Which factor is a possible cause of sickle cell crisis in a patient with sickle cell disease

Acute Painful Episodes (Painful Crises)

The acute painful sickle cell crisis is the hallmark of SCD and is the most common symptom among patients with this disease. It is defined as new onset of pain that lasts at least 4 hours for which there is no explanation other than vasoocclusion and that requires therapy with parenteral opioids or ketorolac in a medical facility.15 Most painful episodes, however, are mild in nature or of moderate severity and are usually treated at home with oral analgesics, bed rest, adequate oral hydration, and the application of local measures, such as a heating pad to the painful area.12,16 Severe painful episodes necessitate treatment in the emergency room or hospital. About 95% of hospital admissions of adult patients with sickle cell disease are for the treatment of acute painful episodes.17 The frequency and severity of these painful episodes vary considerably among patients and in the same patient from time to time.12 Infection, stress of any kind, and emotional upheaval may precipitate a painful crisis.12,18 In most patients, however, no obvious factor precedes the crisis.12,19 Objective signs of a painful crisis, such as fever, leukocytosis, joint effusions, and tenderness, occur in about 50% of patients at initial presentation.12,19 The acute painful episode (painful crisis) evolves through four phases: prodromal, initial, established, and resolving.12,20,21 Objective laboratory signs do occur during these phases in most patients provided the tests are done serially and compared with established steady-state values.12,20,21 Moreover, recent studies have suggested a vasoocclusive “phenotype” that consists of patients with relatively higher hemoglobin levels who clinically display increased frequency of pain, acute chest syndrome, and avascular necrosis.22 About 10% to 15% of patients with SS have very frequent severe crises (10 to 20/y). This subset of patients is almost always hospital or emergency room bound and evokes considerable resentment among some health care providers who, in turn, develop stereotyped misconceptions about SCD in general. Pain usually involves the low back, legs, knees, arms, chest, and abdomen in decreasing order of frequency.12,23 Pain may be throbbing, sharp, dull, or stabbing in nature. Bone marrow infarcts are associated with the most severe pain that is pounding-stabbing in nature and forces the patient to assume certain postures (crouching, raising legs, etc) in an effort to mitigate the intensity of the pain.12,23

Sickle Cell Crises

There are four types of sickle cell crises (Diggs, 1965). These are vasoocclusive, aplastic, splenic sequestration, and hyperhemolytic. The most common is the vasoocclusive (‘painful’) crisis. Vasoocclusive crisis has sudden onset, usually lasts 5–6 days, and may be localized in one area of the body or generalized. Recent evidence suggests that the pain is caused by bone marrow ischemia, which explains why there are so few changes detectable by physical examination and standard laboratory testing. For those severely affected by frequent episodes of pain, treatment with hydroxyurea has been recently shown by the Multi-Institutional Study of Hydroxyurea (Charache et al., 1995) to reduce the frequency of both pain events and acute chest syndrome by 45–50%. The suggestion that hydroxyurea reduces vasoocclusion has led to trials of this drug in young children to determine whether this drug will reduce the frequency or severity of end-organ damage (Ware et al., 2004).

Worsening anemia characterizes the three other kinds of crises. In the aplastic crisis, there is a temporary suppression of the RBC precursor cells in the marrow, usually by a viral infection. Splenic sequestration crisis is characterized by a bacterial infection that causes the spleen to enlarge rapidly, trapping RBCs and preventing them from re-entering the bloodstream. Hyperhemolytic crisis occurs due to infections, certain drugs, or toxins, and results in an acute increase in RBC destruction. In these types of crises, hemoglobin levels fall faster than the bone marrow can manufacture red blood cells, and the anemia becomes life-threatening. Aplastic, splenic sequestration, and hyperhemolytic crises are common only in SCA.

Sickle Cell Disease

Sickle cell disease complications during pregnancy include sickle cell crisis affecting the bones and joints which can occur at any time during pregnancy, labour and the puerperium. Crises during the last 4 weeks of pregnancy and the first 4 days after delivery are more severe, necessitating immediate partial exchange blood transfusion and rapid delivery, by induction of labour or caesarean section as necessary, according to the clinical scenario: delay may cause fatality in a sickle cell crisis situation. The most serious clinical scenario is bone marrow embolism, which has been called pseudotoxaemia. It is characterized by systolic hypertension and proteinuria, without oedema and it is important not to mistake pseudotoxaemia for pre-eclampsia, as inappropriate treatment such as heavy sedation may be given, which can be fatal. Sickle cell crisis can also affect the lungs and brain causing headaches or in the kidneys causing low backache.

Sickle cell disease is associated with anaemia and coupled with malaria and further haemolysis significantly increases the demand for folic acid; 5 mg should be given daily in all pregnant women with sickle-cell disease.

Aplastic crisis is typically a paediatric problem but can be seen in adolescent pregnant girls with sickle-cell disease. A high level of alert for bacterial infection, particularly in the puerperium is required for these patients. Obstetric complications such as haemorrhage, fetal malpresentation, pre-eclampsia and multiple pregnancy in these complicated patients require impeccable obstetric care.4

CLINICAL ISSUES

CLINICAL ISSUES

Other cardiac findings

Although patients with SCD are predisposed to lifelong sickle cell crises involving hypoxia and reperfusion abnormalities, myocardial infarction from atherosclerotic coronary artery disease has been rare. Hence, regional wall motion abnormalities on echocardiography are also not common in SCD. Instead, these patients seem to have evidence of myocardial fibrosis (Fig. 183.3) and abnormal myocardial perfusion reserve suggesting abnormalities in the microvasculature.10 In addition to microvascular dysfunction, individuals with SCD have evidence of aortic stiffness, despite the presence of a normal systemic blood pressure.10 Although sickle cell patients can require a high burden of blood transfusions, the presence of myocardial siderosis is infrequent, in contrast to patients with β-thalassemia.

Acute Synovitis and Septic Arthritis

When the epiphysis is involved by infarction of sickle cell crisis, a joint effusion may develop. This presentation is an acute synovitis and is clinically indistinguishable from a septic joint.25 Synovial fluid should be examined and cultured for accurate diagnosis. In a retrospective review of 2000 consecutive adult patients with sickle cell disease, 3% had septic arthritis.26 The majority of these patients (56/59) had Hb SS. Thirty-six of the 59 infections involved the hip. Symptoms were pain, swelling, and fever higher than 38.2° C, a peripheral white blood cell count of 15,000/mm3, erythrocyte sedimentation rate greater than 24 mm/hour, and C-reactive protein greater than 20 mg/L. Cultures were positive in 96% of the joint aspirates, with staphylococcus and Gram-negative infections the most common. Prior diagnosis of osteonecrosis, osteomyelitis, and comorbid medical conditions of diabetes mellitus and use of corticosteroids and hydroxyurea were associated with septic arthritis. It is suggested that a clinician should have a high index of suspicion for septic arthritis in patients with sickle cell disease who present with fever and joint pain. Distant osteomyelitis was more often the source of a joint infection than contiguous osteomyelitis. If a joint infection is suspected, the patient should undergo aspiration and culture of the synovial fluid.

Another form of arthritis in patients with sickle cell disease is polyarticular (80%) and symmetric (60%) in the majority of patients and generally involves the large joints of the lower extremity.27 Symptoms last less than 1 week, and radiographic changes are consistent with periarticular osteopenia, erosions of bone, and joint space narrowing.

Nervous system

Ketamine, in contrast to volatile anesthetics, is known to elevate intra-ocular pressure (IOP). A small prospective descriptive study in children with glaucoma, investigated the effect of sevoflurane induction followed by intravenous ketamine infusion, on IOP, and to establish the earliest time point at which reliable, repeatable IOP measurements could be obtained [39c]. 25 children received a standardized anesthetic protocol (sevoflurane gas induction, 2 mg/kg IV ketamine bolus and 4 mg/kg/h maintenance for 15 min). IOP measurements were taken in the supine position with a Perkins applanation tonometer. Mean IOP post induction of anesthesia was 3.68 mmHg lower than following ketamine maintenance (P = 0.002). The study concluded that sevoflurane's IOP lowering effect is terminated within 15 min after the discontinuation of inhalational gas if anesthesia is maintained with a ketamine infusion, and that IOP measurements stabilize at this time point until near wakefulness. The absence of awake IOP reference measurements and the small patient cohort may limit the clinical application of this study.

A randomized double-blind controlled trial was conducted to compare ketamine topical wound administration to IM ketamine and placebo for patients after total thyroidectomy [40c]. 90 adult ASA I–II patients (age 18–60 years), who were scheduled for total thyroidectomy were randomized into three groups: Group I: (n = 30) 1 mg/kg ketamine in 10 mL 0.9% saline instilled into the wound, Group II: (n = 30) 1 mg/kg of IM ketamine and Group III: (n = 30) had 10 mL of normal saline instilled into the wound. Total amount of morphine consumption, first request of analgesia and side effects were recorded. VAS pain assessment at rest and on movement, and haemodynamics were assessed immediately and at regular intervals. Total morphine consumption was reduced significantly in Group I (6.20 mg) compared with Groups II and III (13.63 and 16.57 mg, respectively), and in Group II compared to Group III (P = 0.000). The time to first request of analgesia was delayed significantly in Group I (10.70 h) compared with Groups II and III (6.17 and 4.57 h, respectively) and similarly in Group II compared to Group III (P = 0.000). No significant difference was found in hemodynamic variables (BP and HR) or RR.

Sedation scores in the first 6 h were significantly increased in Group II compared with Groups I and III (P < 0.05, score represented in graphical form). Small numbers developed PONV (gp I: N: 13%, V: 10%, gp II: N: 16%, V: 6% and gp 3: N: 16%, V: 10%, NS). Two patients in Group I and 4 in Group II reported headaches and two patients developed hallucinations in Group II. However, no significant differences in side effects was identified between the 3 groups.

Two case reports described the use of ketamine based analgesia for sickle cell crisis in pregnancy [41A]:

Case A: A 25-year-old patient (26/40 weeks gestation) was admitted to hospital with sickle cell crisis and uncontrolled pain. Investigation for infection was negative and she did not improve after 3 days of a hydromorphone PCA infusion, oxygen, and IV fluids. On day 4, she was started on duloxetine and a 10 mg/h ketamine infusion, titrated to effect and tolerance. Higher doses were not tolerated because of dizziness and visual hallucinations; thus, the rate was maintained at 10 mg/h for the duration of therapy. The patient did not self-report a consistent decrease in her pain scores (8/10–10/10 throughout the admission); however, PCA use steadily decreased, over the course of the ketamine therapy, from 35.2 mg/12 h on day 4 to 13 mg/12 h on the final day of treatment. The fetal heart tracing decreased in variability in comparison to prior tracings. However, tocometry showed increased uterine irritability and multiple non-palpable contractions with unchanged cervical dilation. Patient A returned 2 weeks later at 30 weeks and 3 days with premature rupture of membranes and uncontrolled extremity pain. The team restarted a ketamine infusion at 10 mg/h, and the patient discharged home on day 5 post-delivery on oral analgesics.

Case B: A 29-year-old (31/40 gestation) was admitted with sickle cell crisis and started on IV fluids, oxygen, 10 mg/6 h oxycodone and a hydromorphone PCA infusion. Investigation for infection was negative. Due to increasing PCA requirements and with no improvement in pain scores, a ketamine infusion was commenced on day 2. Ketamine was titrated from 10 to 25 mg/h during the first day. However, her pain did not improve throughout the day and she underwent an exchange transfusion. Over the next 4 days, her pain improved from 7/10 to 0/10 and the ketamine infusion was discontinued on hospital day 5. She did not experience dizziness, sedation, or hallucinations. Non-stress tests remained appropriate for gestational age throughout ketamine administration. She was discharged on hospital day 7 on oxycodone and paracetamol for pain control.

The benefit of ketamine in these circumstances was noted; however, it was recognized by the authors that well designed prospective trials are needed in order to validate ketamine use in this setting.

The analgesic properties of ketamine were the focus of an RCT investigating the effects of intranasal (IN) ketamine compared to intranasal fentanyl for children undergoing tonsillectomy [42c]. 63 children were randomised into three groups: Group 1: IV paracetamol 10 mg/kg, Group 2: IN ketamine 1.5 mg/kg and Group 3: IN fentanyl 1.5 mcg/kg. In all three groups, initial dose was administered on induction of anaesthesia and subsequent doses (same dose) administered three times a day for 24 h. The Children's Hospital of Eastern Ontario Pain Scale (CHEOPS Score 0–10) and Wilson sedation scale scores (Score 1–5) were recorded at 15, 30 and 60 min, 2, 6, 12 and 24 h post-operatively. Patients were interviewed on the day after surgery to assess the postoperative pain, nightmares, hallucinations, nausea, vomiting and bleeding. IN ketamine and IN fentanyl provided significantly improved analgesia compared to IV paracetamol at postoperative 15, 30, 60 min and at 2, 6, 12 and 24 h (P < 0.05). Worsening Wilson's sedation scores were observed in the IN ketamine group at 15 min post operatively (Group 1 [Mean ± SD]: 1 ± 0.2, Group 2: 1 ± 0.2, Group 3: 1.2 ± 0.4, P = 0.047), 1 h post operatively (Group 1 [Mean ± SD]: 1.2 ± 0.4, Group 2: 1 ± 0.1, Group 3: 1.2 ± 0.4 P = 0.044) and at 2 h post operatively (Group 1 [Mean ± SD]: 1.2 ± 0.5, Group 2: 1 ± 0.1 and Group 3: 1.3 ± 0.4, P = 0.046). Cognitive impairment, constipation, nausea, vomiting and bleeding were not observed in any of the groups. The preliminary nature of the study and resulting small sample size, and single centre design would necessitate further investigation in order to confirm the results.

IV sub dissociative dose ketamine (SDK) infusions are used for managing pain in the ED. A retrospective chart review of patients (> 18 years) who presented with acute/chronic painful conditions (n = 104) evaluated SDK use and feasibility in the ED [43c]. Infusions started at 0.15 mg/kg/h and were increased every 30 min by 2.5–5 mg as determined by the treating physician. Average dosing of SDK was 11.26 mg/h for a mean duration of 35.87 min. The use of pre-infusion analgesia (any analgesia administration by the treating physician prior to initiation of SDK) and post analgesia (administration of opioid or non-opioid analgesia from the end of infusion to discharge from ED) was noted, in addition to pain scores on a numerical rating scale, and adverse effects. 46.2% of patients did not have documented pain scores which reduced the validity of the results. The average decrease in pain score on a numerical rating scale was 5.04 (P < 0.0001). Pain scores reductions were also observed in individual cohorts: Abdominal pain: 4.95 (P < 0.0001), musculoskeletal pain: 4.78 (P < 0.05) and neuropathic pain: 3.69 (P < 0.005). Patients with abdominal, musculoskeletal and cancer pain had significantly reduced non-opioid analgesia requirements post-SDK (P < 0.05). However, patients with neuropathic pain showed an increase in opioid only analgesic administration (P = 0.064) (total patient numbers not supplied). Five adverse effects were noted in a total of 12 patients. Nausea (5.8%), headache (1.9%), dizziness (1.9%), rash (1%) and confusion (1%). 92 (88.4%) had no adverse effects documented. 2 patients (1.95) required discontinuation of SDK due to severe nausea. The retrospective design of the study, small sample size, lack of documented pain scores in 46.2% of patients, and absence of data on pre and post infusion doses of additional analgesia represent major limitations. However, the study did conclude that the reduction in pain scores and relative lack of major adverse effects made this a feasible option for pain control in the ED and thus merits further investigation for this purpose.

Procedural sedation is a common occurrence in the ED to conduct otherwise painful procedures in a humane manner and avoid unpleasant procedural memories. A prospective observational study was carried out in patients (over 6 years old) from two hospitals investigating the use of ketofol and sequential ketamine/propofol [44c]. Patients received either ketofol (1:1 mix in aliquots of 0.1–0.3 mg/kg followed by additional boluses of 0.1 mg/kg) or sequential ketamine (0.1–0.3 mg/kg) and propofol (0.1–0.3 mg/kg), followed by boluses of 0.1 mg/kg propofol (KP). Supplemental oxygen was administered and standard monitoring was employed throughout. A standardized criterion (Quebec criteria) was used to monitor memory and adverse events at 30 min with telephone follow-up after discharge. The ketofol group had significantly more immediate (2.9% vs 1.6%, OR 1.8, 95% CI 0.6–5.9) and delayed (4.7% vs 1.7%, OR 2.9, 95% CI 1.0–8.4) procedural memories (P values not available). This may be related to a higher dose of ketamine administered. Following multivariate logistic regression analysis, an association with male sex, opiate use, sedation depth and propofol dose was identified. The ketofol group had a significantly increased number of respiratory adverse events including central apnea requiring extra supplemental oxygen, although this must be considered in the context of increased peri-procedural opiates in these patients. Statistical data are limited and so generalizability of these results may also be limited.

Treatment

The management of patients with sickle cell disease is targeted at limiting sickle cell crises and end-organ damage. Factors that trigger sickling, such as infection and dehydration, should be treated aggressively. Exposure to hypoxia, cold, or medications that may induce sickle cell crisis should be avoided. Treatment options include transfusion therapy and, more recently, bone marrow transplantation. Hydroxyurea increases the hemoglobin F concentration, which results in over 40% reduction in the median annual rate of pain crises. However, it is not known whether a reduction in the frequency of sickle cell crises translates to a lower incidence of renal disease. ACE inhibitors should be used in the presence of proteinuric renal insufficiency to retard disease progression. Patients with sickle cell disease who reach ESRD have a 60% survival rate at 2 years after the administration of renal replacement therapy. Dialysis is the most common form of renal replacement therapy employed. Kidney transplantation has been performed in small numbers of patients. One-year survival rates are broadly comparable with other causes of ESRD but there is a trend toward a lower allograft survival thereafter. Nevertheless, patient survival appears better with renal transplantation compared with maintenance hemodialysis.

6.5 Sickle Cell Anemia

A 15-year-old patient, A-positive, presents in sickle cell crisis with a hemoglobin of 7.8 g/dL. She is known to have anti-E and anti-S, and to be serologically negative for the antigens C, E, K, Fya, Fyb, and S. In accordance with institutional protocol for providing matched antigen-negative RBC units for patients with sickle cell anemia, the patient is transfused with a unit that is negative for the E and S antigens, as well as for C, K, Fya, and Fyb. If a full serological phenotype is available, what additional testing is needed for transfusion management?

Test results: Molecular testing with a microarray method predicts the patient's red cell as negative for C, E, K, Fya, Fyb, and S, compatible with the serological phenotype. The molecular test reports that the patient carries the −67t>c mutation in FYB and is homozygous for the RHCE mutation 733C>G (VS + phenotype).

Comment: Molecular typing is indicated because it provides information relevant for transfusion management that is not available with serological testing. The −67t>c mutation in the FYB promoter does not allow for expression of the Fyb antigen on red cells, even though the antigen is expressed in other tissues. The patient will not make anti-Fyb, and prospectively matched Fyb-negative units are not necessary for future transfusions. Expression of the VS antigen is associated with partial c and partial e antigens. As both RHCE alleles carry the 733C>G mutation, the patient has no conventional c and e antigens and is at risk for developing anti-c and anti-e alloantibodies. Since she already has anti-E, it will be nearly impossible to find compatible units, and transfusions must be undertaken with an acknowledgment of the risk of further alloimmunization.