Thrombosis in pediatric critical care









  • Vascular access devices are the most common cause of thromboembolic disease in children; thus, every attempt should be made to limit their use based on real clinical need.



  • Thrombophilia is rarely the major cause of thrombosis in critically ill children; multiple tests to identify thrombophilic states are rarely useful for patient management.



  • For reasons that remain uncertain, heparin-induced thrombocytopenia is rarely seen in children.



  • Care must be taken in the diagnosis of thrombosis in children, as assumptions made in adult diagnostic strategies may not be true in children.



  • Unfractionated heparin is the most useful anticoagulant in critically ill children. However, dosing errors are common, and pediatric intensive care units should spend considerable resources on training and systems to ensure safe management of heparin.



Dramatic improvements in pediatric intensive care have led to the improved survival of critically ill children and to the emergence of previously rare complications. In order to achieve this improved survival, there has been a dramatic increase in the invasiveness of supportive care. The use of central venous access, invasive arterial monitoring, and circulatory support, including ventricular assist devices (VADs) and extracorporeal membrane oxygenation (ECMO), as well as processes such as hemofiltration and hemodialysis, which are performed through large-bore vascular access devices, increases the likelihood of vascular endothelial damage or direct vascular obstruction. Thrombosis may develop within these artificial circuits that can subsequently embolize into the systemic circulation. These insults to the vascular system are often combined with prolonged hypotension, systemic inflammatory states, and infection, all of which may alter endothelial and vascular responsiveness. Finally, there are a multitude of drugs and fluids administered during the periods of critical illness that can impact directly on plasma proteins and endothelial function or that may lead to dilution of critical plasma proteins involved in the coagulation system. Not surprisingly, therefore, thromboembolism is an increasingly common problem faced in the pediatric intensive care setting, contributing significantly to morbidity and mortality.


This chapter describes key issues related to thrombosis in the pediatric intensive care unit (PICU). Developmental hemostasis is a crucial concept both to the understanding of the etiology of thrombosis in children and to the application of diagnostic and therapeutic strategies. The etiology, epidemiology, clinical features, diagnosis, and management of the major types of thrombosis encountered in children in the intensive care unit (ICU) are discussed. However, thrombosis of the central nervous system (CNS), including arterial ischemic stroke and cerebral sinovenous thrombosis, are beyond the scope of this chapter (see Chapter 66 ). As in many areas of pediatrics, high-level evidence is often lacking; however, best available evidence is cited when possible. Extrapolation from adult studies resulting in suboptimal treatment outcomes in children highlights the need for pediatric-specific trials and guidelines.


Developmental hemostasis


The hemostatic system is a dynamic, evolving entity that not only affects the frequency and natural history of thromboembolic disease in children but also the response to therapeutic agents. The global functioning of the coagulation system in neonates and children is different from adults, as are the plasma levels of many coagulation proteins. Overall, the levels of most coagulation proteins increase with age; neonates compared with adults have significantly lower levels of these proteins. The exceptions to this are FV, FVIII, FXIII, and vWF, which are elevated at birth compared with adults. In addition to quantitative differences, there is evidence of qualitative differences in many coagulation proteins, especially in neonates. This is in the context of the entire plasma proteome being dramatically different in children compared with adults. More recently, differences in platelets and cellular interactions have been described that may be of clinical significance. , Although ongoing research in this area is desperately needed, current knowledge regarding the differences between adults and children in plasma proteins most likely to impact on anticoagulation therapy is as follows.


Plasma concentrations of antithrombin (AT) are physiologically low at birth (∼0.50 U/mL) and do not increase to adult values until 3 months of age. Sick premature neonates frequently have plasma levels of AT of less than 0.30 U/mL. This likely has an effect on the action of heparin, whose antithrombotic activity is dependent on catalysis of AT to inactivate specific coagulation enzymes—in particular, thrombin. Some studies suggest that children in PICUs have markedly reduced AT levels compared with age-matched controls, potentially further enhancing this effect ( eFig. 90.1 ). The capacity of plasmas from neonates to generate thrombin is both delayed and decreased compared with adults and is similar to plasma from adults receiving therapeutic amounts of heparin. Both an increased sensitivity and an increased resistance to unfractionated heparin’s anticoagulant activities have been reported in vitro in plasma from neonates. Increased sensitivity to unfractionated heparin is observed in systems based on assays dependent on thrombin generation (e.g., activated partial thromboplastin time [aPTT]). The in vitro effects of unfractionated heparin (0.25 U/mL) on neonates, children, and adults were compared recently. Thrombin generation was delayed and reduced in children compared with adults and virtually absent in neonates. Resistance to unfractionated heparin is observed in systems based on assays that measure the inhibition of exogenously added factor Xa or thrombin and that are dependent on plasma concentrations of AT.




• eFig. 90.1


Antithrombin levels by age group in samples obtained from children in a pediatric intensive care unit (PICU) compared with age-matched controls. Note the reduction in antithrombin levels in sick children.

(Courtesy P. Monagle.)


In vitro, thrombin generation is similar in adults and children at the same concentration of low-molecular-weight heparin (LMWH). However, at 0.25 U/mL LMWH, thrombin generation was delayed and reduced by approximately half in newborns compared with adults. These differences were matched by reductions in rates of prothrombin consumption.


The vitamin K–dependent clotting factors are the most extensively studied group of factors in infants. Factors II, VII, IX, and X have been demonstrated to be one-half to one-third that of adults despite receiving vitamin K prophylaxis at birth. The levels of the vitamin K–dependent factors and the contact factors (factors XI and XII, prekallikrein, and high-molecular-weight kininogen) gradually increase to values approaching adult levels by 6 months of life. For children receiving vitamin K antagonists, the capacity of their plasmas to generate thrombin is delayed and decreased by 25% compared with plasmas from adults with similar international normalized ratios.


Whether the overall activity of the protein C/protein S system varies with age is unknown. However, at birth, plasma concentrations of protein C are very low, and they remain decreased during the first 6 months of life. Although total amounts of protein S are decreased at birth, functional activity is similar to that in the adult because protein S is completely present in the free, active form owing to the absence of C4-binding protein. , α 2 -Macroglobulin appears to play a substantially increased role in thrombin regulation in children compared with adults. Plasma concentrations of thrombomodulin are increased in early childhood and decrease to adult values by late teenage years. However, the influence of age on endothelial cell expression of thrombomodulin has not been determined.


Total tissue factor pathway inhibitor (TFPI) levels in newborns are reported as being similar to levels in older children or adults. Free TFPI is reported as being significantly lower in newborns.


Despite the changes in individual protein levels and in global tests of coagulation, the hemostatic system in neonates and children does not seem disadvantageous compared with the “normal” coagulation system as measured in adults. There are no data to support either an increased bleeding or thrombotic risk during infancy and childhood for any given stimulus; on the contrary, one could argue that the hemostatic system in neonates and children is protective against bleeding and thrombotic complications compared with adults. This is despite the fact that, when considering individual proteins, many proteins exist at levels during stages of infancy that would be associated with disease in adults. There clearly remains much to be learned about the evolution of the coagulation system with age, and this is an area in which there is much ongoing active research. As a better understanding of the neonatal and child coagulation system is achieved over the coming years, thinking may change regarding many aspects of thrombosis development and management in this patient population.


Etiology and epidemiology


Unlike adults, 95% of venous thromboembolisms (VTEs) in children are secondary to an identifiable risk factor. While there are a variety of risk factors to consider, perhaps the most useful concept for the clinician to understand remains Virchow’s triad. Virchow’s triad recognizes that three factors are involved in the development of thrombosis: the blood vessel wall, blood constituents, and blood flow ( Fig. 90.2 ).




• Fig. 90.2


Virchow’s triad, highlighting the importance of each factor in contributing to thrombosis formation.


Patients in the PICU often demonstrate abnormalities in one, two, or all of these factors; the recognition of this can be a useful guide to therapy. For example, in a patient with a cardiac lesion, either primary or postsurgical, where there is extremely poor blood flow in one part of the cardiovascular system, the optimal management is to improve the blood flow. While anticoagulation may have an important role, progressively increasing the intensity of anticoagulation will significantly increase the risk of bleeding and yet may not substantially further reduce the risk of thrombosis, which is being driven primarily by flow. Alternatively, patients with disseminated intravascular coagulation (DIC) have a marked perturbation of function of the vascular endothelium. Therefore, anticoagulation alone is unlikely to prevent thrombotic complications, which will be avoided only by treatment of the primary illness and subsequent resolution of the DIC.


Combinations of these factors are important in many instances. For example, central venous access is a common precipitant of thrombosis most often through interruption to flow (especially in small infants in whom the catheter-to-vein diameter ratio is close to 1:1) and through disruption of the vessel wall at the insertion site. However, thrombosis is seen more commonly when there is an additional abnormality in the blood constituents as well, for example, in protein-losing states such as nephrotic syndrome or enteropathy, or through inflammatory or septic conditions, or via drugs such as oral contraceptives. Consideration of the etiologic factors in this way often enables clinicians to make some attempt at risk stratification and to modify care to reduce some of the multifactorial drivers of thrombosis on an individual basis, even though there may not be clear numeric data from large studies on the actual level of risk.


eTable 90.1 summarizes the epidemiology and known risk factors for most etiologies of common non-CNS thrombosis seen in critically ill children. The most important risk factors for thrombosis in the PICU remain the presence of vascular access devices and recent cardiac surgery. ECMO and VADs are specific circumstances that not only use large-bore cannula that can precipitate thrombosis but also have significant artificial surfaces that interact with blood and increase the thrombotic risk. The mechanics of the circuits that contribute to thrombosis and the common anticoagulant strategies used to maintain these circuits are beyond the scope of this chapter. However, clotting and bleeding remain common causes of mortality and morbidity in such patients; thus, much more research is required to start reducing these complications. Two additional risk factors worth discussing, although they are not often particularly relevant in children, are thrombophilias and heparin-induced thrombocytopenia.



TABLE 90.1

Epidemiology, Clinical Features, Diagnosis, and Complications of the Most Common Types of Non-CNS Thromboembolism in Critically Ill Children



































































































































































Type/Location Age/Sex Incidence Underlying Illness or Risk Factors Clinical Features Diagnosis Complications
Spontaneous VTE Lower limb


  • M = F



  • Teenagers

1.2 per 10,000 hospital admissions


  • Leg, inguinal, or abdominal pain



  • Leg swelling or discoloration

Doppler US


  • Immediate: PE



  • Cardiac extension



  • Chylothorax



  • SVC syndrome



  • Long-term:



  • Recurrent VTE



  • PPS

Axillary


  • M = F



  • Teenagers

Very rare


  • Mass lesion



  • Thoracic inlet obstruction



  • New sport involving arms

Arm swelling, pain, and discoloration Doppler US
CVAD-related VTE Line tip thrombosis Higher in neonates Cancer, sepsis, trauma, surgery, immobility, long-term lines, congenital heart disease, burns, cardiac catheterization Inability to flush or draw from line LinogramEchocardiogram if tip in RA Variceal hemorrhage
Fibrin sleeve Asymptomatic Lineogram, venography



  • CVAD-related DVT



  • Iliofemoral, IVC, jugular, subclavian

1%–75%


  • Asymptomatic



  • Limb or facial swelling, pain, discoloration



  • SVC syndrome, chylothorax




  • Doppler US for neck, limb, and abdominal TE



  • Venography (radiograph, CT, or MR) for intrathoracic TE

PE Up to 30% of children with CVAD-related DVT CVAD-related DVT


  • Asymptomatic (up to 50%)



  • Tachycardia



  • Chest pain



  • Respiratory distress



  • Increased oxygen requirements



  • Acute right heart failure



  • Collapse



  • Sudden death




  • V/Q scan



  • Pulmonary angiography



  • Plain radiography, CT, MR



  • ECG



  • Autopsy most common diagnostic test in children




  • Death



  • Pulmonary hypertension and heart failure



  • Recurrence

Arterial TE


  • Peripheral arterial catheter



  • Radial artery, occasionally foot arteries

Peripheral arterial catheter


  • Acute limb ischemia: blanching, pallor, diminished pulses/CR



  • Loss of patency

Doppler US Ischemia (hand)



  • UAC



  • Celiac, mesenteric, renal, and lower limb arteries

Umbilical arterial catheter


  • Loss of patency



  • Lower limb ischemia



  • NEC/organ ischemia

Doppler US
Contrast angiography



  • Organ ischemia



  • NEC



  • Lower limb TE



  • CNS TE (via PFO)

Cardiac catheterFemoral artery Increased in younger children Up to 10% Repeated manipulations, balloon dilations, raised hematocrit Limb ischemia Doppler US


  • Reduced limb growth



  • Claudication



  • Loss of future access




  • Congenital and acquired arterial disease



  • Coronary, cerebral, peripheral arterial disease

Rare Hyperlipidemia, homocysteinuria, acquired arteritis (Takayasu, Kawasaki)


  • Xanthomata



  • Features of vasculitis or underlying disease




  • Echocardiography



  • Doppler US



  • Angiography




  • Myocardial infarction



  • Stroke

Cardiac valve Murmur, valvular dysfunction


  • Echocardiography



  • Angiography, CT, MR




  • Stroke



  • Limb TE



  • PE

Cardiac shunt, including Fontan 19% post-Fontan patients


  • Mechanical heart valves



  • Shunts, including Fontan

Acute loss of pulmonary blood flow
Renal vein thrombosis Neonates:
Unilateral, 70%
Bilateral, 30%
M = 64% Asphyxia, polycythemia and dehydration, sepsis, cyanotic CHD, infant of diabetic mother


  • Flank mass



  • Hematuria, proteinuria



  • Thrombocytopenia



  • Renal failure

Doppler US (CT, MRI) Adrenal hemorrhage
Renal failure
Hypertension
Older children Nephrotic syndrome, burns, SLE, transplant Diarrhea and vomiting
Dehydration, hypovolemia
Portal vein thrombosis


  • 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



  • Death



  • Portal hypertension and variceal hemorrhage

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

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.


Central venous access devices


The most common risk factor for venous thrombosis in children appears to be the presence of a central venous catheter (central venous access device [CVAD]) although most children have several concomitant risk factors. ,


More than 50% of VTEs in children occur in the upper venous system secondary to the use of CVADs. Three types of CVAD-related thrombosis are described in the literature: clots at the tips of CVADs that impair infusion or withdrawal of blood; fibrin sleeves that are not adherent to vessel walls but may occlude CVADs; and CVAD-related thrombi that adhere to vessel walls, with partial or complete obstruction of vessels where the CVAD is located. This discussion refers to the third type of thrombosis only, that is, obstructive CVAD-related thrombosis. There are a number of mechanisms that may be contributory to the development of CVAD-related thrombosis, including damage to the vessel wall by the CVAD or by substances infused through the CVAD (total parenteral nutrition [TPN], chemotherapy), disrupted blood flow due to the presence of the CVAD, and thrombogenic catheter materials. Use of CVADs occurs most commonly in children who require short-term intensive care, hemodialysis, or long-term supportive care (TPN or chemotherapy).


The incidence of CVAD-related thrombosis reported in the literature varies, reflecting differences in underlying conditions, diagnostic tests, and index of suspicion. A prospective cohort study, which was looking at clinically symptomatic thrombus only in the PICU, reports a risk of 74 clinically symptomatic VTEs per 10,000, which is a significant rise from previous studies reporting between 5 to 55 per 10,000. In many patient populations, the incidence is not accurately known. Many PICUs have attempted to create risk stratification protocols to allow for more targeted prophylaxis. However, in the absence of good data about risk factors, this practice remains speculative. The role for thromboprophylaxis in CVADs remains uncertain and, as yet, there is no current recommendation for routine systemic prophylaxis for short- to medium-term CVADs. A recent landmark study demonstrated the natural history of asymptomatic CVAD-related VTE in children in a PICU population and suggested that asymptomatic CVAD-associated VTE may not require anticoagulation. , The study also suggested that routine radiologic screening for asymptomatic thrombosis was unwarranted. There were differences between upper-system CVADs and femoral vein CVADs, which more likely reflect the clinical state of the child and insertion techniques rather than specific anatomic factors. However, numbers were small, and further study is required.


Arterial access


The most common type of arterial thrombosis in children occurs as a result of placement of arterial catheters. Non–catheter-related arterial thrombosis may be congenital (familial hyperlipidemia and hyperhomocysteinemia) or acquired (Takayasu arteritis, Kawasaki disease, congenital heart disease, and arterial thrombosis in transplanted organs). There are, in general, three types of arterial catheterizations used in children that may result in arterial thrombosis: umbilical arterial catheterization in neonates (not discussed in this chapter), cardiac catheterization, and peripheral catheterization. Arterial occlusion causes tissue ischemia, resulting in tissue necrosis if the vascular occlusion persists. Organ and tissue damage at remote sites may result from embolic events occurring owing to fragmentation of the original thrombus. ,


In the PICU, short-term femoral artery access will often be required or emergency femoral artery puncture will be performed; alternatively, the femoral artery will be inadvertently accessed during attempts at femoral venous access. In terms of understanding the implications of this, one can only extrapolate from the cardiac catheterization literature, recognizing that diagnostic and therapeutic cardiac catheterizations via the femoral artery have some significant differences in terms of thrombosis risk.


Adverse events occurring as a result of femoral artery puncture include arterial spasm and arterial thrombosis. Clinically, vascular spasm and thrombosis are indistinguishable in the initial phases of presentation, with the following symptoms: decreased or absent pulses, pale or mottled limb, and decreased capillary refill. Arterial spasm usually resolves within a few hours in the absence of therapy while arterial thrombosis usually requires therapy. The incidence of femoral artery thrombosis following cardiac catheterization without thromboprophylaxis is approximately 40%. The incidence is inversely proportional to patient age and weight, with infants at highest risk. The frequency of femoral artery thrombosis in PICUs is unclear. Similarly, with peripheral arterial catheterization, the mechanism of injury is endothelial damage and blood vessel occlusion. The exact frequency of peripheral arterial occlusion in the PICU remains unknown.


Cardiac surgery


Children with congenital heart disease constitute a significant proportion of children seen in tertiary hospitals with thrombosis. Recent data show that almost 50% of infants younger than 6 months and 30% of older children with venous thromboembolic disease have underlying cardiac disorders. Similarly, almost 70% of infants (<6 months old) and 30% of children with arterial thrombosis have underlying cardiac defects. In addition, the majority of children receiving primary anticoagulant prophylaxis are being treated for complex congenital heart disease or severe acquired cardiac illness. Presumably, the mechanisms underlying this increased risk of thrombosis are alterations to blood flow (e.g., following Fontan surgery, where venous return is driving the pulmonary blood flow) and disturbances of the vascular endothelium related to intravascular sutures or vascular manipulation. Whether a postsurgical inflammatory state induces changes 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. Perioperative platelet transfusion and postoperative ECMO have recently been reported as risk factors for increased shunt thrombosis. The CLARINET study found no advantage to adding clopidogrel to standard of care (aspirin) in preventing thrombosis of systemic to pulmonary artery shunts.


There have been a number of reviews regarding anticoagulation after Fontan surgery. 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. Multiple studies have looked at thromboprophylaxis strategies but the optimal strategy remains unclear.


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. 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, do not appear to confer thrombotic risk. Recent reports demonstrate an increased risk for thrombosis in families with a second genetic abnormality.


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? , 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. Screening prior to organ transplant would appear to be unhelpful.


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 meta-analyses are based. More recent data show no evidence to support thrombophilia screening in children with CVAD-associated thrombosis. ,


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 5 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.


A number of case reports of pediatric HIT have described patients ranging in age from 3 months to 15 years. 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. Reported rates vary from almost nonexistent in unselected heparinized children up to 2.3% in children in the PICU. However, HIT appears to occur far less frequently in children than in adults—the rationale for this is unclear. 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. Danaparoid, hirudin, and argatroban are alternatives to UFH in children with HIT. However, these drugs have significant risks in children. Most recently, bivalirudin has been used as an alternative to heparinoids. 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.


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 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 was demonstrated to have a sensitivity of 20% for intrathoracic thrombosis but did diagnose jugular thrombi that were missed on venography. The Lineogram, Ultrasound, and Venogram (LUV) study compared these techniques for the diagnosis of symptomatic upper venous system CVAD-related thrombosis. 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. Lineograms consistently underestimated the extent of thrombosis. Ultrasound detected only 7 of 18 thromboses seen on MRV and underestimated the extent of 4 of the 7 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.


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. ,


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 which is unknown. 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.


Arterial thrombosis


There is little specific information related to diagnostic strategies in neonates. 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.


Intracardiac thrombosis


Three studies have specifically compared transthoracic echocardiography (TTE) to transesophageal echocardiography (TEE) in the diagnosis of intracardiac thrombosis following Fontan surgery. Stumper et al., 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., in a similar study, found six thrombi in four pediatric patients using TEE, only one of which was detected by TTE. Balling et al. 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 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 2 cm, nonmobile, and attached to the atrial wall, removal of the CVAD without anticoagulation may be appropriate.


Management


Overall, the management of thrombosis in children is anticoagulation. 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 . 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.


Jun 26, 2021 | Posted by in CRITICAL CARE | Comments Off on Thrombosis in pediatric critical care
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