or two episodes of splenic sequestration symptomatic enough to require RBC transfusion. Monthly transfusions would not have a specific hemoglobin goal, nor a target percentage of HbA. Instead, the therapeutic goal is to provide some amount of normal RBC so that acute splenic sequestration will not have a life-threatening recurrence. Splenomegaly usually persists on this transfusion program, and the spleen can fluctuate in size with some dips in the Hb and platelet count, but without symptoms. Our timing approach
is to continue transfusions through age 24 months, then we immunize the patient against Strep pneumoniae (conjugate vaccine is all we have right now) and Neisseria meningitides and refer the patient for elective splenectomy. Splenectomy is timed to occur immediately after a monthly transfusion, for maximal hematologic reserve. The surgeon and anesthesiologist pay close attention to post-operative analgesia to avoid atelectasis and acute chest syndrome, and we give IV hydration until the child is drinking well.

Another approach is to perform partial splenectomy on children with splenic sequestration, in order to reduce the volume of sequestering tissue while trying to preserve some splenocytes for immune function. The Cuban sickle cell group published a few years experience showing no sepsis at all using this approach, but then gave us personal communication that there was a case of sepsis that occured since the time of publication. Very few sickle cell centers provide years and years of long-term transfusions if splenic sequestration is the only indication for transfusion. With increasing recognition that transfusional iron overload is a problem in sickle cell disease just as in thalassemia, limiting monthly transfusions to about 2 years seems to be the most reasonable wayto accomplish the treatment for splenic sequestration while avoiding ironchelation.

Are there data about hydroxyurea in children so young and in this indication?
---- I am not aware of hydroxyurea specifically for splenic sequestration, but some centers are offering hydroxyurea to children as young as 2 months (Oakland Children's Hospital, Dr. Lori Styles & Elliott Vichinsky, study in progress to attempt preservation of organ function and maintain high levels of HbF ----- discussed at meetings). Reports on hydroxyurea use for treatment of children with frequent vaso-occlusive pain often comment that spleen may have regenerated in a few patients in the group (study groups led by Drs. Win Wang - St. Jude, J. Paul Scott - Milwaukee, and Russell Ware - Duke University). However, Dr. Peter Lane and colleagues recently reported that RBC pit counts in patients on hydroxyurea did not suggest return of splenic function. Accordingly, I think that there is no strong evidence to suggest that hydroxyurea will be useful for the indication of preventing recurrence of splenic sequestration, and some weak evidence that it may persist.

Foods to Eat for Sickle Cell Patients

Question: What foods should sickle cell patients eat?

Answer: If food is taken in moderation and with a generally balanced selection of foods, I cannot think of many foodstuffs that would be hazardous to somebody with sickle cell disease.
Possible harm from excess iron if somebody already has iron overload from multiple transfusions - so there is generally no need for iron supplements in sickle cell disease. Possible harm from too much diuretic effect if excess caffeine or alcohol is taken, because the fluid lost will make dehydration more likely and more tendency for red blood cells to sickle. Be cautious with medications that tend to dehydrate the body, lower the oxygenation or slow the circulation or enhance clotting.

There is a cookbook that is available, we do not endorse it but it may be of help: Back to Our Roots : Cooking for Control of Sickle Cell Anemia and Cancer Prevention by Dawud Ujamaa
Price: $18.95

Paperback 2nd Rev edition (January 1995) Al Mai Dah Pubns; ISBN: 1884938019
This can be ordered from Amazon.com key word search - sickle cell.
We tell our patients to eat foods rich in folic acid to help build new red blood cells. We have found in a small number of patients that concentrated fish oil (Omega N3 Fatty acid) prevents pain episodes. A large national multicenter study is pending. The best success by our patients is found by staying hydrated with water, good balanced nutrition, no smoking or use of street drugs, and not
over exerting.

Avascular Necrosis Prevention

Question: What can I do to prevent or lessen the chance of avascular necrosis?

Answer: The answer to your question is difficult because there are no studies to help. I can give you some suggestions based on my experience. Exercise is good but it must be low impact for the hips and shoulders. Things that require jumping are not good and jogging is especially bad. Sitting and doing leg lifting type exercises are good as are exercises to keep the shoulders strong. Weights, if used, should be light. A multivitamin with vitamin D and calcium is a good idea. Extra calcium may be good but this should be medically supervised because too much vitamin D and Calcium can cause the calcium to become dangerously high.

Hydroxyurea (Hydrea) for Children with Sickle Cell Disease

Question: Can hydrea be used to help children with sickle cell disease?

Answer: Hydroxyurea therapy for pediatric sickle cell patients is in transitionzone between "experimental therapy" and "commonly accepted therapy." In comparison to adult sickle cell patients, the number of pediatric patients treated with hydroxyurea has been small. More teenagers have been treated with hydroxyurea than younger children. Therefore, the descriptions of side effects and crisis reduction benefits are going to change as new information comes out in the next several years of additional experience with hydroxyurea for pediatric sickle cell patients.

In general, the side effects for pediatric sickle cell patients on hydroxyurea look like they are the same as for adult patients:
1) COMMON: MILD NAUSEA OR UPSET STOMACH - many patients have this only for the first few weeks at certain dose, then the nausea goes away. Sometimes nausea is less troublesome if the hydroxyurea is taken at bedtime.
2) COMMON: SUPPRESSION OF BLOOD CELL PRODUCTION - Mild suppression is an
intended side effect of hydroxyurea, but hydroxyurea dosing needs to carefully adjusted and blood cell counts (CBC) monitored frequently (we check every 2 - 4 weeks) to make sure that the suppression does not become severe. Hydroxyurea may suppress the white blood cells too much (leading to increased chances of infection), suppress platelet counts too much (leading to increased chances of bleeding), or red blood cell counts too much (leading to worse anemia, with fatigue and problems for heart & lung function).
3) POSSIBLE THINNING OF HAIR
4) POSSIBLE DARKENING OF SKIN & NAILS
5) RARE: DECREASED KIDNEY OR LIVER FUNCTION
6) RARE: OTHER SIDE EFFECTS NOT CLEARLY ATTRIBUTED TO HYDROXYUREA -
patients on hydroxyurea together with other medications sometimes report dizziness, changes in mood or thought, and other side effects. It is not clear whether these are due to the hydroxyurea or to the patient's other medications.
7) RARE: EXCESS CHANCES OF INTRACRANIAL BLEEDING unrelated to platelet counts - some concerns have been raised about this possibility, but it is not clear whether certain people had bleeding due to hydroxyurea or whether they were going to have a bleed even without hydroxyurea. All of these effects are expected to be reversible (1 thru 7) when the hydroxyurea is stopped. Generally, the medication can then be resumed at a lower dose.

There are POTENTIAL SIDE EFFECTS of long-term hydroxyurea therapy that are major worries, but have not yet emerged as definite problems. We expect that only decades of experience with large numbers of patients will be able to determine whether there are increased risks of
8) leukemia - some people on hydroxyurea for other blood disorders seem to have an increased rate of developing leukemia (cancer of white blood cells). However, it is possible that their blood disorder by itself predisposed those people to leukemia, and not the hydroxyurea treatment. Studies in groups of sickle cell patients on hydroxyurea have not revealed increased DNA damage that would make us suspicious of leukemia development.
9) birth defects - rats treated with hydroxyurea in the lab have shown a higher rate of birth defects than other rats. So far, a handful of babies have been born to mothers on hydroxyurea for sickle cell and have not had birth defects. However, the worry about the possibility of birth defects leads most doctors to give hydroxyurea only when there is no possibility of conception (males or females on hydroxyurea should abstain from sex or use excellent contracepion). It is not known whether being on hydroxyurea for a number of years and then stopping before conceiving a baby will avoid the chances of birth defects.
10) growth and development problems - people have worried that hydroxyurea will slow the growth or development of children with sickle cell disease on hydroxyurea treatment. A few years of tracking several dozen children has not revealed growth & developmen problems so far, but
longer experience is needed.

POTENTIAL LONG-TERM BENEFITS IN SICKLE CELL PROBLEMS: So far, hydroxyurea
treatment seems to be improving only certain aspects of sickle cell disease: pain, acute chest syndrome, priapism, and abnormal red blood cell stickiness to the blood vessel wall (endothelium). Hydroxyurea may not completely eliminate the painful episodes, only decrease their frequency. Small studies have shown no impact of hydroxyurea on the sickle cell damage to the spleen, and perhaps no impact in avascular necrosis of bones such as the hip & shoulder joint bones. It is not clear whether hydroxyurea will affect the risk of stroke in sickle cell disease, but studies examining this question will soon begin. Perhaps there will also be studies on effects of hydroxyurea on retinal damage, kidney damage, and other manifestations of sickle cell disease.

IN SUMMARY - hydroxyurea therapy for a child with sickle cell disease has many possible benefits, and several known risks, and several potential long-term side effects. The full details of the levels of these risks are not known at this time, and probably will not be known until there have
been many more years of experience with sickle cell hydroxyurea treatment.

I strongly recommend an individual discussion with your child's hematologist about the risks & benefits for your child. (We generally have two or three sessions to review the child's medical history and present condition and individualized risks & benefits, give some reading material on the risks & benefits, draw a panel of baseline lab tests (blood counts, vitamin B12 and folate levels, kidney function and liver function, check for hepatitis and HIV infection, test for pregnancy), and check a brain MRI scan for any signs of stroke or abnormal blood vessels that might increase the chances of bleeding in the head.) You need to have a doctor who will follow your child very closely for blood counts and monitor for hydroxyurea-related problems and for other sickle cell
problems.

ALTERNATIVES: Besides managing the complications of sickle cell disease as they occur, the only other alternatives to hydroxyurea therapy presently (July, 1998) are:
1) regular transfusions of RBC
2) bone marrow transplantation - marrow donated by an immunologically-matched (HLA-matched) brother or sister without sickle cell disease.
Both of these alternatives have major risks & major benefits and need individualized discussion with your doctor also. More treatments for sickle cell disease are in the research pipeline, but none is likely to be available outside of a clinical research trial for a couple of years.

Sickle Cell Student with a Sprain and School Guidelines

Question: I am a teacher with a student who has sickle cell disease. Do I use ice on an injury or sprain in a sickle cell patient? What else could I do to keep them well and in class.

Answer: There is no clinical study that solidly demonstrates what to do for asickle cell child with a sprain, but what we have been doing at sickle cell summer camp is a cool compress of wet towel, rather than icepack. Otherwise, the basic recommendations for school is to acknowledge that the child has sickle cell disease, but try to let him or her be as normal as possible with a few caveats:
1) avoid dehydration - allow the child to go to the drinking fountain or bring water bottle as necessary
2) allow for increased urination - may need more frequent trips to the restroom
3) allow for decreased endurance - let the child to set his or her own pace during strenuous exercise, and to take rest breaks when fatigued
4) avoid extremes of temperature - encourage child to dress in layers when the weather is changing, or when going from indoors to outdoors.
5) prompt medical attention for fever (most centers say 38.5C or 101.3F) - need to call parents to bring child for medical evaluation within a hour to rule out sepsis, get blood culture, IV or IM antibiotics
6) develop guidelines with parents for how they would like to have painful episodes managed. Often extra fluids, rest break, and Tylenol or Motrin are sufficient.
7) if child has severe sickle cell disease complications and if the family is willing, perhaps educate classmates about sickle cell disease manifestations such as jaundice, frequent medical absences, decreased endurance, and the need for peers to help the child cope with complicated sickle cell disease. On the other hand, some children have so few sickle cell problems that no special education is needed.
8) remind the family that the child should have regular medical care &
take medications as prescribed.

Leg Ulcers

Question: I am a hematologist/oncologist at the Montreal Children's Hospital and have recently assumed care of a 17 year old girl with SS disease. She
also has a chronic skin ulcer involving her medial malleolus which has
been present for several months. Needless to say it is quite painful.
It measures about 3.5 x 3.5 cm and there is no edema. There doesn't
appear to be any underlying osteomyelitis by radiographic assessment.
Her care, aside from an exchange transfusion program and a protective
dresssing, I have to admit, has been suboptimal in terms of trying to
heal the ulcer and I would like to start from scratch. I was wondering
what protocols you are using for such patients at present and whether
you have routinely incorporated the RGD matrix as part of your therapy
and if so where does it fit in with respect to other dressings, such as
wet-to-dry and hydrocolloid. Have you started using topical oxygen
regularly? Lastly, for patients without a lot of edema, to what extent
do you place them on bedrest?
Thank you in advance for taking the time to address these issues.

Answer: We have used a very conservative approach to treating leg ulcers and I feel that there are many ways to heal these ulcers that work if they are done
regularly and consistently. the care has to be meticulous and constant.
The two major factors in healing are debridement and improving blood supply
by improving venous return. The two primary ways we achieve debredment are
saline wet to dry or Duoderm dressing. The saline wet to dry will only work
if done regularly and correctly. The gauze must be cotton sticking type and
it must be allowed to dry completely and be ripped off. Many patients will
not do this because of the pain. The Duoderm works well for us but I am
sure many other semi-occlusive dressings would also work. The principle is
that an environment must be created that allows natural dissolving of the
eschar by leukocytes. We use duoderm because it seems to do this well. The
other advantage is that the dressing reduces pain for most patients. The
dressing is changed twice a week or when there is breakage and the fluid
leaks out. The patients must be warned that the ulcer will first increase
in size. This occurs because all non-viable tissue is dissolved.

The edema/blood flow problem is more difficult. I truly believe that every
ulcer could be healed in 6 to 8 weeks if the patient were placed on strict
bed rest with the leg elevated above heart level in a way that does not
restrict venous return. I have seen this repeatedly in patients at bed rest
for other problems. This is usually not practical but must still be
stressed with the patient so that they do this as much as possible. We use
Unna boots, zinc oxide paste casts, to control the edema and help provide a
healing environment in patients who are ambulatory. These are changed once
or twice a week and work fairly well. Support stockings, elevation and
elastic wraps are used in patients to prevent recurrence after healing and
occasionally in active ulcers when there is considerable edema.

All patients receive zinc oxide PO 220 mg B.I.D. RGD matrix, PDGF, and
other such preparations may well help speed healing but we have not been
able to use them because of cost.

We have not used topical oxygen because I do not believe any study of leg
ulcers that does not have a blinded control arm. Regular attention, a
number of hours of bed rest, drying and a number of other factors may be
responsible for the uncontrolled observation that oxygen helps.

I hope this information is helpful. We have a regular clinic time for leg
ulcer patients and we really sell the treatment. Our results seem good in
the patients that are regular participants but it takes time. Good Luck
with your patient.

Delayed Transfusion Reactions 

Question: Can antibodies be detected before getting a transfusion to prevent reactions?

Answer: Delayed transfusion reaction is a known risk of any red blood cell
transfusion. They commonly are a reaction to minor blood group antigens
that are not compatible between the blood donor and transfusion recipient. 

Pre-transfusion testing can miss antibodies if they have declined in
concentration because a long time has elapsed from a previous
transfusion (very common) and then the transfusion is a re-exposure that awakens the immune system to make antibodies again (anamnestic response). 
Pre-transfusion testing also cannot predict the possibility of the
person forming new antibodies in response to a transfusion.

Antibody formation is more common in sickle cell patients than in other
American patients on chronic transfusion. Risk of antibodies and
transfusion reactions can be reduced by matching for some of the minor
blood group antigens. See review of sickle cell transfusion issues by
Elliott Vichinsky (Seminars in Hematology 2001 38(1, Suppl 1):14-22 )
or recent textbooks on Transfusion Medicine.

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Last modified: June 11, 2002