Abstract
Sickle cell disease (SCD) is an inherited disorder of hemoglobin that affects approximately 100,000 Americans. Manifestations of the disease occur in every organ system; however, the most common complication is the vaso-occlusive painful episode. These episodes are marked by excruciating corporeal pain and are the most common cause for Emergency Department (ED) visits and hospitalizations. For the emergency provider, management of acute sickle cell pain is challenging. This chapter provides an overview of pain in SCD and strategies for successful management in the ED and during the hospital stay.
Keywords
acute sickle cell pain, sickle cell anemia, sickle cell crisis, sickle cell disease, vaso-occlusive crisis
Sickle cell disease (SCD) is an inherited disorder of hemoglobin that affects approximately 100,000 Americans. The sickle cell gene is found in many ethnic groups, but the majority of those affected are of African or African-Caribbean origins. The average lifespan of those with SCD is about two to three decades less than for Americans without SCD, due in part to acute complications of the disease. Manifestations of the disease occur in every organ system; however, the most common complication is the vaso-occlusive painful episode. These episodes are marked by excruciating corporeal pain and are the most common cause for Emergency Department (ED) visits and hospitalizations in this population. There are approximately 230,000 ED visits related to SCD in the United States each year, and acute care expenditures for SCD are estimated at $1.5 billion annually. For the emergency provider, management of acute sickle cell pain is challenging. Undertreatment can occur due to concerns regarding the etiology of vaso-occlusion as well as the concern for opioid addiction. This chapter provides an overview of pain in SCD and strategies for successful management in the ED and during the hospital stay.
Pathophysiology
SCD is a family of genetic disorders caused by mutations (resulting in altered protein structure or altered production) at the beta-globin gene on chromosome 11. While several abnormal hemoglobins have been described, the most important is the valine-glutamine substitution at codon 6, which results in the formation of hemoglobin S. Individuals who are homozygous for this mutation have hemoglobin SS, the most severe form of SCD (often referred to as sickle cell anemia). Heterozygotes who have a different mutation on their other beta-globin gene are also classified as SCD. The most common heterozygous forms of SCD include hemoglobin SC and hemoglobin Sβ thalassemia. Patients with HbSS or HbSB-thalassemia typically experience more vaso-occlusive crises (VOCs).
Individuals who carry one normal beta-globin gene and one hemoglobin S mutation are defined as having sickle cell trait. In the United States, approximately 2 million people carry the sickle cell trait. The sickle cell trait is found in 8% of African Americans and is also prevalent in persons of Mediterranean, Middle Eastern, Indian, Caribbean, and Central and South American descent. People with this disease do not have vaso-occlusive pain. Pain in an individual with sickle cell trait should prompt the same evaluation as would be performed on a normal individual. These patients have been found to suffer from certain medical problems during times of increased physical stress. Complications include traumatic hyphema, hyposthenuria, and hematuria, especially during strenuous exercise, doubling the number of urinary tract infections during pregnancy. Acute hyphema is the only manifestation of sickle cell trait that can result in vaso-occlusion. Vaso-occlusion can occur in the anterior chamber of the eye; thus all individuals with hyphemae should be admitted for serial intraocular pressure measurements. Patients carrying the sickle cell trait are also at increased incidence for splenic infarction.
The pathophysiology underlying SCD is characterized by a complex state of ongoing hemolysis, inflammation, altered blood rheology, and endothelial dysfunction. Manifestations occur in every organ system; however, the most common manifestation is the vaso-occlusive painful episode or VOCs, typically in the bones and bone marrow. The pathophysiology of vaso-occlusive pain is not completely understood. However, it is presumed that local microvascular occlusion propagates further ischemia, hemoglobin deoxygenation, hemolysis, and tissue damage, which ultimately tips the delicate steady state toward diffuse vaso-occlusion (i.e., the pain is both ischemic and inflammatory in nature). It is thought that recurrent bouts of acute pain can eventually lead to chronic pain, particularly if they are not appropriately treated.
Triggers for such events include stress, dehydration, fever/infection, and trauma, but very often there is no clear precipitating cause. These episodes can be unpredictable, with varying degrees of intensity and frequency.
Clinical Manifestations
VOC pain usually presents with sudden onset, but may occur gradually in some people. The first episode may occur as early as 6 months of age. Pain may occur at any site, but the most common locations for pain are the lower back and the legs. Patients may describe the pain as sharp, throbbing, stabbing, dull, or aching. The pain may be localized or move to different places in the body. In children, painful episodes may be associated with physical findings such as the swelling of digits in dactylitis. With the loss of active bone marrow in small bones, these manifestations wane. In adults, there are no objective physical findings associated with VOC. Vital signs are of no utility in determining if a patient is having a VOC, as blood pressure and heart rate are usually normal. A common misconception is that hemoglobin drops during vaso-occlusion. In fact, hemoglobin is typically at or above baseline during painful episodes. Furthermore, SCD patients with higher steady state hemoglobin are more likely to have painful manifestations of SCD.
Other clinical manifestations of SCD relevant to a discussion of pain include acute chest syndrome, fever, neurological complications, organ infarction, hepatobiliary complications, acute anemia, splenic sequestration, and venous thromboembolism. Acute chest syndrome is the second most common cause for hospitalization and the most common cause of death. The syndrome is clinically identical to lobar pneumonia, presenting with chest pain, fever, and pulmonary opacities. Therapy includes correcting dehydration, if present, pain control, respiratory support, antibiotics, and transfusion therapy. Individuals with SCD are functionally asplenic and thus susceptible to infection with encapsulated bacteria. Additionally, high prevalence of bone disease (osteoporosis and avascular necrosis) further predisposes individuals to infections of the bone. Neurological complications of SCD include ischemic and hemorrhagic stroke, and there is also evidence that individuals with SCD have elevated rates of venous thromboembolic disease. These manifestations are important in the consideration of pain, because an appropriate differential diagnosis must always be formed before the provider assumes the etiology of pain is simply vaso-occlusion.
Differential Diagnosis And Evaluation
For individuals with chest pain, always consider acute chest syndrome, pulmonary embolism, and other life-threatening causes. Abdominal pain should prompt consideration of biliary etiologies, splenic or renal infarction, in addition to other standard non-SCD related causes of abdominal pain (appendicitis, diverticulitis, ovarian torsion, renal stones, etc.). Limb pain should prompt consideration of osteomyelitis and necrotizing fasciitis. There are no laboratory tests or imaging studies that can validate pain. Listening to the patient is key, as they often know what their “typical crisis” feels like and if what they are experiencing is different. Patients have often attempted to control their pain at home, and upon arrival in the ED have already experienced a few days of pain already. It is important to note that a majority of painful episodes are treated at home.
History should focus on triggers for pain, location, intensity, and how it compares with prior episodes. Physical examination should focus on areas of pain and assessment for infection. Laboratory evaluation should include a complete blood count, electrolyte panel, and bilirubin. Reticulocyte count, a commonly ordered test in SCD, is useful in differentiating etiologies of an acute drop in hemoglobin. For simple vaso-occlusion, reticulocyte counts are not necessary. Once alternative etiologies have been ruled out, the emergency provider can proceed with management of acute vaso-occlusive sickle cell pain.
Management Of Acute Sickle Cell Pain
In 2014 the National Heart, Lung, and Blood Institute (NHLBI) released evidence-based guidelines for the management of SCD. Because of a lack of scientific evidence, most recommendations were based on published guidelines by professional organizations and expert consensus. Recommendations included in this publication reflect those of the NHLBI guidelines, and whenever possible are evidence based. The following discussion assumes a diagnosis of simple vaso-occlusive pain and that more serious etiologies of pain have been ruled out.
Keys To Successful Management Of Acute Sickle Cell Disease Pain In The Emergency Department
- 1.
Rapid triage and administration of analgesics is encouraged.
Upon presentation to the ED, the patient should be rapidly triaged and examined to rule out other pain causing pathologies. Proper management of acute SCD pain inevitably involves administration of appropriate doses of parenteral opioids. For a variety of reasons, patients will often fail to tolerate doses of opioid that they have tolerated in the past. All SCD patients with acute pain should be managed in a monitored setting, with continuous pulse oximetry at a minimum. More conservative measures such as cardiac monitoring and (if available) end-tidal CO 2 monitoring should be considered. Taking these precautions will enable the emergency provider to safely administer the necessary doses of analgesic medication required for vaso-occlusive pain.
- 2.
Choose starting opioid dose based on an individualized pain plan or prior opioid consumption.
For the individual with acute sickle cell pain, intravenous (IV) opioids are first-line therapy. It is considered best practice to administer analgesia within 30 minutes of presentation, although there is no empirical data showing this results in better outcomes. The majority of adults with SCD suffer from chronic pain, and chronic opioid use and tolerance are common in the adult SCD population. Thus individuals with SCD often require extraordinarily high opioid doses to achieve adequate pain reduction. Appropriate initial doses will allow patients to receive less opioid overall, which reduces resource demands on nursing and shortens the time to adequate pain relief. There are three methods to determine opioid doses in the ED: patient-specific, consumption-based, and weight-based. Patient-specific opioid dosing involves administering a dose of opioid that has worked successfully for the patient in the past. Patients are often aware of their prior treatment and know what was successful. Patients should be part of the discussion of their treatment plan. Whenever possible, providers of long-term care should work to develop patient-specific ED pain management plans, as this is the preferred method for ED pain management. These pain management plans should be readily accessible to ED personnel upon presentation of the sickle cell patient to the ED. Consumption-based opioid dosing involves calculating the total dose of opioid taken by the patient over the last 24 hours and administering 20% of this total as a first IV dose in the ED. Opioid conversion calculators available online are helpful with this process ( http://www.globalrph.com/narcoticonv.htm ).
For the patient who does not have an individual pain plan and is unable to give a reliable medication history for the provider to calculate a consumption-based dose, weight-based dosing is appropriate. IV hydromorphone is recommended because it is a synthetic opioid with less histaminergic effects, and its time to peak onset is faster than morphine, which allows for safer redosing. The proper weight-based dose of hydromorphone is 10–20 mcg/kg. Morphine can be used as an alternative at a dose of 0.1–0.2 mg/kg. Some patients will give a history of intolerance to both these medications, or have coexisting renal dysfunction. In these cases, fentanyl 1–2 mcg/kg can be used. Meperidine should be avoided, as it is a poor analgesic and its renally cleared metabolite, normeperidine, is neurotoxic.
- 3.
When IV access is difficult or delayed, use oral or subcutaneous opioids; avoid intramuscular.
For patients with difficult access or milder symptoms of vaso-occlusion, oral or subcutaneous opioids are an appropriate alternative. Intramuscular administration is not recommended because it is more painful without pharmacologic advantage.
- 4.
Titrate to pain reduction.
The cornerstone of successful ED pain management in SCD is redosing of opioid analgesics every 15–30 minutes. If the previous dose did not substantially improve the patient’s pain (i.e., <2-point improvement on a 0–10 numerical pain scale), the next dose should be escalated by 25%–50%. The interval between doses is essential. Administration every 15–30 minutes allows for stacking of doses in order to achieve sufficient analgesia. It is common practice among emergency physicians to admit all patients who require more than three doses of opioids. There is very limited data on this topic, and the decision to admit should be made on an individual basis. Hospital admission exposes individuals with SCD to increased risk of venous thromboembolism, infection, and acute chest syndrome (a leading cause of death), and should be avoided whenever possible. Experience from SCD day hospitals suggest that patients can successfully be discharged after more than three doses of opioid without increased complications.
- 5.
Achieve pain reduction before starting patient controlled analgesia (PCA).
PCA is recommended for individuals admitted to the hospital for painful episodes. PCAs are also an attractive alternative to bolus-dosed opioids for patients in the ED, because they alleviate some nursing demands and may result in faster pain relief. It has been shown that PCA can lead to less opioid consumption compared with clinician-administered analgesia. When using PCA (either inpatient or in the ED), it is very important to achieve at least moderate pain reduction before starting the PCA. PCAs deliver small doses of opioid over short intervals (typically every 6–8 minutes). Achieving pain reduction through high-dose opioid boluses prior to PCA initiation is critical for two reasons. First, it helps the provider calculate the proper PCA settings (i.e., a patient who requires 12 mg of hydromorphone before initiation of PCA will require different settings than the patient who requires 6 mg of hydromorphone). Second, it also helps the patient because analgesia will not be delayed.
- 6.
Choose proper PCA settings.
Individuals with SCD often require complex, nonstandard PCA dosing strategies. Basal rates are often appropriate, especially during early phases of VOCs. For opioid tolerant individuals with SCD, consultation with a pain specialist is recommended to ensure that PCA settings adequately mirror the opioid doses required to achieve adequate analgesia. If pain consultation services are unavailable, and the emergency provider is not comfortable starting nonstandard PCA settings, then it is preferable not to use PCA. In this setting, nurse administered bolus opioids in conjunction with oral long-acting medication may be preferred.
- 7.
Continue long-acting home oral meds.
A large percentage of patients take daily long-acting opioids. If the patient is taking long-acting opioids at home, the decision to continue these medications should be made on an individual basis. It may be advisable to continue long-acting opioids, including methadone, to ensure adequate pain relief and avoid withdrawal symptoms. However, long-acting oral opioids may need to be withheld or reduced to prevent oversedation. During the course of admission, as IV medications are tapered down, the patient can return to a dose of long-acting opioid that is appropriate.
- 8.
Do not overhydrate; use appropriate volumes of hypotonic fluids.
Dehydration can precipitate vaso-occlusive pain episodes; therefore, one would think that aggressive rehydration would be therapeutic. However, overhydration—especially with isotonic crystalloid—does not cure crisis and may have detrimental effects. One undesirable effect of normal saline is that large amounts can cause hyperchloremic metabolic acidosis, and lowering the serum pH promotes sickling. Excessive IV fluids have been anecdotally associated with the development of atelectasis. A prospective observational cohort of 3751 patients with SCD identified atelectasis as a risk factor for the development of acute chest syndrome. Therefore isotonic fluids should be avoided unless the patient is overtly hypovolemic. No studies have established which type or quantity of IV fluid is ideal for the patient with VOC. However, hypotonic fluids are associated with reduced sickling in vivo and in vitro. At our institution, we use 5% dextrose in half normal saline at an infusion rate not exceeding maintenance to avoid overhydration.
- 9.
Adjuvant acetaminophen.
There are no clinical trial data to support the use of acetaminophen during vaso-occlusive pain; however, anecdotal experience suggests it may have opioid sparing effects. As acetaminophen is safe and well tolerated, we recommend oral acetaminophen as a first-line therapy in conjunction with IV opioids in the treatment of acute sickle cell pain. IV acetaminophen is attractive because it crosses the blood-brain barrier rapidly and does not undergo first-pass liver metabolism (which limits the potential for hepatotoxicity). Because of the costs of IV acetaminophen, we cannot broadly recommend its use without additional data. At our institution, we use IV acetaminophen for patients with poorly uncontrolled pain who cannot receive additional opioids because of concern for side effects (typically respiratory depression) and in whom nonsteroidal antiinflammatory drugs (NSAIDs) are contraindicated.
- 10.
NSAID use for acute pain.
NSAIDs should be used cautiously in the treatment of acute SCD pain. For acute episodes, NSAIDs may have the ability to improve analgesia when used in conjunction with IV opioids. Four small studies compared NSAIDs with placebo as adjunctive treatment for SCD pain, and only one found reductions in opioid requirements. The potential for NSAIDs to cause or worsen renal damage is particularly concerning for individuals with SCD. Individuals with SCD have hyposthenuria, which leads to increased clearance of creatinine, despite declining glomerular filtration rates. The clinical implication is that creatinine is an unreliable marker of renal function in SCD. As all individuals with SCD have some degree of renal injury due to chronic medullary infarcts, NSAIDs should be used sparingly, even when creatinine levels are normal. However, the current recommendation is to continue NSAIDs if there is no contraindication.
- 11.
Minimize supplemental oxygen.
Monitor oxygen saturation with pulse oximetry. Common practice in the many EDs is to administer supplemental oxygen to all individuals with vaso-occlusive pain. There is evidence, however, that excess administration of oxygen may be harmful because of the potential to reduce endogenous erythropoietin levels. Chronic hypoxemia, associated with pulmonary hypertension and sleep-disordered breathing, is common in SCD and supplemental oxygen is recommended in the ED to keep hemoglobin oxygen saturations above 95%. For individuals who are not hypoxic, supplemental oxygen is not indicated.
- 12.
Nonpharmacologic measures: warm blankets, limit blood pressure measurements.
Nonpharmacologic measures can improve SCD pain management in the ED and during admission. For adults, use manual blood pressure cuffs when possible, and limit unnecessary measurements. Warm blankets or heating pads are helpful, especially when the surrounding environment is cold. For children, distraction from pain by the provider, parent, or child-life specialist is recommended.
- 13.
Address drug seeking behavior, tolerance, dependence, addiction, and diversion.
Keys to successful management of acute SCD pain in the emergency department
- 1.
Rapid triage and administration of analgesics is encouraged.
- 2.
Choose starting opioid dose based on an individualized pain plan or prior opioid consumption.
- 3.
When IV access is difficult or delayed, use oral or subcutaneous opioids; avoid intramuscular injections.
- 4.
Titrate to pain reduction.
- 5.
Achieve pain reduction before starting PCA.
- 6.
Choose proper PCA settings.
- 7.
Continue long-acting home oral meds.
- 8.
Do not overhydrate; use appropriate amounts of hypotonic fluids.
- 9.
Adjuvant acetaminophen.
- 10.
NSAID use for acute pain.
- 11.
Minimize supplemental oxygen.
- 12.
Nonpharmacologic measures: warm blankets, limit blood pressure measurements.
- 13.
Address drug seeking behavior, tolerance, dependence, addiction, and diversion.
IV, Intravenous; NSAID, nonsteroidal antiinflammatory drugs; PCA, patient controlled analgesia; SCD, sickle cell disease.
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