1045 e2 Signs/symptoms 1 Increased pallor 2 Lethargy 3 Poor appetite 4 Shortness of breath 5 Jaundice Evaluation 1 PE 2 CBC, retic, T&S, hemolysis labs, stool, guaiac, UA 3 Measure spleen size 4 Consi[.]
1045.e2 ANEMIA ALGORITHM Signs/symptoms Increased pallor Lethargy Poor appetite Shortness of breath Jaundice Evaluation PE CBC, retic, T&S, hemolysis labs, stool, guaiac, UA Measure spleen size Consider CXR Compare labs to patient’s baseline; fetal Hb and HU can increase MCV, α- and β-thalassemia can decrease MCV HCT ≥18 Hct 6% drop MCV at baseline Consider folate deficiency, check folate, Vit B12 levels ↓Retic below baseline ↓↓Retic below baseline Replete as indicated ↓Erythropoiesis Aplastic crisis Spleen size increased +/– ↓platelets Consider serial monitoring Hct/ retic Consider need for transfusion NL spleen ↑Bili ↑LDH ↑Serum transaminase ↑Bili RUQ pain Daily observation and consider admission to hospital Hyperhemolytic crisis Hepatic sequestration Consider transfusion Consider transfusion Consider transfusion Acute splenic sequestration Consider serial Hct/retic Assess need for transfusion ↓Retic ↓MCV ↓Hct Hct >6% drop MCV at baseline Retic at baseline or increased • eFig 88.15 Clinical guidelines for acute anemia in sickle cell disease Bili, bilirubin; CBC, complete blood count; CXR, chest x-ray; Fe, iron; Hb, hemoglobin; Hct, hematocrit; HU, hydroxyurea; LDH, lactate dehydrogenase; MCU, mean corpuscular volume; NL, normal; PE, physical exam; retic, reticulocytes; RUQ, right upper quadrant; TIBC, total iron-binding capacity; T&S, type and screen; UA, urinalysis; (From Center for Children with Special Needs Sickle Cell Disease—Critical Elements of Care 5th ed Seattle: Seattle Children’s Hospital; 2012.) Consider iron deficiency Evaluate Fe profile TIBC, Fe, % saturation Iron repletion 1046 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology 100,000 people with SCD in the United States, this translates into about 30,000 cases of PAH, making SCD the leading cause of PAH nationally Although there has been concern for overdiagnosing PAH in SCD by an elevated tricuspid regurgitant jet velocity (TRV) on transthoracic echocardiography (TTE), it is increasingly understood that adults with estimated PAPs greater than 25 mm Hg or a tricuspid regurgitation velocity jet velocity (TR jet) of greater than 2.5 m/s have a strikingly higher mortality rate.89–91 Thus, it is essential to have a significantly lower threshold for aggressive intervention for PAH in the hemoglobinopathy patient than in others Pathophysiology and Etiology Multiple pathways contribute to PAH in the sickle cell patient.88 Hemolysis leads to NO dysregulation, vascular dysfunction, injury, and inflammation, which can ultimately lead to PAH.91–93 Progressive increases in pulmonary vascular resistance related to decreases in NO availability and dysregulation ultimately lead to right ventricular failure and decreased cardiac output The 2014 American Thoracic Society Guidelines for PAH in SCD define PAH as a resting mean pulmonary arterial pressure equal to or exceeding 25 mm Hg.87 Frequent confounding factors in the PAH of SCD include (1) hypoxic PAH due to the high incidence of enlarged tonsils, obstructive sleep apnea, asthma, and chronic lung disease; (2) arterial obstructive PAH secondary to increased coagulation and embolic disease; and (3) pulmonary venous hypertension due to cardiomyopathy Contributing to the high morbidity in SCD are the protean manifestations of mild pulmonary hypertension (.25 mm Hg) The majority of patients with SCD and PAH will be asymptomatic or have mild decreases in exercise tolerance (e.g., 6-minute walk) yet have a 10-fold increased risk of death.90 Increased mortality for adults with SCD has been associated with a TRV of 2.5 m/second or higher (10 times greater mortality risk), N-terminal pro b-type natriuretic peptide levels of greater than 160 pg/mL (at least times greater mortality risk), and pulmonary artery pressure higher than 25 mm Hg on right ventricular heart catheterization Sufficient data in children are lacking; thus, some suggest using the American Thoracic Society adult criteria However, the use of adult diagnostic criteria is controversial, as children not appear to confer the same increased risk of death within years of diagnosis as their adult counterparts.94 Diagnosis urrent diagnostic recommendations have focused on adult paC tients, leaving guidelines for younger patients contentious Many use a TRV over 2.5 m/s as measured by echocardiogram as a criterion for diagnosis.90 Though cardiac catheterization is the gold standard for determination of PAH, it is invasive and expensive Catheterization is reserved for those with a TRV greater than 2.8 or greater than 2.5 in adults who have additional risks, such as symptoms and elevated brain natriuretic peptide or decreased 6-minute walk.87,88 Management lthough there is minimal evidence for specific therapies in the A treatment of PAH in SCD, a multitiered approach is accepted by many87,88: (1) identifying and reversing factors potentially contributing to PAH (e.g., tonsillectomy and adenoidectomy, BiPAP or continuous positive airway pressure [CPAP], and nighttime O2 if contributing to obstructive sleep apnea [OSA]); (2) optimizing sickle cell–specific care (e.g., hydroxyurea or chronic transfusions); and (3) applying PAH-specific therapies Hydroxyurea (HU) is the first-line treatment for SCD-specific care, as it decreases hemolysis and sickle cell formation and lowers the incidence of ACS and VOE (both of which are associated with acute increases in pulmonary pressures) Chronic transfusion therapy is the second-line therapy for PAH in SCD, reserved for those who not respond to HU Although controversial and lacking data, the mortality risk of PAH is felt to outweigh the potential side effects of transfusion therapy For those with PAH defined by right heart catheterization, additional therapies are recommended For those with venous thromboembolism and no additional risk factors for bleeding, indefinite anticoagulant therapy is recommended Targeted PAH therapies— such as prostacyclin agonists (e.g., iloprost), endothelin receptor antagonists (e.g., bosentan), soluble guanylate cyclase stimulators (e.g., riociguat), or phosphodiesterase-5 inhibitors (e.g., tadalafil)— and other PAH therapies should be considered, but limited data exist for their use (see also Chapter 53) Despite considerable enthusiasm for the use of sildenafil, a randomized controlled trial was halted early due to an increase in VOE in the treatment group, emphasizing caution in applying accepted PAH therapies to SCD.95 A mainstay of treatment of PAH in the ICU is inhaled NO (iNO), which provides both direct vasodilation of the pulmonary vasculature and simultaneous reversal of the underlying disruption in NO metabolism The major challenge with iNO is the development of rebound PAH on discontinuation of therapy and difficulty in administration, thus driving a focus on alternative therapies Blood arginine is diminished in SCD and correlates with TRJ Oral arginine, a precursor of NO, has been investigated and shown to reduce PAP within days of therapy initiation in a small number of patients with SCD.96,97 Multiorgan Failure Multiorgan failure syndrome is defined as severe pain associated with failure of at least two of the following organs: liver, lung, and kidney It is often associated with severe pain in patients with previously mild disease and a relatively high Hgb.98 Bone marrow necrosis with fat emboli and widespread vasoocclusion are thought to be responsible, though data are lacking Patients present with an atypically severe VOE and a fever followed by a sudden and rapid deterioration, including a drop in Hgb and platelets, diffuse encephalopathy, and rhabdomyolysis Death has been reported in up to 25% of patients.99 Exchange transfusion should be considered early and can result in rapid recovery of organ function as well as improved survival Similarly, ECMO has been used successfully.98,100Antibiotics are often used, though many patients are culture negative There are isolated reports of success with NO or plasma exchange in those with transfusion-resistant disease, consistent with the idea that this may represent a thrombotic thrombocytopenia–like state.101 Renal Conditions The hypoxic, acidotic, hypertonic milieu of the renal medulla is an environment that promotes sickling of RBCs within the renal microvasculature, leading to renal injury.102,103 In SCD, and sometimes even in SCT, sickling in the kidney leads to increased viscosity and ischemia, causing damage to the renal medulla, such as segmental scarring and interstitial fibrosis, which can progress to infarction and papillary necrosis SCD kidney injury generally presents with hematuria, which can range from microscopic to gross Conservative management with bed rest, IV fluids, and maintenance of high urine output to avoid the development of thrombosis usually suffices Transfusions may be needed if blood loss is significant Vasopressin has been used with some success, as has ε-amino caproic acid, though the latter should be used with caution, as it can lead to thrombosis If recurrent transfusions are required or bleeding becomes lifethreatening, resection of the involved region may be indicated CHAPTER 88 Hemoglobinopathies Hyposthenuria, or the inability to concentrate urine, occurs almost universally in people with SCD and has an onset in early childhood It is critical to remain aware of this condition in the ICU, as the production of dilute urine cannot be used as a marker for being euvolemic, and patients are prone to dehydration, leading to vasoocclusive complications Tubule dysfunction can also occur in SCD, including an incomplete renal tubular acidosis that is worsened by the hyposthenuria Hyperkalemia may develop secondary to impaired urinary potassium excretion, the use of potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, or b-blockers Patients with SCD experience recurrent, often insidious renal insults throughout their lives, leading to the development of chronic kidney disease (CKD) in at least 25% of older adults.104 Risk factors include hypertension, hematuria, proteinuria, and worsening anemia Angiotensin-II-receptor-1 blockers and angiotensin-converting enzyme inhibitors can reduce the proteinuria.105 NSAIDs should be used with caution or avoided in those with CKD Worsening anemia can be treated with erythropoietin, though patients may have erythropoietin resistance and often need higher doses than others to achieve the desired effect Iron Overload Unlike in thalassemia, the iron overload of SCD is primarily related to transfusion.106 SCD and thalassemic patients show different temporal patterns of iron deposition, with the heart accumulating iron far less readily in SCD than in thalassemia The acute management in the ICU is similar and is discussed in the Thalassemia section that follows Sleep Conditions and Depression and Suicide in Sickle Cell Disease For a detailed discussion of these topics, see eBox 88.1 Surgery and Anesthesia A detailed care plan for the SCD patient scheduled for surgery and anesthesia is provided in eFig 88.16.22 Major surgery in SCD patients is associated with increased perioperative risks, including VOE pain, ACS, and death, but these can be minimized with specific perioperative care Preoperative direct transfusion targeting an Hgb of 10 minimizes these risks and is preferred over an exchange transfusion in most cases.119,120 Communication and coordination between the anesthesiologist, surgeon, and hematologist are essential Institutions are encouraged to employ a standard perioperative care plan for SCD Most patients are admitted overnight following surgery for supplemental oxygen, pain management to ensure the ability to deep breathe and perform incentive spirometry, and for monitoring for pain and pulmonary complications, even if cleared to return home from a surgical standpoint Because of poor compliance with incentive spirometry, the use of BiPAP in the immediate postoperative period may be beneficial.121 Specific recommendations should be followed (see eFig 88.16) Disease-Modifying and Curative Therapies for Sickle Cell Disease Preventive measures and disease-modifying therapies have led to dramatic improvement in morbidity, mortality, and quality of life for people living with SCD.48 Hydroxyurea and transfusion therapy, discussed in this section, are established interventions 1047 with decades of compelling data to support their use Newer emerging therapies target specific mechanisms involved in the pathophysiology of SCD, some of which are curative (see eFigs 88.17 to 88.20 for an overview).122 Hydroxyurea The intensivist should be aware that most patients with HbS/S and S/b0 thalassemia are now offered hydroxyurea at months of age, as it has been shown to decrease the frequency of pain episodes, ACS episodes, hospitalizations, and transfusion needs, while increasing Hb, quality of life, and life span.20,84,123–126 Hydroxyurea mitigates the symptoms of SCD by inducing the production of fetal Hb and by inducing a relative leukopenia The relative leukopenia induced by hydroxyurea helps decrease inflammation and vascular adhesion (see earlier Pathophysiology and Etiology sections) When assessing CBCs in patients on hydroxyurea, clinicians should be aware that hydroxyurea can cause cytopenias and lead to red cell macrocytosis with mean corpuscular volumes (MCVs) into the 120 fL range There is no recommendation to discontinue hydroxyurea during acute illness or hospitalizations; however, hydroxyurea should be held when the absolute neutrophil count drops below 1200/mL or the platelet count drops below 80,000/mL Hydroxyurea can cause a transaminitis and is renally cleared; thus, dosing should be adjusted or held in those with hepatic or renal compromise Transfusion Guidelines for transfusions in SCD are complex and vary by indication.20,127,128 Because of alloimmunization and other risks, attempts should be made to avoid transfusion unless there is a clear clinical indication, and consultation with hematology is advised The reflective tendency to transfuse SCD patients should be eschewed; in particular, the all-too-common practice of transfusing patients admitted for uncomplicated cases of VOE should be avoided.20,127,128 eTable 88.3 summarizes guidelines; additional information is provided in earlier sections of this chapter.20,127,129–133 General guidelines for transfusion are provided in Chapter 91 for general information regarding blood transfusion SCD-specific issues follow Choice of Product e choice of red cell products for patients with SCD deserves Th several important considerations To minimize the risk of alloimmunization, units should be ordered with an extended cross-match for antigens of clinical significance, which include, at a minimum, the Rh (Cc, D, Ee) and Kell antigens in addition to ABO 20,134–136 Finding compatible units for highly alloimmunized patients may take considerable time Thus, a type and cross should be sent well before blood is needed In some emergent situations, extended matching may need to be forgone Packed RBCs should be leukodepleted to minimize febrile reactions and alloimmunization Although transfusion of red cells from donors with SCT (individuals with SCT have ,40% HbS) is safe and effective, HbSnegative blood should be requested, as it complicates assessment of posttransfusion HbS levels Unlike protocols used for patients with hematologic malignancies, there is no need for blood-product irradiation or cytomegalovirus (CMV)-negative selection unless the patient is waiting for or undergoing transplant Type and Goals of Transfusion oals of transfusion in SCD include increasing O2-carrying capacity G and/or decreasing HbS and can be achieved by simple transfusion, manual exchange transfusion, or automated exchange transfusion (erythrocytapheresis) The target Hb concentration or HbS percentage 1047.e1 • eBOX 88.1 Sleep Conditions and Depression and Suicide in Sickle Cell Disease (SCD) Sleep Conditions Children with SCD have a higher prevalence of obstructive sleep apnea (OSA) than the general pediatric population (20%–41%), likely due to greater airway crowding related to increased tonsillar, adenoid, and cervical node size.107–109 Data from diaries and sleep surveys suggest that sleep disturbances and OSA are correlated with pain, though polysomnography data related to hypoxia and apnea have questioned the relationship.23,109–111 Tonsillectomy and adenoidectomy may be helpful for some with OSA, and noninvasive ventilation with continuous positive airway pressure (CPAP) or biphasic positive airway pressure may be necessary CPAP is generally well tolerated in SCD and has been shown to improve sleep and cognitive function.112 Depression and Suicide With recurrent pain and complications that can occur without warning, it is not surprising that anxiety and depression are increased in patients with SCD.113,114 Interestingly, rates are higher than in cystic fibrosis, spina bifida, or diabetes, with 49% having anxiety symptoms in one study and teens with SCD having nearly twice the rate of attempted suicide compared with healthy peers.114–118 Anxiety and depression as well as suicidal ideation, if present, should be addressed in the acute care setting GENERAL ANESTHESIA AND SURGERY Pro-op evaluation Pre-op transfusion and pulmonary care • Baseline CXR, pulse ox, CBC, retic, U/A • Patient typically admitted the day before for transfusion and hydration while NPO Intraoperative • Minimum 50% O2 with anesthetic agent • Avoid hypoxia • Consider pulmonary • Simple transfusion targeting a Hct of 30–33% should (continuous pulse ox), function tests and/or be strongly considered for all children with Hb SS or hypercarbia, or ECHO for patients Sβ0-thalassemia prior to any procedure requiring hyperventilation with prior history of general anesthesia acute chest syndrome, • Surgery without pre-op transfusion in children with • Avoid tourniquets suspicion of chronic Hb S/S and Sβ0- thalassemia may be considered in • Avoid hypothermia lung disease or selected cases of non- or minimally invasive procedures decreased exercise (e.g., PE tubes or MRI/MRA) Note: tonsillectomy performance and/or adenoidectomy is not considered a minor • Coordination of periprocedure Recommendations for patients with Hb operative plan with S/C and Sβ+-thalassemia vary In general, transfusion hematology, surgery is not required for smaller procedures such as and anesthesia tonsillectomy and/or adenoidectomy, but transfusion is required for abdominal surgery Due to a high baseline Hct, these patients often require exchange transfusion Post-operatives • O2 by nasal cannula at L/min and continuous pulse ox even if O2 saturations are high Continue O/N and assess the next day Maintain saturations >93% • Document O2 saturations on room air intermittently to screen for increasing O2 need • Encourage early ambulation, activity ã IV + PO 11.25 ì maintenance Avoid excessive hydration, which may precipitate acute chest syndrome • Strict adherence incentive spirometry: 10 breaths q hr while awake Use of pain medication before this may be useful • Use antigen-matched if available, sickle-negative, leukocyte-depleted PRBC (at a minimum RhD, Cc, Ee and Kell) • Practice incentive spirometry or developmentally appropriate substitute (e.g., bubbles) • If history of obstructive disease, start steroid inhaler days before and scheduled albuterol the night before surgery ã IV hydration 11.25 ì maintenance while NPO before procedure Hold while receiving blood transfusion • eFig 88.16 Clinical guidelines for perioperative care in sickle cell disease CXR, chest x-ray; CBC, com- plete blood count; ECHO, echocardiography; Hct, hematocrit; IV, intravenous; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; NPO, nothing by mouth; O/N, overnight; PE, pharyngoesophageal; PRBC, packed red blood cells; U/A, urinalysis; (From Center for Children with Special Needs Sickle Cell Disease—Critical Elements of Care 5th ed Seattle: Seattle Children’s Hospital; 2012.) 1047.e2 • eFig 88.17 Novel agents targeting adhesion and coagulation in sickle cell disease Numerous adhesive interactions among sickle red blood cells (sRBCs), neutrophils, and endothelial cells contribute to sickle cell vasoocclusion Activation of endothelial cells leads to the recruitment of neutrophils, which is initiated by rolling of neutrophils on endothelial selectins, followed by adhesion Adherent neutrophils receive a secondary wave of signals transduced through E-selectin, leading to the activation of aMb2 (Mac-1) integrin on the leading edge Activated Mac-1 on adherent neutrophils mediates the capture of circulating sRBCs In addition, sRBCs express multiple adhesion molecules that interact with ligands on endothelial cells or the subendothelial matrix either directly or via bridging molecules in the plasma Rivipansel targets E-selectin predominantly, while crizanlizumab and sevuparin inhibit P-selectin–mediated adhesive interactions Intravenous immunoglobulin (IVIG) interferes with neutrophil-mediated sRBC capture Propranolol blocks various sRBC-endothelial interactions that are stimulated by b-adrenergic signaling such as LW (ICAM4)-aVb3 and BCAM/Lu-Laminin UFH and tinzaparin, in addition to their anticoagulant effects, target P-selectin ESL, E-selectin ligand; ICAM, intercellular adhesion molecule; LM, laminin; PSGL-1, P-selectin ligand; UFH, unfractionated heparin (From Morrone K, Mitchell WB, Manwani D Novel sickle cell disease therapies: targeting pathways downstream of sickling Semin Hematol 2018;55[2)]:68–75.) ... Hemoglobinopathies Hyposthenuria, or the inability to concentrate urine, occurs almost universally in people with SCD and has an onset in early childhood It is critical to remain aware of this condition... criteria is controversial, as children not appear to confer the same increased risk of death within years of diagnosis as their adult counterparts.94 Diagnosis urrent diagnostic recommendations... correlates with TRJ Oral arginine, a precursor of NO, has been investigated and shown to reduce PAP within days of therapy initiation in a small number of patients with SCD.96,97 Multiorgan Failure