New advances in the treatment of sickle cell disease: focus on perioperative significance.

Sickle cell diseases comprise a group of inherited disorders that alter hemoglobin, ultimately causing hemolytic anemia and reoccurring instances of vascular occlusion that produce acute and chronic pain. Many patients with sickle cell disease require surgery for conditions associated with their disease. Painful vaso-occlusive episodes, which can be debilitating and require long hospital stays, are often precipitated by the stress of surgery. Poorly controlled postoperative pain also can worsen an impending painful crisis. Traditional therapy for patients with sickle cell disease undergoing surgery has included preoperative transfusion and postoperative opioid therapy. Recent studies have demonstrated that aggressive preoperative transfusion therapy is not beneficial over a more conservative approach. Postoperative pain control trends include nonsteroidal anti-inflammatory drugs such as ketorolac and opioid agonist-antagonist agents such as nalbuphine, as well as epidural analgesia to minimize respiratory depression. New preventive therapy for vaso-occlusive crisis includes hydroxyurea, a chemotherapeutic agent that stimulates the production of fetal hemoglobin. Inhaled nitric oxide is being used in clinical trials with success in slowing the sickling process and unsickling cells. Phase III clinical trials are in progress for 2 drugs that decrease sickling: poloxamer 188 and fructose 1-6 diphosphate. These new therapies should help improve the anesthetic course of the patient with sickle cell disease, reduce postoperative complications, and shorten hospital stays.     

Sickle cell vaso-occlusive pain crisis in adults: alternative strategies for management in the emergency department.

The gene for sickle cell disease is carried by 8% of the African-American population in the United States. The primary care physician is often called upon to recognize and treat one of the major sequelae of sickle cell disease--vaso-occlusive pain crisis. An injectable nonsteroidal anti-inflammatory drug has recently become available and may offer some improvement in outcome of vaso-occlusive pain crises. We present five case reports reviewing various current therapeutic options, including newer pharmacologic agents, and comment on alternatives to impatient management of pain crises. The use of the emergency department short-term observation unit as an alternative to hospitalization is discussed.     

The utility of screening laboratory studies in pediatric patients with sickle cell pain episodes

The purpose of this study was to determine whether blood counts discriminate between sickle cell pain episodes that lead to successful discharge from the emergency department (ED) and those that result in complications. This retrospective review compared the hemoglobin, reticulocyte count, and white blood cell count with differential during complicated and uncomplicated ED visits. Complicated visits were pain episodes followed by admission, by readmission within 48 hours, by acute chest syndrome, by an aplastic crisis, or by the administration of blood or antibiotics. There were 2 statistically important differences between complicated and uncomplicated pain episodes. Children successfully discharged were younger than those experiencing a complicated visit (8.9 v 11.2, P = 0.04). At a difference of 0.4 g/dL, the change in hemoglobin from baseline among children with complicated versus uncomplicated pain crises was not clinically useful. Routinely performed blood counts do not reliably identify the course of sickle cell pain crises.     

Hydroxyurea therapy: improving the lives of patients with sickle cell disease

Sickle cell disease anemia is an inherited blood disorder that affects many people of color in the U.S. Patients with sickle cell disease make abnormal blood cells that tend to clog and occlude blood vessels. Many sickle cell patients suffer from vaso-occlusive crisis and other complications leading to end-organ damage and failure. Hydroxyurea has been used to treat cancer patients for many years. Moreover, clinicians and researchers have determined that this medication increases fetal hemoglobin levels. Fetal hemoglobin does not interfere with sickle hemoglobin polymerization, yet prevents red blood cells from sickling. Hydroxyurea therapy significantly reduces the number of deaths from sickle cell complications. Additionally, hydroxyurea significantly reduces the number of hospitalizations, vaso-occlusive crisis, and acute chest problems; thereby reducing severity of the disease. Pediatric studies also have shown that hydroxyurea can be safely used in children.     

Fluosol in the treatment of sickle cell crisis

The enhancement of oxygen delivery to ischemic tissue has long been a goal of sickle cell treatment. Fluosol, a member of the family of compounds known as perfluorocarbons, solubilizes large volumes of oxygen which should be beneficial in vaso-occlusive crises. A clinical trial using Fluosol in the management of sickle cell crisis was undertaken in seven patients, three men and four women, aged 18–37 y, with homozygous S-S disease. Patients were randomized within 12 h of hospital admission to standard supportive care, with or without Fluosol, 20 mL/kg, given intravenously over 4–10 h. Presenting symptoms in most patients were leg and back pain. A crossover design allowed both methods of treatment to be tested in each patient. Parameters evaluated included subjective pain intensity, rapidity of pain relief, cumulative narcotic use, and duration of crisis. At 48 h, pain intensity and narcotic use were not measurably different between Fluosoltreated crises and those treated with standard supportive care. Acute toxicity, in the form of hypertension and vomiting, prompted the withdrawal of one patient, and two others experienced hematuria and worsening of back pain, respectively, following Fluosol administration. In summary, this study was not able to demonstrate that Fluosol improved treatment. Variables including the timing of drug administration, dose, and stage of crisis may need to be assessed in a larger trial before concluding that Fluosol has no role in sickle cell disease.     

Drépanocytose et réanimation

Sickle cell disease is an inherited disease characterized by the presence of an abnormal haemoglobin. It is the most prevalent genetic disease at birth in the Ile-de-France area. Internists and intensivists are involved in the management of acute complications, particularly acute vaso-occlusive crisis. Sickle cell disease can be complicated by acute vaso-occlusive crisis, chronic visceral involvement related to the ischaemic process, and infectious complications. In adults, acute vaso-occlusive crisis is the major clinical problem prompting admission to the hospital and the main cause of death. It mainly manifests by osteoarticular pain but other clinical complications can be observed such as acute chest syndrome, priapism, ischaemic or haemorrhagic stroke, abdominal pain and acute multivisceral failure. The treatment of acute vaso-occlusive crisis is symptomatic. Simple transfusion or partial exchange transfusion is required in the more severe form of vaso-occlusive crisis. The management of adult patients with sickle cell disease must be based on a multidisciplinary approach. At the present time, more than 50% of patients survive beyond the fifth decade. This better and longer life in developed countries has resulted from basic investigations and symptomatic treatments.     

Posttransfusion crises in sickle cell anemia: role of delayed hemolytic reactions to transfusion

We describe ten patients with sickle cell anemia who became acutely ill within a few days after a blood transfusion. Two patients died. In eight cases the posttransfusion detection of alloantibodies suggested that delayed hemolytic reactions to transfusion were involved in precipitating the acute illness. In some cases the illnesses mimicked vaso-occlusive crises, with bone marrow infarction, while in other cases transient biliary obstruction or transient renal insufficiency was documented. Profound anemia mimicked aplastic crises, but we observed a remarkable capacity of the bone marrow to restore the hemoglobin level without further transfusion. In view of the prevalence of delayed hemolytic transfusion reactions in these patients receiving frequent transfusions and whose red cell antigens differ from those of the white population, we suggest that efforts to more closely match recipient and donor red cell antigens would be clinically, technically, and financially advantageous. Moreover, criteria for transfusion in sickle cell anemia should be strictly scrutinized. Quantitation of transfused hemoglobin A has proved useful in confirming delayed hemolytic reactions in sickle cell disease.     

Urinary creatine: biochemical indicator for evaluation of sickle cell crises

In a patient with known sickle cell beta 0-thalassemia we measured serum lactate dehydrogenase (LD) activity and 24-h urinary creatine excretion rate as markers to evaluate sickle cell crises. We believe that a distinction based on biochemical findings can be made between hemolytic and painful vaso-occlusive sickle cell crises with muscular involvement. To assess hemolytic crises by objective biochemical measures, we have used assay of LD activity, and to assess painful crises with muscular involvement objectively, the 24-h urinary creatine excretion rate. We conclude that hemolytic crises are characterized by high serum LD activities. Furthermore, we conclude that--at least in this patient--painful crises are accompanied by high 24-h urinary creatine excretion rates. Our findings suggest that muscle involvement may play an important role in painful vaso-occlusive sickle cell crises.     

The management of sickle cell crisis pain as experienced by patients and their carers

This study sought to provide insights into the personal experiences of individuals with sickle cell disorder and nurses involved in the management of painful sickle cell crisis. The sample consisted of 10 patients who experienced hospitalization for the management of pain during sickle cell crisis and 10 nurses who have cared for patients during such crises. The method of data collection used a combination of group and individual interviews, utilizing a 'guided conversation approach'. Data analysis consisted of content analysis of transcribed interviews which resulted in the identification of the following categories of problems: poor pain management, anxieties about pethidine, loss of control, lack of individuality and playing up. The results revealed that pain control during sickle cell crisis is often inadequate, with nurses admitting that they often have to resort to 'trial and error' strategy to manage pain. The findings are discussed in terms of attitulnal and knowledge factors and an individualized approach to pain management.     

Advances in the Treatment of Sickle Cell Disease

Sickle cell disease (SCD) is a monogenic disorder that afflicts approximately 100,000 Americans and millions of people worldwide. It is characterized by hemolytic anemia, vaso-occlusive crises, relentless end-organ injury, and premature death. Currently, red blood cell transfusion and hydroxyurea are the major disease-modifying therapies available for SCD. Hematopoetic stem cell transplant is curative, but barriers to treatment are substantial and include a lack of suitable donors, immunologic transplant rejection, long-term adverse effects, prognostic uncertainty, and poor end-organ function, which is especially problematic for older patients. Gene therapy to correct the β^s point mutation is under investigation as another curative modality. Deeper insights into the pathophysiology of SCD have led to the development of novel agents that target cellular adhesion, inflammation, oxidant injury, platelets and/or coagulation, vascular tone, and hemoglobin polymerization. These agents are in preclinical and clinical trials. One such agent, L-glutamine, decreases red blood cell oxidant injury and is recently US Food and Drug Administration approved to prevent acute pain episodes of SCD in patients 5 years of age or older. The purpose of this review is to describe the currently established therapies, barriers to curative therapies, and novel therapeutic agents that can target sickle cell hemoglobin polymerization and/or its downstream sequelae. A PubMed search was conducted for articles published up to May 15, 2018, using the search terms sickle cell disease, novel treatments, hematopoietic stem cell transplantation, and gene therapy. Studies cited include case series, retrospective studies, prospective clinical trials, meta-analyses, online abstracts, and original reviews.     

Blood pressure in acute vaso-occlusive crises of sickle cell disease

OBJECTIVE: We compared blood pressure (BP) in patients with sickle cell disease (SCD)-related crises and black patients without SCD. METHODS: We retrospectively reviewed charts of emergency department (ED) patients with SCD crises in a 2-year period, recording BPs and demographic and SCD data. A cohort of consecutive black patients without SCD was compared. RESULTS: Included were 459 SCD-related visits, 187 by men and 272 by women, representing 106 patients. Women had significantly lower BP than men, diastolic BP was significantly lower in patients with hemoglobin SS disease than in those with hemoglobin SC disease, and systolic BP was significantly lower in patients with bilateral versus unilateral pain. One SCD patient had a history of hypertension. The 125 non-SCD patients, excluding 25 with a history of hypertension, had significantly higher systolic and diastolic BP than patients in SCD crisis. CONCLUSION: No patients seen in SCD crisis were hypertensive. Patients who were female, had SS disease, or had bilateral pain had lower BP. Significantly higher BP and more hypertension occurred in black patients without SCD.     

Integrative approaches to treating pain in sickle cell disease: Pre-clinical and clinical evidence

Sickle cell disease (SCD) is a genetic disorder characterized by hemolysis, end-organ damage, inflammation, and pain. Recurrent and unpredictable episodes of acute pain due to vaso-occlusive crises are a unique feature of SCD. Many patients also develop lifelong chronic pain. Opioids are the primary method of pain treatment in SCD; however, continued use is associated with several adverse effects. Integrative approaches to treating pain in SCD are increasingly being explored to prevent the side effects associated with opioids. In this review, we highlight the mechanisms of pain in SCD and describe mechanism-based integrative approaches for treating pain.     

Characteristics of pain managed at home in children and adolescents with sickle cell disease by using diary self-reports

Pain can begin in the first year of life for individuals with sickle cell disease (SCD) and continue in an unpredictably recurrent manner throughout their life span. Sickle vaso-occlusive pain (sickle pain) can also occur simultaneously with pain of other origins, complicating both assessment and management. Aims of this research were to describe the reliability and validity of a daily diary for data collection with children and adolescents with SCD and to describe characteristics of vaso-occlusive sickle pain episodes (VOE) and other pain reported by children and adolescents with SCD along with home pain management strategies. Thirty-nine children and adolescents (mean age, 10.9 +/- 3.6 years) completed diaries twice daily at home for up to 3 years (mean, 417.9 +/- 272.2 diary days) with excellent compliance. Sickle pain alone was reported on 8.4% of days (n = 1515 days), whereas other pain occurred on 2.7% of days (n = 490) and both sickle pain and other pain on 5.7% (n = 1041 days). Other pain only episodes were shorter and involved fewer sites than sickle pain only episodes. Sickle pain occurred in the extremities and hips, whereas most other pain occurred in the head-neck area. Analgesic medication was taken on 85% of days of sickle pain, whereas analgesics were taken on only 60% of days with other pain. The diary used in this study is a valid and reliable self-report tool. The use of home diaries will improve the understanding of sickle pain and its management and assist in identifying other pain syndromes that may require alternative management.     

Are there phases to the vaso-occlusive painful episode in sickle cell disease?

The purpose of this study was to describe the pain experience of children with sickle cell disease who were hospitalized for vaso-occlusive painful episodes. The pain experience, and signs and symptoms prior to admission and during hospitalization, are presented in the context of whether there is evidence to support the existence of phases to a vaso-occlusive painful episode. Children were interviewed about the onset of the painful episode and were asked to describe their pain from the day of admission to the day of discharge from the hospital. They were also observed for the absence or presence of signs and symptoms associated with the painful vaso-occlusive episode. Findings from this study provide some evidence to support previous observations related to changes during the evolution of painful episodes that may be occurring in phases (e.g., evolving, inflammatory, resolving), as previously described in adults and children. These phases had different names, although the concepts were similar.     

Acupuncture: an evaluation in the painful crises of sickle cell anaemia

An evaluation of acupuncture for pain relief was made in 10 patients with sickle cell anaemia during 16 pain crises. A model was developed in which the patient served as his own control and in which both patient and examiner were unaware of whether an acupuncture point or a sham site was treated. The results show (1) that pain relief was obtained in 15 of the 16 painful episodes regardless of whether an acupuncture point or a sham site was treated, demonstrating considerable overlap between the effects of needling acupuncture points and sham sites; (2) that needling at acupuncture points for pain relief is not significantly superior to treatment at sham sites; (3) that needling, per se, whether at acupuncture points of at sham sites can be useful for alleviating pain in sickle cell crises. The model could be useful for evaluation of pain relief by needling in other diseases.     

Alternative Agents in Pharmacological Management of Sickle Cell Pain Crisis Complicated by Acute Pancreatitis

Pain is a prominent presenting complaint in the vaso-occlusive crisis of sickle cell anemia and that of acute pancreatitis. The treatment of pain may extend for hours or days up to weeks for an episode. Treatment by pharmacotherapy often includes opiate/opioid analgesics, nonopiate analgesics and coanalgesics. Repeated acute painful episodes expose the patient to opiate induced effects. This case report describes a treatment option that was developed in order to provide effective analgesia while minimizing the iatrogenic effects produced by commonly used opioids. The use of partial agonists, mixed agonists, nonsteroidal anti-inflammatory agents and coanalgesics can provide objective and subjective analgesia without precipitating drug seeking behaviors or significant iatrogenic effects. Pain management in this clinical setting requires a balanced biopsychosocial approach.     

Red cell distribution width parallels dense red cell disappearance during painful crises in sickle cell anemia

We reported previously that painful crises in patients with sickle cell anemia are accompanied by striking decreases in the percent of densest red cells (fraction 4) when studied with isopyknic Percoll-Stractan gradients. We report that an alternative to density gradients is the red cell distribution width (RDW), an estimate of red cell size variation measured with a Coulter counter. In 17 painful crises in 12 patients with homozygous sickle cell anemia the RDWs decreased in each crisis, from an initial mean of 16.2 +/- 1.8 SD to 12.8 +/- 1.3 (P less than 0.001). In patients in whom serial measurements of both RDW and fraction 4 (very dense) red cells were taken during crisis, the two measurements declined in parallel. The decrease of RDW is a readily observable and objective laboratory concomitant of painful sickle crisis.     

Cell heterogeneity in sickle cell disease: quantitation of the erythrocyte density profile

An increasing body of experimental evidence demonstrates that intracellular hemoglobin concentration and composition is a primary determinant of pathophysiology in sickle cell disease. To quantitate more precisely the heterogeneous distribution of intracellular hemoglobin concentrations in a given individual with this disease, we have calibrated the phthalate ester separation technique by using discontinuous Stractan density gradients to isolate subpopulations of red cells of relatively uniform corpuscular hemoglobin concentration values. We find that blood from individuals with sickle cell anemia exhibits a markedly broader distribution of corpuscular hemoglobin concentration values, containing both very light and very dense cells, than the red cell density profile from normal individuals. This increased breadth of cell densities in patients with sickle cell anemia remains even after exclusion of the very light and very dense subpopulations. In patients with stable sickle cell anemia, there appears to be minimal variation in the distribution of cell densities that are unimodal but skewed toward higher density values. The phthalate ester method can conveniently be used to follow changes in cell densities during vaso-occlusive events, to monitor therapy targeted at modifying intracellular hemoglobin S concentrations, and in sequential applications in large field trials designed to determine the relationship between red cell heterogeneity and specific manifestations of the sickle cell syndromes.     

Cholelithiasis in sickle cell anemia: surgical considerations

Gallstones are frequently found in patients with sickle cell anemia. The differentiation between acute calculous biliary tract disease and sickle cell crisis can be difficult and should be based on the clinical presentation, comparison with previous episodes of abdominal pain, and judicious use of hepatobiliary radionuclide scanning. Emergency cholecystectomy is associated with a high morbidity and should be avoided if possible. Elective cholecystectomy is associated with a lower but still significant risk of complications. We believe patients with sickle cell anemia and symptomatic cholelithiasis should have elective cholecystectomy. Careful management is essential to minimize the danger of postoperative complications.