Pathophysiology and Principles of Treatment - James Eckman, MD

The biochemistry of hemoglobin S and the hypothesized pathophysiologic mechanisms of complications provide principles for treatment of complications in sickle cell syndromes. These principles must be applied in preventing and treating almost every complication observed during the clinical course of patients. The pathophysiology of pain and principles of pain management are also reviewed to provide a rational basis for the use of analgesics to treat pain associated with complications.

The clinical manifestations result from changes of red blood cell deformability and fragility, increases in blood viscosity with blockage of small blood vessels, and red cell membrane changes contributing to hemoglobin polymerization, adherence of erythrocytes to vascular endothelium, and phagocytosis by macrophages. The end result is a hemolytic anemia, increased incidence of serious infection, and ischemic damage throughout the body. In individuals with sickle syndromes, there is a life-long risk of having complications, however, there are specific ages when many of the manifestations develop. The more common problems in sickle cell syndromes will be presented by the age usual onset.

Early Symptoms

The majority of infants are being diagnosed at birth by newborn screening. The symptoms occurring in the first few months of life in infants with sickle cell syndromes are non-specific and include jaundice, irritability, colic, failure to thrive, fever, nausea, and vomiting. Findings include hepatosplenomegaly, pallor, and heart murmurs.

Unfortunately, undiagnosed infants may present with overwhelming infection as the first manifestation of the illness in the first few months of life.

Anemia

Anemia is lifelong, starting in the first year of life as the fetal hemoglobin level falls. The average red cell survival is reduced from a normal of 120 days down to an average of 10 to 20 days in sickle cell anemia. This produces anemia, a high reticulocyte count, and a striking proliferation of red cell precursors in the bone marrow to compensate for the hemolysis. Other problems related to the anemia are jaundice (elevated indirect bilirubin), changes in bone structure, and a high lactic dehydrogenase. In later childhood and early adult life, pigment gallstones are very common, related to increased catabolism of hemoglobin. These cause cholecystitis in many individuals and removal is advocated by many as soon as stones are documented.

Sequestration episode

Splenic sequestration episode occurs in highest frequency during the first five years of life in children with sickle cell anemia. Splenic sequestration occurs at any age in individuals with the other sickle syndromes. In all sickle syndromes, sequestration may be seen primarily in the liver in older individuals. This complication is characterized by onset of life-threatening anemia with rapid enlargement of the spleen and/or liver with a high reticulocyte count. In older individuals with primarily hepatic sequestration, there may be rapid deterioration of hepatic function, rhabdomyolysis, and renal insufficiency. This syndrome has been termed acute multiorgan failure. ⁶ Treatment of the acute episode requires early recognition, careful monitoring, aggressive transfusion support, and occasional emergent splenectomy. Episodes tend to be recurrent so many advocate splenectomy or chronic transfusion.

Aplastic episode occurs in highest frequency during early childhood, however, can occur at any age. The complication is characterized by very rapid onset of life-threatening anemia caused by the absence in production of new erythrocytes. The reticulocyte count is low and erythroid precursors are absent or markedly reduced in the bone marrow. The syndrome is now known to be caused by infection with the parvo virus B19. Many viral and bacterial infections will cause worsening of anemia with a reduced reticulocyte count from partial suppression of erythropoiesis. Treatment includes careful observation and transfusion support until red cell production recovers.

Infections

Infections are a major cause of morbidity and mortality in patients with sickle cell disease. Bacterial infections are the major cause of death in children during the first five years of life. Those under three are at greatest risk for fatal sepsis, however, overwhelming infections can be seen at any age. The increased susceptibility to overwhelming infection from encapsulated organisms is likely the result of loss of splenic function early in life. Organisms which are particularly virulent in these patients include Streptococcus pneumoniae, salmonella, Hemophilus influenza, and meningococcus. Serious infections such as sepsis, meningitis, and pneumonia caused by these organisms are common and often may be life-threatening. There is also an increased incidence of infections of the bones and joints which may be related to ischemic damage with secondary infection. Infections of the urinary system are more common and may be more severe than in individuals without a sickle syndrome. Reduction in morbidity and mortality from these complications requires prevention, early recognition, and aggressive treatment with appropriate antibiotics. Preventive measures include initiation of prophylactic penicillin at birth, administration of pneumococcal and hemophilus b polysaccharide vaccine at age 2, immunization for hepatitis, meningococcus, and influenza, and routine immunization for childhood diseases. Treatment includes early recognition, aggressive diagnostic evaluation, judicious use of empiric antibiotics in patients with significant fever, and adequate treatment of documented infection with appropriate antibiotics.

Sickle dactylitis is one of the first ischemic complications in sickle cell syndromes with the highest incidence between ages six months and two years. About one third to one half of patients may experience this complication during early childhood but it is very rare in later life. This painful swelling of the dorsum of both hands and feet was the most common presenting symptom that led to diagnosis before newborn screening became common. Management includes hydration, pain control with acetaminophen, and reassurance of the parent. Bone changes occurring during episodes of dactylitis can be caused by or mistaken for osteomyelitis.

Strokes

Hemiplegia secondary to cerebral vascular ischemia occurs with high frequency in children with sickle syndromes. The onset may be in the first year of life and 80% occur before the age of twenty. There is a very high recurrence rate approaching 85% in the three years after the first episode. Other neurological presentations such as seizures, transient ischemic attacks, coma, and sensory loss also occur. Treatment is with chronic transfusion to maintain the Hb S level at less than 30% to prevent recurrences. Present evidence suggests that the need for transfusion may be life-long and complications such as alloimmunization, iron overload, and exposure to infectious disease may be common complications. Allogenic bone marrow transplantation from an available HLA identical sibling may offer these children the best chances for a more normal life. Children with increased risk for stroke may be detected by Trans-Cranial Doppler(TCD)Ultrasound screening. The first stroke may be prevented by beginning transfusion therapy..

Priapism

Priapism is the painful erection of the penis caused by sickling in the corpora cavernosa. This complication usually has an onset at age 5 to 35. It often occurs as a severe episode requiring hospitalization following multiple episodes of short duration termed stuttering. Episodes may be precipitated by infection, intercourse, masturbation, or nocturnal erections. Onset in the early morning awaking the patient is common. Treatment includes pain relief, alpha adrenergic agonists, hydration, exchange transfusion, and surgical shunt procedures between the corpora cavernosa and the corpus spongiosum. Impotence is a long-term sequelae of repeated episodes in half to one third of cases.

Weight may lag behind that of appropriate controls, however, there is considerable variability. Height is less in older children and adolescents but differences disappear in adulthood. Puberty is delayed significantly in males and females with sickle cell disease. Factors contributing to the delay include anemia, fetal hemoglobin levels, increased protein turnover, and zinc deficiency. Treatment includes good general nutrition, vitamin supplementation for deficiencies, and reassurance that normal maturation will occur.

Pain Episodes

The most common acute problem and distressing manifestation in the patient with sickle cell disease is the sickle pain episode (also unfortunately termed pain "crisis"). A pain episode is defined as a self-limited episode of diffuse, reversible pain often occurring in the extremities, back, chest, and abdomen. The severity of pain has been reported to range from mild transient attacks of five minutes to excruciating pain lasting days or weeks requiring hospitalization. This intense pain is believed to be caused by the inflammatory response to bone or marrow necrosis, ischemic muscle, and ischemic bowel resulting from the obstruction and sludging of blood flow produced by sickled erythrocytes. The pain episode is almost never a cause of mortality, however, affected individuals often fear serious complications or death. The frequency of pain episode varies with each individual depending upon their hemoglobin phenotype, physical condition, and many other variables. Precipitating factors include alterations which cause increased physical and psychological stress, especially fever, dehydration, overexertion, rapid temperature change, or anger. Episodes, however, frequently occur without apparent antecedent causes.

Management of pain episode begins with a thorough clinical evaluation to exclude correctable precipitants, life threatening complications, and causes of pain unrelated to sickle cell disease. A detailed history and physical examination is important to identify correctable precipitating factors such as infection, dehydration, acidosis from any cause, emotional stress, extreme temperature exposure, or ingestion of other substances such as alcohol or other recreational drugs. There are no characteristic clinical findings which make the diagnosis or define the severity of a pain episode so the patient’s assessment must be accepted. Uncharacteristic pain, new physical findings, or changes in laboratory values suggest complications rather than an uncomplicated pain episode. Treatment of a pain episode includes oral or intravenous hydration, administration of analgesics, bed rest, and treatment of the underlying causes such as infection. Pain should be managed as an acute pain syndrome tailoring the analgesic, route of administration, dosage, and frequency of administration to the level of pain and response to therapy experienced by the patient.

Chronic Pain

More prolonged and constant pain can be seen with bone infarction, sickle arthritis, and aseptic necrosis of the femur or humerus. With chronic pain, non-steroidal anti-inflammatory medications with renal sparing properties should be administered continuously to maintain analgesic blood levels during these episodes. TENS units, relaxation techniques, occupational and physical therapy approaches may be useful in reducing pain and maintaining a functional lifestyle. Education and support are often required to prevent the inappropriate continuous use of opiate analgesics for these chronic pain states.

Peripheral arterial occlusions, beginning in childhood, may lead to neovascularization with risk of vitreous hemorrhage, retinal detachment, and blindness. Patients with Hb SC disease, and perhaps sickle thalassemias, are at increased risk for retinal complications. Yearly eye examination by an ophthalmologist with appropriate use of laser photocoagulation and surgery may reduce the severity of these complications.

Kidney damage starts very early and progresses throughout life causing major complications in many individuals with sickle syndromes. Hyposthenuria, which starts in the first ten years of life, causes nocturia and enuresis, predisposes to dehydration, and reduces resistance to urosepsis. Hematuria and papillary necrosis are common. With advancing age, proteinuria, renal tubular acidosis, nephrotic syndrome, glomerulosclerosis, and renal insufficiency may occur. All patients should be screened for proteinuria annualy using a 24 hour quantitave urine protein beginning at age 13.

Pneumonias, acute chest syndrome caused by sickling in pulmonary arteries, and fat embolization, are acute complications seen with increased frequency in patients with sickle syndromes. They present difficult differential diagnostic problems because manifestations of chest pain, cough, fever, pulmonary infiltrates, and severe hypoxia are common to all. Treatment includes hospitalization with careful monitoring of hemoglobin and blood gasses, oxygen for hypoxia, judicious hydration and pain treatment, antibiotics, and exchange transfusion in episodes with severe hypoxia, rapid progression, or diffuse pulmonary involvement. Chest syndrome may be prevented by the use of incentive spirometry in all hospitalized patients. Reactive airway disease is common and may be more prevalent in patients with sickle cell disease. Older patients may develop chronic restrictive lung disease, pulmonary hypertension, and cor pulmonale.

Leg ulcers cause chronic disability in 10 to 15% of older children and adults with sickle cell anemia. They are likely related to vascular stasis explaining the chronicity and recurrence. Treatment includes saline wet-to-dry debridement, Unna’s boots, hydroscopic dressings, and antibiotics for cellulitis. Transfusion and skin graphs may be of benefit in recalcitrant cases.

Pathophysiology and Principles of Treatment

The biochemistry of hemoglobin S and the hypothesized pathophysiologic mechanisms of complications provide principles for treatment of complications in sickle cell syndromes. Because no specific therapeutic interventions are presently effective and these mechanisms appear to be clinically relevant, these principles must be applied in preventing and treating almost every complication observed during the clinical course of patients. The pathophysiology of pain and principles of pain management are also reviewed to provide a rational basis for the use of analgesics to treat pain associated with complications.

Biochemistry of Sickle Polymerization Deoxygenation provides the major stimulus for hemoglobin polymerization. Factors, summarized in Table 1, such as temperature, pH, and hemoglobin concentration have important influences on the rate of hemoglobin polymerization and sickling. Because sickling takes a significant length of time after deoxygenation, all of these factors appear to have clinical relevance in the treatment of complications.

 Although the routine use of oxygen during complications has no benefit and may be harmful, blood gas determinations and treatment of significant hypoxia are important in patients with acute pulmonary complications and in those with chronic lung disease.

Because the polymerization of sickle hemoglobin requires energy, sickling is increased by fever. Infections need to be sought and treated in all patients with fever, with or without other complications. Consideration should be given to suppression of high fever in patients with other complications.

The rate of polymerization is increased by acidosis. This can become important in complications which reduce tissue perfusion causing lactic acidosis. Respiratory acidosis can be precipitated by over-sedation with narcotic analgesics, antiemetics, and sedatives. Older patients with renal involvement may be predisposed to severe mixed metabolic and respiratory acidosis because of renal tubular acidosis which reduces buffering capacity and ability to excrete an acid load.

Changes in intracellular hemoglobin concentration markedly influence the rate of hemoglobin polymerization. It has been estimated that the rate of polymerization changes in proportion to the thirtieth power of the hemoglobin concentration. Because the erythrocyte is an ideal osmometer, fluctuations in the state of hydration of the patient influence intracellular water concentration by changing effective plasma osmotic pressure. The resulting small changes in intracellular hemoglobin concentration have profound effects on the rate of hemoglobin polymerization and sickling. The state of hydration is made even more important in the clinical management of patients by the prevalence of a renal tubular defect which prevents conservation of free water by the kidney. Many older children and adults have an obligatory free water loss of three liters of water a day, predisposing them to rapid dehydration if complications increase free water loss, as with fever, or decrease free water intake, as with anorexia caused by pain. Stressing oral hydration early in complications is an important principle of prevention. Assessing the state of hydration and aggressively hydrating with hyponatremic fluids that will increase intracellular hydration is a cornerstone of treatment for almost all complications.

Whole blood viscosity is often increased during complications in sickle cell disease. Anemia may be severe enough to compromise tissue oxygenation during complications. Transfusions are considered beneficial during certain complications because oxygen carrying capacity is increased and the cells containing sickle hemoglobin are diluted out by cells with normal hemoglobin. There is good evidence that chronic transfusion prevent recurrence of central nervous system events. Acute transfusions may be lifesaving during aplastic and sequestration crises, and may benefit severely ill individuals with pulmonary or cardiac compromise. They are advocated in a number of other situations.

There are special considerations that must always be pondered when transfusing a patient with sickle cell syndromes. There are the usual concerns about exposure to infectious disease such as hepatitis, HIV, CMV, and others. Volume overload can be a problem because the plasma volume is often normal or expanded in these patients with chronic anemia. Iron overload is a universal complication of chronic transfusions in a patient that is not loosing iron. There appears to be a significantly increased risk of alloimmunization in patients with sickle syndromes receiving transfusion because of exposure to antigens commonly missing from their red cells.

One of the major considerations in all transfusions, is the effects of the transfused cells on whole blood viscosity in the presence of sickle cells. Blood containing mixtures of normal and sickle cells has increased viscosity until the percentage of normal cells is greater than 70%. The viscosity increases very rapidly when the hematocrit is over 30% in these mixtures. Clinical manifestations caused by this increase in viscosity are observed when the hematocrit is increased above 33% while the percentage of Hb A is less than 50%. Simple transfusion can be used to increase the percentage of Hb A in patients with severe anemia. Exchange transfusion is indicated to accomplish this goal when the initial hemoglobin level is high. Transfusion to raise the hemoglobin above 12 grams/dl or the hematocrit above 35% is rarely indicated and then only if the measured Hb A is greater than 70%.

The gate control theory of pain sensation postulates that noxious stimuli are transmitted by peripheral nerves to three systems in the spinal cord: 1) cells in the substantia gelatinosa, 2) dorsal column fibers that project toward the brain, and 3) spinal column T cells that transmit information to the brain. Transmission of impulses cause by noxious stimuli along afferent nerve fibers to spinal cord T cells is controlled by a gating mechanism situated in the dorsal horn. The "opening and closing" of this gate mechanism is controlled by the amount of activity in small diameter, C and A-gamma fibers and large diameter, A-beta fibers. The spinal gating mechanism is also modulated by neural impulses from the brain. This system provides a mechanism by which stimuli perceived as pain can be modulated by spinal reflexes and cortical input.

Another system which provides another potential modulator of pain is found in the midbrain. Stimulation of areas in the midbrain causes release of endogenous opiate substances, the enkephalins and endorphins. Secretion of these analgesic endogenous opioids can be stimulated directly by neuronal activation from higher brain centers or indirectly by relaxation techniques, acupuncture, and transcutaneous electrical nerve stimulation (TENS). Binding of these endogenous opioids or exogenous opiates to opiate receptors appears to be the final pathway of analgesia produced by this system.

Serotonin may also modulate pain sensation by decreasing perception of pain and enhancing the effect of other analgesics. Tricyclic antidepressants and L-tryptophan, both of which increase brain serotonin levels, can be effective adjuncts in control of chronic pain.

Pain can potentially be treated by three independent approaches including reduction of stimulation of pain fibers in the tissues, reduction of transmission of pain signals in the spinal cord, and reduction in perception of pain in the brain. Anti-inflammatory agents such as aspirin and non-steroidal anti-inflammatory drugs (NSAIDs), heat, and tissue immobilization appear to reduce local stimulation of pain fibers in tissues. TENS units and acupuncture which may block transmission of pain signals at the spinal cord level. Placebo effects which activate endogenous opiates, narcotics which stimulate opiate receptors, antidepressants, anti-anxiety agents, acetaminophen, biofeedback and relaxation techniques appear to alter the perception of pain at the level of the brain. All of these approaches alone or in combination may be useful in managing pain states occurring in patients with sickle syndromes.

The most common acute problem in sickle cell disease and the most distressing manifestation of the disease for the patient is the sickle pain episode. Pain episode is defined as a self-limited episode of reversible pain caused by the inflammatory response to bone or marrow necrosis, ischemic muscle, and ischemic bowel resulting from the obstruction and sludging of blood flow produced by sickled erythrocytes often occurring in the extremities, back, chest, and abdomen. The severity of pain has been reported to range from mild transient attacks of five minutes to excruciating pain lasting days or weeks requiring hospitalization.

Management of Acute Pain Episode- _adapted from Vichinski et al. 1982.

- Exclude a precipitating complication or other cause of pain.

- Bed rest and oral or intravenous hydration.

- Tailor the analgesic used, dosage, route and frequency of administration to the severity of pain and the patient’s reported response.

- Always provide the pain medication on a fixed schedule of administration, on the duration of drug action. (NOT PRN, based) Periodic adjustments should be based on pain control and level of sedation.

- Intravenous administration is recommended because of rapid onset of action, predictable absorbtion, and relief of pain with injections. Monitor the patient for excessive euphoria, respiratory depression, and a shorter duration of action. Use multiple drugs with different modes of action based on the WHO pain treatment ladder. As pain improves, reduce the amount of medication per dose not frequency of administration.

- If treatment is required for more than 10 days, physical withdrawal may occur so the medication should be tapered over several days after pain improves.

Some of the more common side effects of narcotic analgesics include itching from histamine release, somnolence, respiratory depression, nausea, vomiting, hypotension, constipation, increased bladder tone, acute urinary retention, irritation at the site of injection, and decreased seizure threshold. The synthetic agonist-antagonist agents such as buprenorphine (Buprenex) and nalbuphine (Nubain) and (Stadol) may cause dysphoric reactions in any patient and a withdrawal syndrome similar to naloxone in patients with very frequent narcotic usage. Aspirin should not be used in febrile children because of potential for causing Reye’s syndrome in children with certain viral infections.

In patients with chronic pain, non-steroidal anti-inflammatory drugs (NSAIDs) should be administered continuously to maintain analgesic blood levels. TENS units or nerve blocks can be useful in controlling localized pain. In general, narcotics should not be used for chronic pain and should be reserved for acute pain episodes. This requires considerable educational effort in patients with sickle syndromes and chronic pain. Severe pain can be managed using the long acting properties of oral preparations like sustained release morphine, oxycodine, hydromorphone, or methadone. Some patients with severe, chronic pain may benefit from tricyclic antidepressants.

Teaching cognitive-behavioral techniques such as cognitive coping, progressive relaxation, biofeedback control, self hypnosis, relaxation imaging, and others may complement medicinal approaches.

The maintenance of normal functioning and outside activities, within the limitations permitted by the pain, are critical to combating the chronic pain syndrome. Occupational and physical therapy may be very useful in preserving physical function and allowing the individual to pursue a functional lifestyle. Vocational rehabilitation which assesses skills, interests and limitations, and matches these to appropriate jobs will improve both functioning and self-image.

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