Sickle Cell

The Outcome of Preoperative Transfusion Therapy in Sickle Cell Disease Patients Undergoing Surgery: A survey of Practice in Saudi Arabia

Sickle cell disease was first discovered and described in 1904, in a dentistry student in Chicago (Savitt & Goldberg 1989). Admitted to a hospital suffering from “anemia,” Walter Clement Noel — a wealthy man from the West Indies in his first year of study towards becoming a dentist — was examined by Dr. James B. Herrick, who noticed, “peculiar elongated an sickle-shaped” red blood cells in his patient’s samples (Savitt & Goldberg 1989). Though it would be some time before the disorder was more fully understood, and indeed the symptoms of sickle cell and been noted decades prior to Herrick’s discovery, this was the beginning of identifying the underlying cause of the disease (Saviit & Goldberg 1989).

A specific mutation to the HBB gene leads to the development of sickle cell disease, leading to a malformation of the beta-globin component of hemoglobin known as hemoglobin S, or HbS (NIH 2010). HbS is formed when valine is substituted for glutamic acid in part of the beta-globin formation; other often concurrent mutations in the HBB gene can also lead to an under-production of beta-globin, which leads to a separate yet often comorbid disorder of thalassemia (NIH 2010). Many more individuals are heterozygous for this trait and show typically show no symptoms than are homozygous for the mutation, which leads to a much higher prevalence of the gene in the gene pool due to a lack of symptom presentation and much longer lives without treatment compared to those that present symptoms (NIH 2010).

The actual physical shape of the malformed red blood cells — the sickling caused by the incorrect synthesis of the beta-globin that forms HbS instead — is the mechanism by which the symptoms of sickle cell disease are caused. Not only do these cells fail to carry and deliver oxygen as healthy red blood cells do, but they have a tendency to become trapped in capillaries and obstruct blood flow (WHO 2006). This can lead to acute chest syndrome, where a combination of low oxygen and reduced blood flow to the lungs cause severe respiration difficulties (WHO 2006). Sickled cells also have a tendency to gather in the spleen, especially in young children with the disease, causing enlarged spleens and a lack of spleen functionality, both of which can lead to complications resulting in death either from additional infections or through sudden and profound anemia brought on by the enlargement (WHO 2006).

The infections that can be caused by reduced spleen function present only one of the many complications that can arise out of sickle cell disease. Anemia and vasculopathy are the primary and hallmark symptoms of sickle cell disease, yet the acute painful syndromes and acute chest syndromes are more frequent causes of mortality resulting from the disease (NIH 2006). Severe anemia can be exacerbated or triggered during surgical events, as well, when reduced blood volume coupled with the low oxygen capacity of a sickle cell disease patient’s blood leads to greatly reduced oxygenation throughout the body (Buck et al. 2005). General organ failure as a result of reduced blood flow and/or lack of oxygen supply can also trigger mortality and is a fairly common complication (NIH 2010).

There are several different diagnostic methods and tests that can be employed to determine if an individual has sickle cell disease, including complete blood count tests (CBCs) and measures of oxygen saturation, though these are not conclusive in and of themselves (NIH 2010). Other methods that are more conclusive include Hb electrophoresis, which analyzes the movement of red blood cells in the blood stream and can identify the unique movement patterns of sickled cells, simple blood films on which the sickling of cells can be directly visually observed, and newer methods of DNA analysis to determine the presence (or lack thereof) of the disease-causing mutation on the HBB gene (Saiki et al. 1985). DNA testing techniques can be utilized for testing in utero fetuses, leading to potentially fewer births of affected children depending on ethical perspectives (WHO 2006).

Cholecystectomy, the removal of the gall bladder, is the most common surgical procedure performed on individuals with sickle cell disease as a result of their tendency to form large and pigmented gallstones, which can cause immense pain and are potentially life0hreatening (Haberkern et al. 1997). Other common surgeries include total hip replacements, adenotonsellectomies, and splenectomies; some of these surgeries — especially splenectomies and cholecystectomies — can now be performed laproscopcailly, reducing blood loss during the operations and thus minimizing risks to the patient that are a result of the drop in blood volume added to the already-low oxygen saturation that is characteristic of many individuals with sickle cell disease (Buck et al. 2005; Vichinsky et al. 1995).

The perioperative complication associated with sickle cell disease have led to several different transfusion and transfusion-exchange methods meant to minimize the risks to patients with sickle cell disease undergoing surgery, but as of yet there is no medical consensus in this area (Buck et al. 2005; Vichinsky et al. 1995; Haberkern et al. 1997; Hirst & Williamson 2001; Al-Samak et al. 2008). Some studies have found that transfusions do not cause any statistically significant improvements in post-operative success when compared to surgeries on individuals with sickle cell disease that do not have transfusions (Al-Samak et al. 2008; Buck et al. 2005; Hirst & Williamson 2001). Other studies comparing aggressive vs. conservative transfusion therapies have found little to no difference between these approaches, but imply a difference between the use of transfusion therapies and their complete preoperative absence (Hirst & Williamson 2001; Vichinsky et al. 1997).

In addition to the differences of opinion and evidence regarding the utility and benefits, if any, of perioperative and/or preoperative transfusions for patients with sickle cell disease undergoing surgery, there are also different transfusion techniques with varying degrees of study presenting different evidence as to their efficacy. These techniques can basically be divided into simple transfusions, consisting of “topups” and blood packing to ensure adequate oxygen delivery before and after surgery, and exchange transfers in which patients are bled and then receive specific amounts of saline and packed red blood cells, increasing not only the volume of blood but also the proportion of healthy red blood cells (Buck et al. 2005; Al-Samak et al. 2008).

A highly effective though still scantily-prescribed treatment for sickle cell disease is hydroxyurea, which has multiple effects on blood cell types and counts and has a significant impact on the symptoms that present with sickle-cell anemia (Ware & Aygun 2009). Specifcally, hydroxyurea — which can be administered orally with great success — greatly increases the production of fetal hemoglobin (HbF), increases the overall concentration of hemoglobin in the blood and the mean corpuscular volume allowing greater blood flow, while decreasing white blood cell count, absolute neutrophil count (ANC), absolute reticulocyte count, and lactate dehydrogenase (LDH) as well as leading to morphological changes that reduce the number of harmful deformabilities in red blood cells that are the hallmark of sickle cell disease (Ware & Aygun 2009). Despite these positive effects and the extremely low-risks associated with daily use of hydroxyurea, it remains only sparingly prescribed for adult patients and has not been approved for use with children (Ware & Aygun 2009).

Sickle cell disease is often associated with hypercoagulative activities, even when there is no injury or tear triggering such coagulation (Ataga & Key 2007). For this reason, heparin can be a useful way to manage the disease in standard care and in post-operative settings, where natural and necessary coagulative responses can cascade into detrimental levels of coagulation (Ataga & Key 2007). There is some risk involved in the use of heparin following surgery as it can lead to greater levels of bleeding, but with proper management and care these risks are easily mitigated in hospital settings (Atage & Key 2007).

Methods

For the purposes of this research, a retrospective analysis was deemed appropriate as it allowed for a longer comparative study while not requiring the length of time necessary for a purposeful clinical trial. The study’s population consisted of patients with sickle cell disease undergoing surgery at the King Fahd Hospital in Jeddah, Saudi Arabia. A variety of different surgical procedures were performed on the members of the studied population, which totaled seventy-five individuals over the past five years. Inclusion in the study was based on a review of medical records; approximately three-hundred-and-fifty to four-hundred patients consulted with the haematology department at the hospital on an annual basis, and all records were examined to select those patients with sickle cell disease that also received a surgical treatment of one kind or another in other departments of the facility.

The past medical histories of the study’s subjects, including the number and frequency of vasso-occlusive crises and acute chest syndromes, formed an important consideration for this research. Of primary concern to the research at hand was the use (or non-use) of transfusion therapies as pre- and post-operative measures and the number and severity of perioperative and postoperative complications. The use of hydroxyurea and postoperative heparin prophylaxes were also included in the recorded observations made by the researchers. Standard statistical techniques including regression analysis were used to determine the levels of correlation that existed between transfusion therapy, pharmaceutical use, and complications.

Materials

As this was a retrospective study that did not involve any direct experimentation or even direct observation, the materials used were rather minimal compared to many other clinical surveys. Patient records formed the entirety of the research materials used; these were accessed in accordance with privacy laws and ethical standards for the use of private medical information, with the records rendered anonymous prior to primary research being conducted and with full hospital permission. Records were accessed primarily electronically, though hard copies of the seventy-five case histories actually used as subjects in the study were also obtained after having been sanitized of identifying information.

Materials used in analysis were equally minimal, as the statistical analysis performed in this retrospective manner required only a computer terminal and the software necessary to perform statistical analysis after information from the seventy-five included case histories had been input as data. Standard software was used for this purpose, with the bulk of the analysis conducted using the latest available version of the SPSS software mist typically used for statistical analysis in such cases. Encryption of data was utilized to some degree, though to a fairly minimal extent as there was not considered to be a high risk of unauthorized access nor of potential damage caused by the unauthorized release of any of the data used in the study, as no personally identifying information was entered into the software program alongside the individual data points that formed the primary data for this research.

Discussion of Tables

The current literature shows a great deal of disagreement as to the benefits, if any, of various forms of perioperative and preoperative procedures as a means of reducing postoperative complications in patients with sickle cell disease undergoing surgery (Al-Samak et al. 2008; Buck et al. 2005; Hirst & Williamson 2001; Vichinsky et al. 1995; Haberken et al. 1997). It was hoped that this research would help provide more conclusive results as to the efficacy of various preoperative and perioperative treatments and their effects on postoperative outcomes, despite the relatively small sample size and the use of only a single medical institution in the retrospective analysis. As might have been expected based on previous results of similar research, however, this did not prove to be the case, and the results of this research as discussed below remain fairly inconclusive in these regards.

The preoperative and perioperative treatments that were specifically examined in this study were the administering of heparin prior to surgery, the administering of hydroxyurea as a standard course of medication and/or prior to surgery, and transfusions — whether simple transfusions or exchange transfusions — prior to and during surgery. Measures of postoperative complications that were examined in this research included levels and rates of postoperative fever, vaso-occlusive crises, acute chest syndromes, and length of hospital stay. Information regarding basic demographic, the type of surgery performed in each case, and the preoperative appearance of vaso-occlusive crises and acute chest syndromes was also collected, but was not analyzed for correlation.

The subjects in the study had a mean age of twenty-four-and-a-half years; surgery durations had a mean of sixty-seven minutes with a standard deviation of approximately forty-eight minutes, and mean hemoglobin concentration was measured at just below ten (9.9) with a standard deviation of one-point-four (1.4) following surgery, compared to a mean measure of preoperative hemoglobin levels nine-point-four (9.4) with a standard deviation of one-point-eight (1.8). Even from these preliminary statistics, it can be seen that little statistically significant variation in hemoglobin levels existed regardless of pre-, peri-, or postoperative treatment measures. Over thirty percent (30.7%) of subjects received no transfusion as a part of treatment, with approximately one-quarter each of subjects receiving a top-up transfer (26.7%) or a complete exchange transfer (25.3%) and the remaining 17.3% receiving a partial exchange transfer. Approximately ninety percent of subjects had experienced a vaso-occlusive crisis or acute chest syndrome prior to surgery (89.3% and 92.0%, respectively).

Table 1 provides a comparison of different subject groups divided by transfusion type received and postoperative outcomes. There do appear to be slight correlations between transfusion type and rates of postoperative vaso-occlusive crises and postoperative acute chest syndrome experiences, but these correlations are not strong enough to be entirely reliable given the sample size nor are they adequately supported by the methods of analysis employed. Length of stay showed the greatest degree of variation between groups, yet information regarding this variation is also inadequate for a definite correlation to be stated.

Table 2 shows a comparison of these same groups and their postoperative outcomes as correlated with hydroxyurea and heparin treatments, and the results are show even less statistically significant differences than appear in table one. There might be a slight reduction in postoperative occurrence of fever when hyrdoxyurea is used as a preoperative treatment, but again the correlation is not strong enough to derive a definitive conclusion from the available data. Levels of vaso-occlusive crisis actually show a slight rise in patients treated with heparin, as well, though again not to a statistically significant degree, meaning that even if one were to conclude (prematurely and erroneously) that hydroxyurea conferred an advantage of limiting fevers following operations, this benefit would be certainly outweighed by the dangers presented. Heparin had even less effect in all areas than hydroxyurea.

Table 3 shows the correlation between hemoglobin levels after transfusions and the presence of postoperative complications. There does appear to be a negative correlation here, meaning that the higher the levels of hemoglobin measured following a transfer, the less chance there was of there being a postoperative complication. This was less true for postoperative acute chest syndromes, and there was actually a very slight positive correlation with the duration of postoperative hospital stays — those with higher hemoglobin levels stayed slightly longer — but again this is not very statistically significant. Even the relationships that do appear to exist to a significant degree must be backed up by further research before they can be stated with confidence.

References

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Ataga, K. & Key, N. (2007). “Hypercoagulability in Sickle Cell Disease: New Approaches to an Old Problem.” Hematology.

Buck, J.: Casbard, A.; Llewelyn, C.; Johnson, T.; Davies, S. & Williamson, L. (2005). “Preoperative transfusion in sickle cell disease: a survey of practice in England.” European journal of haematology 75, pp. 14 — 21.

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Hirst, C. & Williamson, L. (2001). “Preoperative blood transfusions for sickle cell disease.” Cochrane library of systematic reviews (3), pp. 1-23.

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Saiki, R.; Scharf, S.; Faloona, F.; Muullis, K.; Horn, G.; Erlich, H. & Arnheim, N. (1985). “Enzymatic amplification of beat0globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia.” Science 230(4732), pp. 1350-4.

Savitt, T. & Goldberg, M. (1989). “Herrick’s 1910 case report of sickle cell anemia: The rest of the story.” Journal of the American medical association 261(2), pp. 266-71.

Vichinsky, E.; Haberkern, C,; Neumayr, L.; Earles, A.; Black, D.L Koshy, M.;…Iyer, R. (1995). “A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease.” New England journal of medicine 333(4), pp. 206-13.

Ware, R. & Aygun, B. (2009). “Advances in the use of hydroxyurea.” Hematology, pp. 62-9.

WHO. (2006). “Sickle cell anaemia.” World health organization: 59th world health assembly 24 April.