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The Vaso-occlusive Pain Crisis

The pain of vaso-occlusive crisis in SCD can be excruciating and often debilitating. It is the most common reason for hospitalization in patients with SCD.44,45 About 20% of sickle cell patients have frequent, severe crises that require parenteral narcotics and hospitalization. Forty percent rarely have a painful crisis, and the remaining 40% suffer a single painful crisis per year.46 Patients with frequent pain episodes have a higher mortality.46 Severe pain can occur at unpredictable intervals and in patients as young as 6 months of age.10 Bone infarction is a common component of a vasoocclusive pain crisis. The most commonly affected bones are long bones, but infarction can occur in the ribs, spine, sternum, skull, and clavicle.29,47,48

Infection, dehydration, physical or emotional stress, fatigue, cold, or high altitude may precipitate acute pain episodes. More frequently, there is no obvious precipitant, and attacks begin with little warning.

History


One of the most important questions to ask the patient with a painful crisis is "How much pain are you in?" This question is also relevant after every round of pain medication administered. Ask the patient to rate his or her pain upon arrival on a scale of 1 to 10 or on a visual analog scale (VAS). This provides an important baseline against which to judge the efficacy of ED treatment. One study showed that the use of self-reports of pain and a standardized analgesic protocol improved the management of painful vaso-occlusive crises in children and adolescents.49

During a vaso-occlusive crisis, pain is frequently widespread and often migratory. Determine the location of the pain, and ask if this is the same as the patient's "typical pain crisis." Common locations include the low back, femurs, hips, knees, abdomen, chest and head.21 While it has not been closely studied, many authorities believe that deviation from the patient's typical pain may be a clue to either underlying infection or a second pathological process. In one small study on surgical illness in patients with SCD, a change in the pattern of the crisis was an important clue to surgical pathology.50

Vomiting is somewhat rare in children with a painful abdominal crisis. In one study, only 10 out of 106 children with a painful abdominal crisis had emesis.51 During the patient interview, it may be helpful to explore other aspects of the present illness, including precipitants and associated complaints such as cough or fever.

The past medical history can also yield crucial information. Patients can often tell the physician which medicines in which amounts are most effective for their pain. Many can recite their last hemoglobin level, date of their last transfusion, and the nature of any prior complications. Determine whether febrile patients have received the pneumococcal vaccine and if they are chronically on an antibiotic such as penicillin.

Physical Examination

The general appearance of the patient can gauge the severity of illness. Signs of respiratory distress are ominous and may presage pneumonia or acute chest syndrome.

Pulse oximetry (the "fifth" vital sign) may be illuminating in those with chest pain, tachypnea, and those suspected of ACS. One recent study showed that while pulse oximetry underestimates arterial saturation, the bias is clinically insignificant.52 However, another investigation suggests that pulse oximetry is often falsely low in SCD. In this study of 21 children, one-third of children who had normal oxygen saturation on blood gas analysis were falsely diagnosed as hypoxic by pulse oximetry.53 The authors suggested that "making treatment decisions based on pulse oximetry data alone in patients with SCD who are not acutely ill may be inappropriate."

While many patients in significant distress may be tachycardic, lack of a rapid heart rate does not rule out the presence of pain. Hypotension in any ill patient is, of course, worrisome, but in the sickler it may represent sepsis or dehydration, while in the young child, it may represent splenic sequestration. Hypertension is rare in sickle cell crisis. In one review of over 450 ED visits for vaso-occlusive crises, no patient was found to be hypertensive.54

The head exam occasionally provides clues to complications of SCD. Scleral icterus may be chronic or appear with hyperhemolytic states. Ask the patient (or family members) if his or her eyes have gotten more yellow over the past several days.

During examination of the chest, listen for rales or other abnormal lung sounds. The presence of adventitial sounds or signs of respiratory distress should prompt chest radiography. Cardiac murmurs are frequent in patients with SCD and do not necessarily indicate acute pathology.55 In one series of 100 patients with SCD, nearly 80% had murmurs.56

Many patients have pain and tenderness as a component of their vaso-occlusive crisis. However, rigidity and rebound should always suggest an intraabdominal process. In one retrospective review, 43 children with SCA presented on 106 occasions with an abdominal painful crisis (defined as abdominal pain during a vaso-occlusive crisis without other intraabdominal pathology). Most of these children had normal bowel sounds and no guarding or rebound tenderness.51 In another study, about one-third of patients with abdominal pain due to a painful vaso-occlusive crisis had distention and/or ileus.57

During the abdominal exam in young children, pay particular attention to the size of the spleen. A large spleen in a hypotensive child may be the best clue to acute splenic sequestration. Recognize, however, that splenomegaly is common in HbSC disease. In one study, 34% of children with HbSC had palpable splenomegaly at baseline.58

The extremity examination should target painful joints. In a vaso-occlusive crisis, the joint may be somewhat painful to move, but it should not be especially red, hot, or swollen. These findings suggest a septic joint or osteomyelitis. Infectious causes for the pain may be more likely if the pain is confined to a single site, especially if this is different from the patient's "typical" pain.25 Never forget that you cannot palpate bone marrow; many patients will tell you the location of the pain, but palpation commonly does not elicit tenderness.

The neurological exam is most important for the patient with suspected cerebral thrombosis from sickling.

Diagnostic Studies

Two studies have examined the usefulness of obtaining routine chest radiographs and urinalyses on adults presenting to the ED in acute sickle cell pain crisis. The first was a prospective trial that evaluated patients more than 14 years old with sickle hemoglobinopathies who presented to the ED with a painful crisis. Seventyone patients with 134 ED presentations were studied over a six-month period, and eight diagnoses of acute pneumonia and 10 diagnoses of urinary tract infection (UTI) were made. Eleven of these 18 infections (61.1%) had no clinical findings of bacterial infection. The authors concluded that in SCD patients with pain crisis, "Routine chest radiography and urinalysis may be clinically useful and cost-effective in the early diagnosis of crisis-related infection."59

However, a more recent study conflicts with these results. In this study, the authors examined 38 patients totaling 94 visits to the ED. Among patients with painful crises, six had pneumonia and three were diagnosed with a UTI. All six patients with pneumonia had signs and symptoms of pneumonia; however, two of three patients with UTI were asymptomatic. These authors concluded that chest radiography could be ordered on clinical grounds in patients with sickle cell pain crisis, but that routine urinalysis may be indicated.60

Radiography
Chest X-Ray


Most physicians order a chest x-ray based on a concerning history or physical examination. But is fever alone enough reason to order a chest film in a patient with a painful sickle crisis? A recent study would suggest that the answer is "yes." In this prospective study, 73 patients with SCD with 96 febrile events were evaluated over a one-year period. While 24% of the patients had evidence of acute chest syndrome on routine radiography, the emergency physician was able to predict fewer than 40% of cases based on the history and physical examination.61

Recognize that the baseline chest film of an adult with SCD is likely to demonstrate chronic changes such as lung fibrosis, large pulmonary arteries, and cardiomegaly.62

Abdominal CT Scan

Most sickle cell patients who present with abdominal pain require no diagnostic imaging. A history and physical examination alone can usually rule out serious abdominal pathology. However, the presence of local abdominal tenderness or peritoneal signs (especially when accompanied by fever) may require surgical consultation, diagnostic imaging, or both. In one review of 30 patients with worrisome clinical findings, CT proved a reliable diagnostic tool.63 Other studies show that CT is especially useful in the diagnosis of splenic abscesses.64

Biliary Studies

Most patients with SCA will have gallstones. (Those that don't probably had a cholecystectomy.) Thus, the presence of gallstones on ultrasound should be accompanied by other findings of gall bladder inflammation (e.g., ductal dilatation, edema of the gall bladder wall, pericholecystic fluid) before making a sonographic diagnosis of cholecystitis. In one series, biliary studies (ultrasound and biliary scans) had a low positive predictive value for detection of acute biliary disease.65 However, a normal biliary scan obviated the need for surgery in some patients.

Laboratory Studies

As many as 80% of emergency physicians order a CBC in the evaluation of patients with acute vaso-occlusive sickle-cell crisis. But what does the CBC tell us? How does it help in the decision-making process?

Surprisingly, there is little research devoted to this question. In fact, there are no good studies that show a correlation between the afebrile patient with a painful sickle cell crisis and the need for admission. Furthermore, there are no good data to support that elevation of the white count or an abnormal differential indicates an infectious etiology in the afebrile (or even febrile) patient. Even those who champion the CBC as a diagnostic tool cannot provide an evidence-based number for an abnormal count. Recall that the average WBC count in children with SCD who are not sick or in crisis is 12,400/mm3.66

One study examined the relationship between ED disposition and the CBC in patients presenting with painful sickle crisis.67 Part 1 of this two-part study involved a retrospective chart review of patients with a sole ED diagnosis of acute sickle cell crisis, while part 2 prospectively evaluated consecutive patients presenting in painful crisis. In both parts, there was no difference between patients who were admitted to the hospital or discharged from the ED in regards to the hemoglobin level or reticulocyte count. In the retrospective arm, the mean WBC count did not differ between the admitted vs. released patients, but in the prospective arm, there was a difference between admitted (15,800/mm3) compared to the released (12,800/mm3) patients. However, in this study, the WBC count was shown to the emergency
physician before they made the decision to admit.67

In one small series in children, an erythrocyte sedimentation rate (ESR) of greater than 50 seemed to correlate with the presence of severe infection; however, this finding has not been validated.68

Urinalysis

As noted, a urinalysis (dip or microscopic) may provide clues to asymptomatic bacteriuria in the patient with a painful sickle cell crisis. Recognize, however, that statistically, any sexually active male with pyuria is more likely to have a sexually transmitted disease than a true UTI.69

Treatment

Severe pain is an emergency. A recurring theme in the research on sickle cell crisis is that pain medicines are given too little, too late.70 (See also the December 1999 issue of Emergency Medicine Practice, "Pain Management In The ED: Prompt, Cost-Effective, State-Of-The-Art Strategies.") Opioids are the drugs of choice for managing severe pain in the patient with SCD. They should never be withheld during an acute crisis for fear of producing drug addiction.

An interesting model involves treating sickle cell pain like cancer pain. One hospital evaluated its experience with IM meperidine (75-125 mg q3h) and shortacting oral opioids for the treatment of sickle cell pain. They later switched to an institutional protocol using IV morphine (5 mg initially followed by 5 mg/h, with appropriate dose adjustment) followed by oral controlled- release morphine. Using the new protocol, hospital admissions for sickle cell pain fell by 44%, while ED visits decreased by 67%.71

There are no good studies that show a clear superiority of one drug vs. another in the treatment of sickle cell pain, but on a theoretical basis, morphine may be one of the better choices (as discussed later in the text). For severe attacks, the preferred route of administration of opioids is IV, but many sickle cell patients have poor vascular access due to multiple previous IV lines. IM or subcutaneous opioids are reasonable alternatives in many patients. Those who present with early or moderate pain crises who are not vomiting may require only oral or IM medications.

In one study, a protocol that emphasized oral narcotic analgesia had a positive effect on resource utilization. Of the 100 adult sickle cell syndrome patients registered at a New York hospital, 15 were identified as "frequent users." Using an oral narcotic protocol, their frequency of admissions to the hospital dropped by 75% and significantly decreased the amount of narcotics dispensed in the ED.72

What Dose And How Often?

The dosing regimen should be individualized for each patient. The patient can often tell you how much of which drug he or she needs and how often it needs to be given. The starting dose, like with any narcotic, is determined by the intensity of the pain and prior analgesic history of the patient. For most narcotics, you can safely give one-half of the starting dose after each reassessment—even at intervals as often as every 30 minutes.6 Fixed doses of opioids given at fixed intervals are often not effective because of individual variations in pain perception and opioid metabolism.

Patient-Controlled Analgesia

If a patient faces a prolonged stay in the ED, a patientcontrolled analgesia (PCA) pump may be useful.6 While few EDs routinely use this technology, at least one study showed that PCA pumps are safe and effective when used in ED patients with a painful crisis.73 Multiple studies demonstrate the efficacy of PCA pumps in hospitalized patients with SCA, in both children and adults.74-78 While the risk of meperidine-related seizures is low when it is given in isolated bolus injections, seizures may be more common if meperidine is administered in a PCA device in large or prolonged amounts.79

Adverse Effects

While respiratory depression is the most serious complication of opiate use, constipation is the most common adverse effect. However, respiratory depression is usually only seen in patients without previous significant opioid exposure and is usually preceded by sedation. Patients who have impaired respiratory function or asthma are at greatest risk of experiencing significant respiratory depression in response to the usual doses of drugs. In general, patients who frequently require narcotics rapidly develop tolerance to the sedative and respiratory depressive side effects. While naloxone can reverse opioid-induced respiratory depression, it is indicated only for significant hypoventilation, as it may
precipitate narcotic withdrawal.6

Morphine

Morphine is one of the most frequently used opioids in the treatment of a painful crisis. The duration of analgesia is 4-6 hours, and the starting dose is 0.10-0.15 mg/kg IV for children and 5-10 mg IV for adults (15 mg is generally the maximum initial dose). Some patients may experience rash, pruritus, hypotension, or GI intolerance.29,80

Morphine can be given by many different routes—IV, IM, oral, subcutaneous, or rectal.81 One study compared oral controlled-release morphine in a dose of 1.9 mg/kg q12h to continuous IV morphine. In this doubleblind, randomized, parallel-group study, the oral morphine proved a reliable, noninvasive alternative to continuous IV morphine in 56 children with vasoocclusive crisis.82 All children received an initial loading dose of IV morphine of up to 0.15 mg/kg followed by the oral preparation.

Meperidine

Meperidine is perhaps the most often prescribed opioid for acute sickle cell pain crisis, yet it has the worst pharmacological profile.83 Due to its effect on serotonin release, meperidine may contribute to serotonin syndrome in patients taking selective serotonin reuptake inhibitors (such as fluoxetine [Prozac], paroxitine [Paxil], sertraline [Zoloft], and nefazodonehydrochloride [Serzone]), MAO inhibitors (such as phenelzine [Nardil]), fenfluramine (Pondimin), dexfenfluramine HCl (Redux), antihistamines, and carbidopa-levdopa (Sinemet). This can cause a life-threatening hyperthermia. Meperidine is highly psychologically addicting due to its serotonin enhancement characteristics. Guidelines from the American Pain Society suggest, "Meperidine should not be used if frequent large doses or long treatment durations are anticipated."(The authors rated the evidence for this as Grade B [i.e., moderate support in the literature].) 22 However, they did not caution against ED use.

Some authorities believe that meperidine should be avoided altogether in SCD patients.84 They argue that repetitive dosing can lead to accumulation of its toxic metabolite, nor-meperidine, which can cause seizures. This accumulation is more common in patients with renal disease but can occur with repeated dosing in patients with normal renal function.6,85 However, in one recent retrospective study (examining a mostly pediatric population), meperidine-related seizures were rare, occurring in only 0.4% of patients and 0.06% of admissions.86

The starting dose is for meperidine is 1 mg/kg, preferably given intravenously. While some physicians fear larger doses of narcotics, one study of 72 ED patients 18-63 years old showed that respiratory depression did not occur in those who received anywhere from 1.5-3.0 mg/kg of IV meperidine.87
 
Fentanyl

Fentanyl is less often used to treat painful crises because of its relatively short duration of action. However, on the plus side, it does not produce the histamine release associated with morphine.6 Dosing is typically 1-2 mcg/ kg (that's micrograms) IV in children and 50-150 mcg IV in adults, depending on tolerance. Fentanyl has the uncommon but disturbing side effect of producing chest wall rigidity if given too quickly.

One small study examined the use of transcutaneous fentanyl in children with sickle cell crisis. While the transcutaneous fentanyl was not associated with any adverse effects, it was associated with a  significant delay in achieving therapeutic levels.88

Nonsteroidal Anti-inflammatory Drugs

In the guidelines published by the American Pain Society, the committee suggested, "Pharmacological management of mild-to-moderate-pain should include nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen, unless there is a contraindication."22 Furthermore, the authors designated this recommendation as having the highest level of evidence (Grade A) based on a review of the medical literature.

Several groups have examined the use of ketorolac (Toradol) in the treatment of vaso-occlusive crises. The data regarding its value are mixed. One prospective study examined the use of IV ketorolac and IV fluids in 51 children with 70 episodes of vaso-occlusive pain. IV ketorolac (0.5-1.0 mg/kg) resulted in adequate resolution of pain in 53% of episodes. However, children with four or more painful sites or those with an initial VAS score greater than 70 usually required additional IV analgesics.89 On the other hand, in a separate placebocontrolled study of children with a painful crisis, ketorolac had no additional effect when given with a standard dose of IV morphine.90 Other studies question the value of ketorolac in adults with vaso-occlusive crises. One series examined 18 adult patients who presented to the ED with sickle cell crisis pain a total of 24 times. These patients were randomized to either 60 mg of IM ketorolac or placebo in addition to a standardized dose of meperidine based on severity of pain. The use of IM ketorolac did not reduce the need for narcotics during the four-hour treatment period.91

While NSAIDs are frequently used to control pain in vaso-occlusive crisis, they carry certain risks. They may cause or contribute to renal failure, especially when used chronically. There is one report of irreversible renal failure attributed to IV ketorolac used in a child suffering from a painful crisis.92 NSAIDs may also cause gastrointestinal bleeding, which can be especially dangerous for the patients with SCD, who typically suffer from baseline anemia.

Other Agents

While acetaminophen alone may be effective in the treatment of mild vaso-occlusive pain, it is unlikely that such mild symptoms would provoke a trip to the ED.

Adjunctive Therapies
Fluids


In some EDs, patients with a painful crisis routinely receive IV fluids. This may stem from from the belief that hydration increases circulating volume, thereby enhancing the flow of sickled RBCs through the vasculature. From this perspective, some authors suggest IV fluids, using D5 NSS or half normal saline as the initial fluid replacement. They reccomend giving one and one-half times the patient's daily fluid requirement over the course of the ED stay, or administering both replacement and maintenance fluid requirements.29

Finding scientific support for this approach remains a challenge, as the need for IV fluids in patients with a painful crisis remains unproven. A MEDLINE search reveals no randomized trials showing that IV fluids provide better outcome than oral fluids (or any additional fluids) in patients with a painful crisis. Aggressive IV hydration may enhance the risk for the development of non-cardiogenic pulmonary edema and/ or acute chest syndrome in a patient with vaso-occlusive crisis.93 In light of these considerations, one respected reference suggests that oral fluids are preferred over the IV route in patients with a painful crisis who have no overt evidence of volume depletion.94

Oxygen

The routine need for oxygen appears to be another myth of sickle cell treatment. Although deoxygenation induces sickling in vitro, no controlled clinical studies prove that oxygen administered in the ED improves outcome or pain control. Still, the practice of indiscriminately placing patients who are not hypoxic on oxygen persists. The best evidence would suggest that oxygen therapy be reserved for those patients who are hypoxic or have respiratory distress.

In one randomized, double blind, placebo-controlled study of O2 vs. air, the use of 50% oxygen by facemask did not affect the severity or duration of pain.95 Other studies show similar results.96

Oxygen therapy is not benign—it may produce undesirable effects such as depression of erythropoiesis during prolonged use.6

Steroids

At least one study has examined the impact of steroids on vaso-occlusive crises in children. In this randomized, controlled trial, 36 children and adolescents with SCD who had 56 acute episodes of severe pain were studied. The authors found that a short course of high-dose methylprednisolone (15 mg/kg of body weight, to a maximum of 1000 mg given on admission to the hospital and 24 hours later) decreased the duration of severe pain in children and adolescents with SCD. However, patients who received methylprednisolone had more rebound attacks after therapy was discontinued.97 No follow-up studies have since been catalogued in MEDLINE.

Hydroxyurea

Hydroxyurea is a chemotherapeutic agent used in the chronic treatment of SCA. It primarily acts by increasing HbF concentrations and causes a small but significant rise in total hemoglobin.3 Various studies in adults with SCA show that hydroxyurea reduces the frequency of pain crises, ACS, need for transfusion, and admission.142 Similar results have been seen in limited studies with children.3

Hydroxyurea is not without its drawbacks. But more importantly, there is no indication for starting hydroxyurea in the ED. Its use is best reserved for hematologists.3

Indications For Admission

In one study that retrospectively examined 146 ED visits by 56 children with SCD, 73 (50%) were classified as "painful events," 43 (29%) as "febrile events," 20 (14%) as "painful and febrile events," and 10 (7%) as "other." Patients with recent onset of pain (< 24 hours in duration before the ED) were frequently hospitalized (P = 0.002). For children with febrile events, or painful and febrile events, the total WBC count and absolute neutrophil count were not associated with hospitalization.98

The need for admission depends on multiple factors, not the least of which is the severity of illness. (See Table 2.) However, other considerations such as the patient's social situation may be of nearly equal importance. If sent home, will they be able to return should they worsen? Do they have a phone to call 911? Do they have a friend or family with a car? 



The prudent emergency physician should also pay attention to the patient's concerns about the need for hospitalization and seek treatable precipitants of the crisis.

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Last Modified: 07/23/2017
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