1075 e2 TABLE 90 1 Epidemiology, Clinical Features, Diagnosis, and Complications of the Most Common Types of Non CNS Thromboembolism in Critically Ill Children—cont''''d Type/Location Age/Sex Incidence U[.]
1075.e2 TABLE Epidemiology, Clinical Features, Diagnosis, and Complications of the Most Common Types of Non-CNS 90.1 Thromboembolism in Critically Ill Children—cont'd Type/Location Age/Sex Incidence Underlying Illness or Risk Factors Cardiac valve Clinical Features Diagnosis Complications Murmur, valvular dysfunction Echocardiography Angiography, CT, MR Stroke Limb TE PE Doppler US (CT, MRI) Adrenal hemorrhage Renal failure Hypertension Death Portal hypertension and variceal hemorrhage Mechanical heart valves Shunts, including Fontan Acute loss of pulmonary blood flow Asphyxia, polycythemia and dehydration, sepsis, cyanotic CHD, infant of diabetic mother Flank mass Hematuria, proteinuria Thrombocytopenia Renal failure Nephrotic syndrome, burns, SLE, transplant Diarrhea and vomiting Dehydration, hypovolemia Neonates: UVC Children: Liver transplant, abdominal sepsis, splenectomy, sickle cell disease, APLA Up to 50% idiopathic Acute abdomen Portal hypertension– GI bleeding, splenomegaly Doppler US MRI/MRA CT Hepatic artery thrombosis Asymptomatic Pulsed Doppler real-time US Angiography CT/MRI Renal artery thrombosis Anuria, renal failure Other signs of acute rejection Doppler US 19% postFontan patients Cardiac shunt, including Fontan Renal vein thrombosis Neonates: Unilateral, 70% Bilateral, 30% Older children Portal vein thrombosis M 64% APLA, Antiphospholipid antibody; CHD, congenital heart disease; CNS, central nervous system; CR, capillary return; CT, computed tomography; CVAD, central venous access device; CVAD, central venous catheter; DVT, deep venous thrombosis; ECG, electrocardiogram; F, female; GI, gastrointestinal; IVC, inferior vena cava; M, male; MR, magnetic resonance; MRA, MR angiography; MRI, MR imaging; NEC, necrotizing enterocolitis; PE, pulmonary embolus; PFO, patent foramen ovale; PPS, postphlebitic syndrome; RA, right atrium; SLE, systemic lupus erythematosus; SVC, superior vena cava; TE, thromboembolism; UAC, umbilical arterial catheter; UVC, umbilical venous catheter; US, ultrasound; V/Q, ventilation/perfusion; VTE, venous thromboembolism 1076 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology in the blood constituents that predispose to thrombosis is also unknown Two classic examples of cardiac surgery–related thrombosis are the Blalock-Taussig (BT) shunt and Fontan procedure The incidence of thrombotic occlusion of BT shunts in the literature ranges from 1% to 17% Risk factors for patency and stenosis include the age of the patient and graft size.45 Perioperative platelet transfusion and postoperative ECMO have recently been reported as risk factors for increased shunt thrombosis.46 The CLARINET study found no advantage to adding clopidogrel to standard of care (aspirin) in preventing thrombosis of systemic to pulmonary artery shunts.47 There have been a number of reviews regarding anticoagulation after Fontan surgery.48–50 The Fontan procedure, or a modified version, is the definitive palliative surgical treatment for most congenital univentricular heart lesions Thrombosis remains a major cause of early and late morbidity and mortality Reported incidences of venous thrombosis and stroke ranged from 3% to 16% and 3% to 19%, respectively, in retrospective cohort studies in which thrombosis was the primary outcome and from 1% to 7% in retrospective studies assessing multiple outcomes Thrombosis may occur anytime following Fontan procedures but often presents months to years later No predisposing factors have been identified with certainty, although this may be due to inadequate power and the retrospective nature of the studies.51 Multiple studies have looked at thromboprophylaxis strategies but the optimal strategy remains unclear.52–54 Thrombophilia Congenital thrombophilia is usually defined as having the following features: (1) positive family history, (2) early age of onset of thromboembolism, (3) recurrent disease, and (4) multiple or unusual thrombosis locations Clinically, the most significant inherited prothrombotic conditions are deficiencies of AT, protein C (PC), and protein S (PS) because of the large increase in relative risk that these deficiencies confer Activated PC resistance/factor V Leiden (FV-R506Q) and prothrombin G20210A (IIG20210A) polymorphism, while having less impact on individual risk, are significant because of their frequencies in certain populations A large number of other candidate genes have been proposed as risk factors for congenital thrombophilia.55 However, most of these candidates have not undergone careful segregation or population studies to define their pathogenic role In fact, some of the seemingly obvious candidates, such as abnormalities in fibrinolysis, not appear to confer thrombotic risk.56 Recent reports demonstrate an increased risk for thrombosis in families with a second genetic abnormality.57 The major question with thrombophilias is whether they are involved in the pathogenesis of thrombosis in children and, then, does knowledge of their presence change treatment and potentially outcome?58,59 The reality is that, for most conditions, these questions remain unclear owing to poor level of evidence in children The role of thrombophilia in childhood stroke remains controversial However, some authors suggest that they are helpful in predicting risk recurrence.60 Screening prior to organ transplant would appear to be unhelpful.61 Earlier meta-analysis suggested that thrombophilia is a significant risk factor in childhood thrombosis However, there are serious limitations to the published literature on which these metaanalyses are based.62 More recent data show no evidence to support thrombophilia screening in children with CVAD-associated thrombosis.63,64 Uniform screening of children with major illnesses, and/or those who require CVADs, for congenital prothrombotic disorders in order to provide prophylactic therapy cannot be recommended In the PICU, it is likely that the dominant factors are clinical risk factors for thrombosis and that, if it contributes at all, thrombophilia may act as an additional hit in a multihit pathogenesis However, there remains no evidence to support routine screening for thrombophilia, and there are certainly no data to support primary prophylaxis of children with inherited heterozygous thrombophilia Further, there is no evidence that the presence or absence of thrombophilia changes acute treatment once a venous thrombosis is diagnosed Given the inherent difficulties in interpreting at least the functional assays of protein levels in acutely sick children, there seems little role for thrombophilia testing in the PICU Heparin-Induced Thrombocytopenia Heparin-induced thrombocytopenia (HIT) occurs in approximately 3% to 5% of adults exposed to unfractionated heparin (UFH) and is typically associated with a reduced platelet count, occurring to 10 days after heparin exposure, and an increased risk of thrombosis despite the thrombocytopenia HIT is the result of a complex antigen-antibody interaction; the most important therapeutic intervention once HIT is diagnosed is the immediate withdrawal of all heparinoid anticoagulants and substitution with nonheparinoid drugs until the risk of thrombosis is ameliorated.65 A number of case reports of pediatric HIT have described patients ranging in age from months to 15 years.66–70 UFH exposure in these cases ranged from low-dose exposure during heparin flushes used in maintaining patency of venous access devices to supratherapeutic doses given during cardiopulmonary bypass and hemodialysis Studies specifically examining the frequency of HIT in children have varied in their reported results, likely related to differences in patient inclusion and laboratory techniques.71–76 Reported rates vary from almost nonexistent in unselected heparinized children74 up to 2.3% in children in the PICU.75 However, HIT appears to occur far less frequently in children than in adults—the rationale for this is unclear.74 Many patients in the neonatal intensive care unit/PICU who are exposed to UFH have multiple potential reasons for thrombocytopenia and/or thrombosis, and recent papers confirm that many positive HIT tests are, in fact, false positives.77 Danaparoid, hirudin, and argatroban are alternatives to UFH in children with HIT.78–82 However, these drugs have significant risks in children Most recently, bivalirudin has been used as an alternative to heparinoids.83 Until such time as the true clinical incidence of HIT in children is understood, the diagnostic tests have higher sensitivity and specificity, and there are safe and reliable alternatives to heparin therapy in acutely sick children, the diagnosis of HIT in children should be made with caution Careful attention to the diagnostic criteria, exclusion of other causes, and rational use of test results are all required.84 Clinical Features The clinical symptoms and complications of venous thrombosis in children can be classified as acute or long term The acute clinical symptoms include loss of CVAD patency; swelling, pain, and discoloration of the related limb; swelling of the face and head, with superior vena cava syndrome; and respiratory compromise CHAPTER 90 Thrombosis in Pediatric Critical Care with pulmonary embolus (PE) The long-term complications include prominent collateral circulation in the skin (face, back, chest, and neck as sequelae of upper venous thrombosis, and abdomen, pelvis, groin and legs as sequelae of lower venous thrombosis), repeated loss of CVAD patency, repeated requirement for CVAD replacement, eventual loss of venous access, CVAD-related sepsis, chylothorax, chylopericardium, recurrent thrombosis necessitating long-term anticoagulation and its risk of bleeding, and postthrombotic syndrome The clinical presentation of PE in children is often masked In critically ill children, sudden cardiorespiratory deterioration can be due to a multitude of causes; the difficulty in performing appropriate imaging to confirm the diagnosis of PE often means that the diagnosis is either not considered or unable to be substantiated Further, previously healthy children tend to tolerate large PE remarkably well Thus, shortness of breath or dyspnea is often transient and the resolution of symptoms betrays the significance of the underlying pathology Many children with substantial PE have no symptoms at all until they demonstrate those of chronic venous hypertension or a subsequent further PE has fatal consequences Clinical suspicion for PE must be high in all critically unwell children, especially those with CVADs in situ The clinical presentation of arterial thrombosis in children is often more straightforward, with cold, pale, pulseless limbs acutely related in time to the placement of an arterial catheter However, other systemic arterial thrombosis, for example, emboli to abdominal organs, may present with vague and nondiscriminatory symptoms Arterial thrombosis related to transplanted vessels may present as sudden graft loss Diagnosis Venous Thrombosis Little is known about the precision and accuracy of the noninvasive imaging techniques that are commonly used to make the diagnosis of venous thrombosis in neonates There are few studies comparing currently used diagnostic tests The low pulse pressure and small vessels in premature newborns can make ultrasound more difficult to interpret Similarly, the presence of CVADs makes compressibility difficult to assess and, accordingly, greatly reduces the sensitivity of ultrasound In neonates with umbilical vein catheters, Doppler ultrasound was shown to be poor compared to contrast venography in detecting asymptomatic thrombi The exception is renal vein thrombosis (RVT), for which ultrasound is the radiographic test of choice because of its sensitivity in detecting an enlarged kidney as distinct from the ability to detect intravascular thrombosis Color Doppler ultrasound may demonstrate absent intrarenal and renal venous flow in the early stages of RVT Magnetic resonance imaging (MRI) and computed tomography (CT) have also been used for RVT but have no apparent advantages over ultrasound In summary, in neonates with suspected venous thrombosis, venography remains the gold standard where possible Clinicians will often be forced to use a combination of clinical assessment and suboptimal imaging to make clinical decisions because the gold standard is practically unachievable This must be factored into progressive decision-making In older children, there is a little more data about diagnostic strategies A well-designed substudy of the PAARKA investigation compared venography versus ultrasound for the diagnosis of asymptomatic upper venous system CVAD-related VTE Ultrasound 1077 was demonstrated to have a sensitivity of 20% for intrathoracic thrombosis but did diagnose jugular thrombi that were missed on venography.85 The Lineogram, Ultrasound, and Venogram (LUV) study compared these techniques for the diagnosis of symptomatic upper venous system CVAD-related thrombosis.86 Most of the thrombi in this study were located in the jugular veins and diagnosed by ultrasound (80% sensitivity) but not venography Another study compared magnetic resonance venography (MRV) to ultrasound and lineograms in 25 children with multiple CVAD insertions who were suspected of having major central venous thrombosis.87 Lineograms consistently underestimated the extent of thrombosis Ultrasound detected only of 18 thromboses seen on MRV and underestimated the extent of of the thromboses In all cases, ultrasound identified jugular thrombosis but failed to identify more central thrombosis Further, MRV identified a patent vein for reinsertion of CVADs in 22 of 25 children At operation, venous patency was confirmed in 20 patients (91%) There are no studies determining the sensitivity and specificity of diagnostic testing for lower venous system CVAD-related thrombosis in children There has been much interest in the use of point-of-care ultrasound by nonradiologists to diagnose thrombosis in children However, studies suggest that accuracy of such an approach— especially in the PICU setting related to CVAD-associated thrombosis—may be poor.88 In summary, for children with suspected upper system thrombosis, a combination of ultrasound (jugular veins) and bilateral upper limb venography (subclavian and central veins) is recommended The temptation to extend ultrasound imaging below the clavicles should be resisted MRV may be a viable alternative to formal venography depending on local expertise For children with suspected lower system thrombosis, ultrasound is a reasonable alternative for veins distal to the groin based on adult experience As in adults, serial ultrasound may be required to exclude thrombosis in specific circumstances For more proximal veins, venography or MRV should be considered Of importance, while there is considerable literature about the value of sensitive d-dimer assays in excluding deep venous thrombosis (DVT) in adults, there are no such data in children Furthermore, given the preceding medical and surgical therapies that most children with DVT have received, d-dimer is unlikely to be of use At this time, d-dimer is not part of the recommended diagnostic strategy for venous thrombosis in hospitalized children, although there may be a role in teenagers who present de novo to the emergency department with venous thrombosis or pulmonary embolus.89,90 Pulmonary Embolus There are no studies determining the sensitivity and specificity of diagnostic testing for PE in children However, literature would support that PE is significantly underdiagnosed in children, especially those in intensive care settings A number of potential difficulties with interpreting ventilation/perfusion (V/Q) scans in children at risk from PE have been identified This is particularly the case in children following specific cardiac surgeries, such as Fontan surgery, in which total pulmonary blood flow may not be assessed by isotope injected into an upper limb The true impact of these difficulties on diagnostic accuracy remains to be determined In addition, there are concerns about the safety of perfusion scanning in children with significant right-to-left cardiac shunts, as it is likely that significant amounts of macroaggregated albumin will lodge in the cerebral circulation, the impact of 1078 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology which is unknown.91 V/Q scanning remains the recommended first-line investigation for PE in neonates and children Pulmonary angiography remains the gold standard Clinicians will frequently need to make a presumptive diagnosis based on clinical findings and the presence or absence of source thrombosis CT pulmonary angiography may be an alternative, especially in the specific populations in whom V/Q scanning is more worrisome (e.g., large right-to-left shunts), but CT may miss small peripheral PE Further, repeated CT angiogram may cause significant radiation exposure to breast tissue.92 Arterial Thrombosis There is little specific information related to diagnostic strategies in neonates.37 Contrast angiography remains the gold standard Peripheral arterial thrombosis is usually diagnosed clinically Ultrasound remains unproven, although serial measurements may provide useful information Aortic thrombosis, usually secondary to umbilical artery catheterization, requires radiologic diagnosis Contrast angiography is rarely feasible in critically ill newborns Noninvasive imaging techniques have not been validated In fact, in one of the only comparative studies, ultrasound failed to visualize aortic thrombosis in four patients, three of whom had complete aortic obstruction by contrast angiography Thus, clinicians must often use clinical findings and suboptimal imaging to make clinical decisions In older children, many arterial thromboses are diagnosed on clinical grounds alone, for example, after femoral artery puncture False negatives are reported using ultrasound to diagnose spontaneous femoral artery thrombosis in children False-positive magnetic resonance angiography has been reported for chronic femoral artery obstruction when compared with formal angiography In suspected peripheral artery thrombosis, clinicians should consider the possibility of intramural or external hematoma causing arterial compression as a differential diagnosis and, for peripheral arteries, ultrasound may not be sufficiently sensitive to exclude this phenomenon Other important arterial thromboses are those that occur in the arterial supply to transplanted organs For hepatic artery thrombosis after liver transplantation, serial testing with pulsed Doppler combined with real-time ultrasound of the liver parenchyma has a sensitivity of approximately 70% Both false-positive and false-negative results occur, such that angiography is usually required to confirm the diagnosis A CT scan of the liver may be of aid in equivocal cases Spiral CT scanning has been shown to be sensitive and specific in adults The value of MRI is yet to be fully determined detected using TTE Thus, TTE is likely insufficient to exclude intracardiac thrombosis in children after Fontan surgery, although the studies published had a number of design flaws The validity of TEE in other clinical situations is unknown Clinicians should consider the local expertise, availability of TEE, and the clinical situation before determining the diagnostic approach in any individual child Right atrial and intracardiac thromboses are most common in children with CVADs extending into the right atrium Risk stratification based on clot size and mobility is suggested For low-risk patients with clot size smaller than cm, nonmobile, and attached to the atrial wall, removal of the CVAD without anticoagulation may be appropriate.96 Management Overall, the management of thrombosis in children is anticoagulation.97 There are a multitude of reasons why anticoagulation therapy in children is more difficult to manage than anticoagulation therapy in adults, some of which are listed in Table 90.2.98 The indications for surgical intervention or thrombolysis are few and far between A limited drug arsenal exists in terms of drugs for which there is experience in children In critically unwell children, there are often multiple relative or even absolute contraindications to anticoagulation, and the balance of risk versus benefit is difficult to ascertain owing to the lack of well-designed studies In general, anticoagulation is best managed by a pediatric hematologist experienced in thrombosis and anticoagulation in consultation with the critical care team At all times, the overall management of the child’s underlying condition must be kept in perspective versus the management of an individual thrombosis TABLE Factors That Increase Complexity of Anticoagulant 90.2 Therapy in Children Compared With Adults Factor Impact Epidemiology of thrombosis Increased proportion of sick children with multiple comorbidities Developmental hemostasis Affects response to therapeutic agents Pharmacokinetic differences Volume of distribution, binding, and clearance of drugs vary with age Concurrent illnesses Increased frequency of intercurrent infections (and, hence, medications) in children Less diagnostic certainty Requirement for general anesthetic to perform diagnostic studies impairs ability to investigate and monitor thrombosis in children Intracardiac Thrombosis Limited vascular access Delivery of intravenous therapy and monitoring of anticoagulant therapy more difficult Three studies have specifically compared transthoracic echocardiography (TTE) to transesophageal echocardiography (TEE) in the diagnosis of intracardiac thrombosis following Fontan surgery Stumper et al.,93 in a cross-sectional survey of 18 patients, found three intracardiac thromboses using TEE, only one of which was detected by TTE Fyfe et al.,94 in a similar study, found six thrombi in four pediatric patients using TEE, only one of which was detected by TTE Balling et al.95 performed a cross-sectional study of 52 patients after Fontan surgery Seventeen patients (33%) had thromboses seen on TEE, only one of which was identified on TTE Several other publications reported intracardiac thromboses diagnosed by TEE or angiography that were not Drug formulations Almost all anticoagulants are off label in children and there are no specific pediatric preparations, making accurate dosing difficult Dietary differences Formula-fed versus breast-fed infants have vastly different responses to certain drugs (e.g., vitamin K antagonists) Compliance Age significantly affects ability to understand and cooperate with therapy Parental supervision Children in dysfunctional families present special management issues not seen in adults CHAPTER 90 Thrombosis in Pediatric Critical Care In terms of specific guidelines for managing thrombosis in children, the American Society for Hematology recently published pediatric VTE guidelines.99 Previously, the American College of Chest Physicians published evidence-based guidelines.98 However, in the PICU setting, these guidelines are often not followed.100,101 The most common drug used in critically unwell children is UFH Of all currently available anticoagulants, it is the only intravenous preparation with a short half-life and rapid onset and offset for which there is a known antidote Bivalirudin is increasingly used in children on circuits, particularly VADs.83,102,103 A direct thrombin inhibitor with a short half-life, it has some advantages over UFH However, there remain questions around optimal target ranges, dosing strategies, and monitoring assays Trials of bivalirudin versus heparin in cardiopulmonary bypass support heparin as the ongoing first-line agent.104 LMWHs such as enoxaparin, tinzaparin, and dalteparin are all indicated for subcutaneous use in children In 2019, dalteparin became the first anticoagulant approved by the US Food and Drug Administration (FDA) for use in children While there are many situations in which LMWHs are advantageous, their long half-life and lack of reversibility with protamine usually make them poor anticoagulants for critically unwell children Oral anticoagulation with coumarin derivatives such as warfarin are suitable for long-term anticoagulation, but the need for oral administration, slow onset of action, and long half-life make them unsuitable for acute anticoagulation of critically unwell children There are a multitude of newer anticoagulants available for use in adults; their use in children has been reviewed recently.105 Thus, until further research identifies an alternative anticoagulant that has the advantageous properties of UFH, UFH will remain the anticoagulant of choice in PICUs Unfractionated Heparin in Children UFH can be used as a first-line intervention to treat arterial and venous thromboses in infants and children In addition, UFH has numerous indications for primary thromboprophylaxis in infants and children, including cardiac angiography, artificial circuits (e.g., cardiopulmonary bypass, hemodialysis, ECMO), arterial cannulation, and veno-occlusive disease prevention during bone marrow transplantation The short half-life of UFH makes it the ideal antithrombotic agent for use in critically ill children who are at greater risk of bleeding complications but who nonetheless require antithrombotic therapy.106 UFH is a complex glycosaminoglycan capable of binding to many circulating proteins as well as to the vascular endothelium.107–110 The anticoagulant effect of therapeutic doses of UFH is largely limited to its interaction with AT and TFPI UFH binding to AT occurs via a unique pentasaccharide sequence present in approximately one-third of UFH molecules.111–113 The UFH:AT complex produces a thousand-fold increase in AT inhibition of coagulation protein activity compared with AT alone Following intravenous administration of UFH, TFPI release from the vascular endothelium increases in a dose- and concentration-dependent manner UFH is believed to increase the antithrombotic effect of TFPI by increasing its affinity for factor Xa by simultaneously binding to both proteins (Table 90.3).114 The monitoring of UFH therapy in the PICU is a major problem For many indications, there is no clear therapeutic range and certainly no clinical outcome data in pediatrics to support any particular therapeutic range In addition, each of the monitoring 1079 TABLE Factors in Children That Affect the Action 90.3 of Unfractionated Heparin (UFH) UFH Factor Age-Related Difference UFH acts via AT mediated catabolism of thrombin and factor Xa Reduced levels of AT3,4 Reduced capacity to generate thrombin10,11 Age-related difference in anti-Xa/ anti-IIa activity98 UFH is bound to plasma proteins, which limits free active UFH Alterations in plasma binding98 Endothelial release of TFPI Age-related differences in amount of TFPI release for same amount of UFH98 AT, antithrombin; TFPI, tissue factor pathway inhibitor tests available has significant limitations, particularly in children Clearly, global measures of hemostasis, such as the APTT, will always be limited by confounding variables that affect results Direct measurement of UFH’s ability to inhibit specific coagulation proteins (e.g., factor Xa) while producing definitive values represents only one component of UFH’s inhibitory effect on in vivo coagulation Protamine titration has been viewed as the gold standard with respect to the measurement of UFH; however, the lack of automation renders protamine titration less clinically practical A summary of the available tests for monitoring UFH and their shortcomings in pediatrics is presented in Table 90.4 The most important adverse effect from heparin therapy in children is bleeding One cohort study reported bleeding in 1.5% (95% confidence interval [CI], 0.0%–8.3%) of children treated with UFH for DVT/PE.115 However, many children were treated with subtherapeutic doses of UFH (compared with the target APTT) in this study.115 A more recent single-center cohort study reports a major bleeding rate of 24% in children in pediatric intensive care receiving UFH therapy.116 Further studies are required to determine the true frequency of UFH-induced bleeding in optimally treated children Osteoporosis has rarely been reported in children receiving UFH, with or without concomitant steroid therapy Given the convincing relationship between UFH and osteoporosis in adults, clinicians should avoid long-term use of UFH in children when alternative anticoagulants are available HIT has been discussed previously in this chapter When considering bleeding as an adverse effect of UFH, clinicians frequently view this complication as a consequence of trying to manage the balance between bleeding and clotting in critically ill children However, one of the most common reasons for heparin-associated bleeding is accidental overdose of UFH This often occurs in children who are receiving low-dose UFH flushing of vascular access devices, intended, for example, to be 50 U UFH/ mL Errors in vial selection and failure of bedside checking procedures could lead to 5000 U UFH/5 mL being injected; in small infants, this would result in a massive overdose of UFH While reports of such events rarely occur in the medical literature and, in fact, there have been no specific reports of this in the literature for over 20 years, the popular press is littered with reports of medicolegal activity and deaths of children due to such errors A Google search of heparin overdose in children will highlight many recent incidents, many with fatal outcomes.117 eFig 90.3 summarizes the range of heparin preparations found in a typical PICU ... are available HIT has been discussed previously in this chapter When considering bleeding as an adverse effect of UFH, clinicians frequently view this complication as a consequence of trying to... small infants, this would result in a massive overdose of UFH While reports of such events rarely occur in the medical literature and, in fact, there have been no specific reports of this in the... suboptimal imaging to make clinical decisions because the gold standard is practically unachievable This must be factored into progressive decision-making In older children, there is a little more