79: Vasospasms and Thromboembolism

An infant with an indwelling umbilical artery catheter develops a vasospasm in one leg. The nurse notifies you that another infant with an indwelling umbilical line has no pulses in the lower legs with severely decreased perfusion. Infants are at a high risk for thromboembolism because of their immature hemostatic system and smaller vessel size, and the fact that they require frequent catheter use. The majority of neonatal thromboembolisms are iatrogenic from umbilical artery or venous catheters, indwelling central catheters, and peripheral arterial lines.

1. Can the catheter be removed? Evaluate the need for the catheter. If the catheter can be removed, this is the treatment of choice. Vasospasm is most commonly related to the use of umbilical artery catheters (UACs), but it can also occur in other catheters such as radial artery catheters. Over 80% of venous thromboembolisms in newborns are secondary to central venous lines. Arterial thrombosis is less common than venous thrombosis. The incidence of UAC-related thrombosis is 14–35% by ultrasound, and up to 64% by angiography. In some cases of thrombosis, the catheter should not be removed so thrombolytic medication can be given through it.

2. Was a medication given recently through the catheter? Most medications, if given too rapidly, can cause vasospasm.

3. How severe is the vasospasm? Deciding on the severity of the vasospasm may dictate treatment choices (see Section IV.B.1 and 2).

4. Is there a pulse in the affected extremity? A loss of pulse with a thrombus is a medical emergency.

5. Does the infant have any risk factors for thromboembolism?

   1. Maternal. Autoimmune disorders, premature rupture of membranes (PROM), diabetes, preeclampsia, infertility, oligohydramnios, prothrombotic disorder, intrauterine growth restriction (IUGR), chorioamnionitis, family history of thrombosis, antiphospholipid or anticardiolipin antibodies.

   2. Delivery. Instrumentation, fetal heart rate (FHR) abnormalities, emergency cesarean section, traumatic delivery.

   3. Neonate. Central arterial catheters (most common risk factor for arterial thromboembolism), central venous catheters (one of the most common risk factors for venous thromboembolism), some congenital heart diseases, birth asphyxia, sepsis, small for gestational age (SGA), respiratory distress syndrome (RDS), polycythemia, necrotizing enterocolitis (NEC), pulmonary hypertension, dehydration, surgery, extracorporeal membrane oxygenation/extracorporeal life support (ECMO/ECLS), congenital renal vein defects, congenital nephrotic or nephritic syndrome, prematurity, hypotension, disseminated intravascular coagulation (DIC), impaired liver function, fluctuations in cardiac output, low cardiac output, prothrombotic disorders.

   4. Inherited factors. Protein C, protein S deficiency; factor V Leiden mutation; antithrombin deficiency; prothrombin gene G20210A mutation; elevated lipoprotein a levels; and others.

1. Vasospasm. A muscular contraction (spasm) of an arterial vessel, manifested by acute color change (white or blue) in the perfused extremity (upper or lower extremity, sometimes only on the toes or fingers). Occasionally, the color change extends to the buttocks and the abdomen. The change in color may be transient or persistent. It may be caused by prior injection of medication or a manifestation of thromboembolism/thromboembolic phenomenon. Arterial blood sampling can also be a predisposing factor.

2. Thromboembolism. A thrombus is a blood clot formation in an artery or vein and can cause partial or complete obstruction. An embolus is a clot that is mobile and lodges in a blood vessel and may cause obstruction or vasospasm. Neonates are the most commonly affected age group with an incidence of ∽41 cases in 100,000 per year. The initial sign is usually that the catheter does not work. One cannot infuse fluid or withdraw from the line. Thrombosis can be iatrogenic (catheter related) or spontaneous (non–catheter related).

3. Inherited thrombophilias. Less commonly, thromboembolic phenomena are due to inherited or acquired thrombophilias. Positive family history, early onset of disease, and more than one thromboembolism are clues to an inherited thrombophilia. Prothrombotic genetic mutations do not appear to increase the risk of umbilical catheter–associated thrombosis.

   1. Inherited. Deficiencies of protein C, protein S, antithrombin III, factor V Leiden (heterozygous or homozygous). Also, prothrombin mutation G20210A, elevated factor VIII, homocystinemia, elevated lipoprotein, fibrinogen abnormalities (dysfibrinogenemia and plasminogen abnormalities), dysplasminogenemia, and hypoplasminogenemia.

   2. Acquired. Deficiencies of protein C, protein S, or antithrombin III; elevated factor VIII activity; antiphospholipid antibodies; lupus anticoagulant and anticardiolipin antibody. Placental transfer of antibodies can cause an acquired thrombophilia in the newborn. Newborns with sepsis have an increased and ongoing consumption of coagulation factors and platelets, with reduced levels of protein C.

   3. Neonatal purpura fulminans is rare and may be inherited or acquired. If inherited, it is caused by a deficiency in protein C or S or antithrombin III and presents after birth with ecchymosis, venous and arterial thromboses, and DIC. The acquired form is usually in older infants but has been described in neonates. It is idiopathic or can occur secondary to a bacterial or viral infection that can result in a decrease in levels of protein C.

1. History. Obtain a detailed family history of any inherited clotting or other hematologic disorder. Did anyone in the family have any clotting disorders?

2. Physical examination. The severity of the vasospasm and thrombosis must be assessed because it dictates treatment. The areas of involvement, appearance of the skin over the involved areas, and pulses of the affected extremity are measures of severity. Compare the affected extremity with the other extremity. A handheld Doppler is useful to assess peripheral arterial flow. An acute scrotum (discoloration and pain upon palpation) can be caused by renal vein thrombosis.

   1. Severe vasospasm. Involves a large area of one or both legs, the abdomen, or the buttocks. In the upper extremity, a severe vasospasm includes most of the arm and all of the fingers. The skin may be completely white. Decreased perfusion is present, and pulses of the affected extremity are weak but detectable.

   2. Less severe vasospasm. Involves a small area of one or both legs (usually some of the toes and part of the foot). In the arm, it can involve part of the extremity and some fingers. The skin has a mottled appearance and pulses are present but can be diminished.

   3. Thrombosis. If pulses are completely absent, an arterial thrombosis, which is a medical emergency, is likely. Persistent bacteremia and thrombocytopenia may be associated with thrombosis. Venous thrombosis is more common.

      1. Venous thrombosis. Iatrogenic venous thrombosis in the newborn occurs most commonly from an indwelling venous catheter (90% central venous pressure [CVP] or umbilical venous catheter [UVC]) or from a non–catheter related reason (most commonly renal vein thrombosis). If from a catheter, presentation includes difficulty infusing and withdrawing from the line. Other symptoms are persistent thrombocytopenia and persistent infection. Sites in which a venous thrombosis can occur are mesenteric, adrenal veins, hepatic veins, portal vein, femoral vein, inferior and superior vena cava, and cerebral sinuses.

         1. Extremities (peripheral thrombosis). Extremities are swollen, cyanotic, hyperemic, and discolored with distended superficial veins.

         2. Kidney. Renal vein thrombosis is the most common type of spontaneous venous thrombosis. Triad of macroscopic hematuria, thrombocytopenia, and a palpable abdominal mass can be seen. Risk factors are perinatal asphyxia, dehydration, and maternal diabetes mellitus. Acute hypertension, proteinuria, and renal dysfunction can also occur. There is a higher male prevalence, usually unilateral (70%) or left kidney (64%), increased in premature infants, with a high level of thrombophilia.

         3. Inferior vena cava thrombosis. Presents with palpable kidneys and hematuria. Edematous lower limbs, respiratory distress, and hypertension can also be seen.

         4. Superior vena cava thrombosis. Common after repair of complex congenital heart disease.

         5. Intracardiac thrombosis. In infants with complex congenital heart disease from right atrial catheter placement. Right atrial thrombi can be life threatening and disseminate into lungs or obstruct the right pulmonary artery. Pericardial tamponade and symptoms of right heart failure are consequences.

         6. Central nervous system (CNS). Neonatal cerebral sinovenous thrombosis (CSVT) is a rare multifactorial disease. It is most commonly caused by coagulopathy. Early signs within 48 hours of birth (respiratory distress, poor tone, asphyxia, fetal distress) or later signs (seizures, lethargy, fever, poor feeding, apnea) are typical. Most common sites are superior sagittal sinus, transverse lateral sinuses of the superficial venous system, and the straight sinus of the deep venous system. Thalamic hemorrhage suggests cerebral sinovenous thrombosis.

         7. Intestine. Neonatal portal vein thrombosis is uncommon but is increasing. Risk is higher in neonates than in children. Clinical presentation is nonspecific or asymptomatic in 90%. Impaired liver function, portal hypertension, hepatomegaly, and splenomegaly can be seen. Umbilical catheterization, exchange transfusion, and sepsis and thrombophilia are all risk factors. Mesenteric venous thrombosis presents with gradual onset of abdominal pain with later signs once necrosis develops. Heme-positive stool is seen.

         8. Umbilical vein thrombosis. Rare, and if it occurs, portal vein thrombosis should be ruled out.

      2. Arterial thrombosis. Less common than venous thrombosis. Iatrogenic catheter-related arterial thrombosis is usually from UAC, peripheral arterial line (PAL), and femoral artery catheters. It usually presents with line dysfunction, blanching or cyanosis of the extremity, sepsis, and persistent thrombocytopenia. Spontaneous (not catheter-related) arterial thromboses are rare but usually involve the iliac artery, left pulmonary artery, aortic arch, and descending aorta, and symptoms depend on the location. Neonatal arterial thrombosis can occur in the aorta and present as cyanotic heart disease such as coarctation of the aorta.

         1. Aortic thrombosis. Rare in newborns. UAC will stop working and blood pressure will be higher in the arms than in the legs. Decreased or no pulses in the lower extremities with color change and a decrease in perfusion, hematuria, hypertension, oliguria, and NEC can all be seen. Cytomegalovirus (CMV) infection can cause aortic arch thrombosis.

         2. Extremities (peripheral arterial thrombosis). Radial, posterior tibial, and dorsalis pedis arterial lines are rarely associated with thrombosis. Weak or absent peripheral pulse, pallor of the extremities, coldness, and decreased perfusion of the extremity can be seen. Acute arterial occlusion in a limb in a newborn is rare. Neonatal arterial thrombosis at birth is very rare and has been reported in the left subclavian, axillary, and brachial arteries.

         3. Intestine (mesenteric thrombosis). Bloody stools, bilious aspirates, abdominal pain, feeding intolerance, pneumatosis.

         4. Kidney (renal artery thrombosis). Causes elevated blood pressure.

         5. Lung (pulmonary embolism). Very rare in neonates. It can be seen in infants with congenital heart disease with right heart failure, poor oxygenation, and ventilation/perfusion mismatch.

         6. CNS. Ischemic perinatal stroke (cerebral artery thrombosis) most commonly occurs in the left hemisphere within the middle cerebral artery often secondary to indwelling intravascular catheters but can also be secondary to lupus anticoagulant. Placenta pathology may play a role in the etiology. Signs include seizures, lethargy, apnea, poor feeding, and hypotonia.

      3. Systemic air embolism (SAE). In neonates, it is devastating and usually fatal. Most iatrogenic air emboli are venous and occur from central venous catheters (UVC, peripherally inserted central catheter [PICC]), but rarely can also occur from peripheral venous or arterial lines. A disconnected line is a common cause. Air embolism secondary to mechanical ventilation (barotrauma leads to systemic gas embolism) is rare but can occur in premature infants. Suspect embolism if air bubbles are in the infusion line. Clinical symptoms of systemic air embolism (SAE) are usually sudden and dramatic and can include pallor, cyanosis, hypoxemia, seizures, shock, bradycardia, respiratory distress, mottling of the skin, or neurologic deficits (if CNS emboli) such as paraplegia. Infants with cyanotic congenital heart disease are at a risk for cerebral arterial gas embolism (CAGE) from infusion lines.

   4. Inherited thrombophilias. See Chapter 87.

3. Laboratory studies. Not usually needed for vasospasm. However, the following laboratory tests should be obtained if a thrombosis is suspected and clot-dissolving medication is to be used.

   1. Coagulation profile. Prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time, plasma fibrinogen concentration.

   2. Hematocrit.

   3. Platelet count. The thrombus itself and the use of heparin can cause thrombocytopenia.

   4. Genetic tests. May be done at some point to evaluate congenital thrombophilia.

   5. CMV workup. See Chapter 90.

   6. Workup for suspected prothrombotic disorder. See Chapter 87.

4. Imaging and other studies

   1. A plain radiograph of the abdomen. For catheter placement.

   2. Ultrasound or computed tomography (CT) of the head. To evaluate for cerebro-sinovenous thrombosis. Also to evaluate for intraventricular hemorrhage (IVH) before initiating thrombolytic therapy.

   3. Real-time ultrasonography with color Doppler flow imaging. This can be used to diagnose thrombosis. It is the most common study used but can be unreliable. It can also be used to monitor the progress over time. Renal vein thrombosis shows enlarged echogenic kidneys and absence of flow in the main or arcuate renal veins.

   4. Contrast angiography (the gold standard). Performed through the umbilical artery catheter and can be used to diagnose aortoiliac thrombosis. In several studies, this procedure was found to be the most effective diagnostic technique. A contrast study should be considered before administrating a fibrinolytic agent. Remember this test is difficult to perform in sick neonates.

   5. “Linograms.” Injecting radio-opaque dye directly into the line is sometimes done, but this method may also miss thrombosis.

   6. Contrast venography is considered the gold standard for diagnosing venous thrombosis. Done by injection of contrast through peripheral vessels.

   7. Magnetic resonance (MR) angiography. Recommended in ischemic neonatal stroke.

   8. MR venography. Also done at some centers.

   9. Imaging for air embolism. CT scan of the head for intracranial air bubbles. Echocardiogram of venous air embolism: acute obstruction of the right ventricular (RV) outflow tract secondary to air embolism (known as an “air lock”).

Management of vasospasms is controversial. Management of thrombosis is largely based on treatment plans for older children and adults. Lack of organized studies in neonates adds to the problem. Current management protocols for thrombophilia can be obtained from the International Children's Thrombophilia Network (phone: 1-800-NO-CLOTS). The network was established as a free consultative service and to develop collaborative research studies.

1. Key points

   1. Monitor for potential signs of vasospasm or thromboembolic complications in all infants with any intravascular catheter.

   2. Thromboembolism can occur in newborns and produce little or no clinical symptoms.

   3. Heparin is often added to neonatal infusions as it prolongs patency, extends catheter life (UACs, UVCs, PICCs, peripheral arterial catheters), and may also decrease the incidence of thromboembolic occlusions. For extremely low birthweight infants, use the lowest dose. There are no randomized trials of heparin use in PICCs, but its use is common in neonatal intensive care units (NICUs). Heparin use in UVCs is controversial but the majority of NICUs use heparin in UVCs. Heparin is not used in peripheral intravenous lines. Common recommendations:

      1. Central venous lines (UVC and PICC). The American College of Chest Physicians Evidence-Based Clinical Practice Guidelines study recommends heparin in central venous access devices. They recommend UFH continuous infusion at 0.5 U/kg/h to maintain CVAD patency.

      2. Peripheral arterial catheters. The American College of Chest Physicians Evidence-Based Clinical Practice Guidelines study recommends UFH continuous infusion at 0.5 U/mL at 1 mL/h.

      3. UACs. Heparin (0.25–1 U/mL) for a total heparin dose of 25–200 U/kg/d to maintain patency. Cochrane Review notes the use of heparin (as low as 0.25 U/mL) is recommended to prolong the life of the catheter by decreasing the incidence of catheter occlusion. It does not decrease the incidence of aortic thrombosis. Heparinization of intermittent flushes alone is ineffective in preventing catheter occlusion. The American Academy of Pediatrics (AAP) recommends low doses of heparin (0.25–1.0 U/L) through the umbilical arterial catheter. The American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (2012) recommends prophylaxis with a low-dose UFH infusion via the UAC (heparin concentration of 0.25–1 U/mL, total heparin dose of 25–200 U/kg/d to maintain patency.

   4. Umbilical lines should be removed as soon as possible as duration of both UACs and UVCs is a significant risk factor for thrombosis. The Centers for Disease Control and Prevention (CDC) recommend that UACs should not be left in place >5 days and umbilical venous catheters should be removed as soon as possible, but can be used up to 14 days.

   5. High umbilical arterial catheters have a lower incidence of thrombotic complications and a longer catheter life. Low umbilical arterial catheters are associated with an increased incidence of vasospasms and cyanosis. Cochrane Review and the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines recommend high position for UACs.

   6. Use a peripheral arterial line over an umbilical artery catheter.

   7. If there is difficulty infusing into the line, consider a thrombotic event.

   8. Heparinization of flush solution without heparinization of the infusate is inadequate. Use of intermittent heparin flushes has no benefit over normal saline (NS) flushes.

   9. Always use umbilical artery catheters with a hole at the end and not the side, as the side hole may increase aortic thrombosis risk. Single-lumen construction is associated with a decrease in thrombosis.

   10. The use of multiple lumen umbilical venous catheters is associated with a decrease in the need for peripheral intravenous lines in the first week of life but with an increase in catheter malfunctions.

   11. Heparin-bonded catheters versus polyvinyl chloride catheters showed no difference in the incidence of aortic thrombosis or duration of patency.

   12. A PICC line has a lower incidence of thrombosis when compared to a central line. The highest incidence is in femoral lines.

   13. Papaverine was found to prolong the patency of peripheral arterial catheters in a study of neonates, with no difference in the incidence of IVH (controversial).

2. Vasospasm. Treatment is controversial, and guidelines vary extensively. Check your institution's guidelines before initiating treatment. Use of heparin and thrombolytics is not uniformly recommended. If the vasospasm does not resolve with treatment and the tissue ischemia persists, rule out a vascular thrombosis. This can be secondary to a peripheral arterial line or umbilical artery catheter.

   1. Severe vasospasm of the leg/arm

      1. If possible, remove the catheter. Spontaneous resolution is likely.

      2. Warming the contralateral leg/arm. Wrap the entire unaffected leg in a warm (not hot) washcloth. This measure should cause reflex vasodilatation of the vessels in the affected leg, and the vasospasm may resolve. Treatment should continue for 15–30 minutes before a beneficial effect is seen.

      3. Gentle massage at the site of occlusion can be attempted.

      4. Topical nitroglycerin therapy (controversial). (2% ointment, 4 mm/kg, applied as a thin film over the area.) Nitroglycerin has a direct vasodilating effect on vascular smooth muscle and improves circulation. Reports note one application but some repeat it every 8 hours for 2–27 days. Improvement was usually seen within 15–45 minutes. Observe for hypotension.

      5. If it is not possible to remove the catheter (as in a tiny infant) and this is the only catheter. Consider a papaverine-containing solution (60 mg/500 mL in 1/2 NS with 1.0 U/mL heparin) through the catheter as a continuous infusion for 24–48 hours (controversial). If the vasospasm resolves, the infusion may be stopped. If the vasospasm does not resolve, remove the catheter. Exercise caution using this technique in premature infants in the first few days of life where the incidence of developing an intracranial hemorrhage is high.

      6. Lidocaine has been used intra-arterially for vasospasm. Results are questionable, from dose-dependent issues to controversial antispasmolytic effect.

      7. Intra-arterial lidocaine and papaverine have been used successfully to treat a catheter-induced vasospasm during arterial catheterization (controversial, case reports only).

   2. Less severe vasospasm of the leg/arm

      1. If possible, remove the catheter.

      2. Warming the contralateral leg/arm. Wrap the entire unaffected leg in a warm (not hot) washcloth. This measure should cause reflex vasodilatation of the vessels in the affected leg, and the vasospasm may resolve. Treatment should continue for 15–30 minutes before a beneficial effect is seen.

      3. Gentle massage at the site of the occlusion can be tried.

      4. Papaverine (controversial). A spasmolytic is an opium alkaloid that has a direct action on vascular smooth muscle. Dosing is 1 mg intramuscularly, in the unaffected leg. Papaverine is a mild vasodilator; the effect is apparent within 30 minutes.

      5. Topical nitroglycerine (controversial). Two percent ointment, 4 mm/kg, applied as a thin film over the area.

      6. If it is not possible to remove the catheter (as in a tiny infant) and this is the only catheter. Consider a papaverine-containing solution (60 mg/500 mL in 1/2 NS with 1.0 U/mL heparin) as above (controversial; see above).

      7. Lidocaine/intra-arterial lidocaine and papaverine. As above.

3. Problems after vasospasm with peripheral tissue ischemia. Ischemia can sometimes occur after a vasospasm. Even after a catheter has been removed, a persistent vasospasm or small emboli in distal end arteries can cause poor perfusion of an extremity. Topical 2% nitroglycerin ointment (4 mm/kg of body weight) can be applied to the ischemic area with resolution, with no adverse effects except mild episodes of decreased blood pressure (controversial).

4. Thromboembolism. If suspected and there is loss of pulses in the affected extremity, it is a medical emergency. Symptomatic thrombosis can lead to irreversible organ damage or loss of limbs or digits. The most common treatments are observation with supportive care, anticoagulation therapy with heparin or low molecular weight heparin, thrombolytic agents (clot-dissolving drugs, streptokinase, and tissue plasminogen activator), or surgery. Clot-dissolving drugs can cause severe bleeding and there are no current randomized trials comparing these treatments. Management is controversial. Treatment depends on the extent and severity of the thrombus. Management is identical for peripheral arterial thrombosis, venous thrombosis, and aortic thrombosis.

   1. Mild or minor thrombosis. This can present with decreased limb perfusion, hypertension, and hematuria and can usually be treated with removal of the catheter, supportive care, and close ultrasonographic follow-up. Many of these resolve spontaneously.

   2. Moderate thrombosis. This has all the findings of mild/minor thrombosis plus oliguria and congestive heart failure. Can be treated with systemic heparin therapy and with management of systemic hypertension.

   3. Major thrombosis. Presents with all of the above plus major multi-organ failure. Should be treated aggressively with systemic heparin therapy, antithrombolytic agents, and supportive care. May require further evaluation for underlying hypercoagulative disorder.

5. General guidelines for thrombosis treatment. Treatment involves supportive care, observation only, thrombolytic and/or anticoagulant therapy, and surgery. (See also Chapter 87.)

   1. Supportive care

      1. Prompt removal of the catheter is indicated unless it is needed to facilitate arteriography or thrombolytic drug infusion.

      2. Treatment of volume depletion, electrolyte abnormalities, sepsis, thrombocytopenia, and anemia is essential. Control hypertension and any coagulation deficiency or hypofibrinogenemia before initiation of treatment.

      3. Emergency consultation with vascular surgery and pediatric hematology is recommended.

      4. Evaluate patients for intraventricular hemorrhage (IVH) before initiating thrombolytic therapy. During treatment, ultrasounds of the head should be obtained at regular intervals.

      5. Absolute contraindications for anticoagulant and thrombolytic therapy. If the infant has had CNS surgery or ischemia or birth asphyxia in the last 10 days, or evidence of major active bleeding (gastrointestinal, pulmonary, or intracranial), invasive procedures within 3 days, or seizures within 48 hours, anticoagulant and thrombolytic therapy is contraindicated.

      6. Relative contraindications for anticoagulant and thrombolytic therapy. Hypertension, severe coagulation deficiency, platelet count <50 × 10⁴/μL (<100 × 10⁴/μL for ill neonates), fibrinogen concentration <100 mg/dL, international normalized ratio (INR) >2.

   2. Heparin therapy is recommended for clinically significant thrombosis with the purpose of preventing embolism or expansion of the clot. Low molecular weight heparins are best because of the following advantages: reduced need for laboratory monitoring, subcutaneous dosing, longer half-life, decreased risk of osteopenia and heparin-induced thrombocytopenia, and decreased risk of hemorrhage. Monitor platelet counts if heparin is used. Obtain daily complete blood count (CBC) and aPTT. General recommendations are:

      1. Low molecular weight heparin (LMWH) therapy using enoxaparin (Lovenox). The treatment of choice in preterm neonates and most widely used in neonates. Other LMWH preparations include dalteparin and reviparin. For therapeutic treatment, <2 months of age, use enoxaparin 1.5 mg/kg/dose every 12 hours subcutaneously; if >2 months, 1.0 mg/kg/dose subcutaneously. Follow antifactor Xa levels 4–6 hours after dose (0.5–1 U/mL and adjust accordingly, or 0.5–0.8 U/mL in a sample taken 2–6 hours after subcutaneous injection). Adjust as needed. Some studies suggest that preterm neonates require higher mean maintenance doses to achieve target levels (2.0 mg/kg every12 hours if preterm).

      2. Unfractionated (standard) heparin. Load 75 U/kg IV over 10 minutes, then 28 U/kg/h maintenance through a dedicated IV line. (Premature infants: 25–50 U/kg/h over 10 minutes, then 15–20 U/kg/h). Adjust based on aPTT 4 hours after initiation of after each dosing change (target aPTT 60–85 seconds). Duration of therapy is generally 5–14 days. Always increase or decrease the infusion amount by 10%, depending on the aPTT. If the aPTT is >96 seconds, hold the heparin for 30–60 minutes and start at a lower infusion rate.

      3. If urgent reversal of unfractionated heparin effect is needed. IV protamine can be given based on the total amount of heparin administered in the previous 2 hours. Stopping the infusion is usually sufficient for LMWH, and protamine is only partially effective.

   3. Warfarin therapy. (Oral anticoagulant.) Not recommended in neonates (bleeding risk, difficulty in maintaining therapeutic doses, drug interactions including vitamin K content of the diet, tablet formulation).

   4. Thrombolytic drugs. Do not use in milder cases, and few studies have been done in very preterm infants. With extensive thrombosis, life-threatening thrombosis, right atrial thrombosis, and the possibility of limb loss or organ damage, one of these drugs may be used. Treatment is controversial, and it is best to follow institutional guidelines. When using thrombolytic therapy, maintain a platelet count >50–100 × 10⁴ μL and fibrinogen >100 mg/dL using platelet transfusion and cryoprecipitate. Monitor PT/INR, partial thromboplastin time (PTT), and fibrinogen every 4 hours. If the catheter is still patent, the medications can be given through it. If the catheter is obstructed and needs to be removed, systemic therapy is used.

      1. Recombinant tissue plasminogen activator (tPA) (Alteplase) has become the drug of choice (lowest risk of allergies, the shortest half-life, less manufacturing concerns). See Chapter 148 for dosage.

      2. Infusion of intra-arterial streptokinase has been successful in some infants. Dose: 2000 U/kg IV over 30–60 minutes, 1000–2000 U/kg/h as continuous infusion for 6–12 hours. Lower doses (500 U/kg/h) have been effective. In one study of aortoiliac thrombosis, a dose of 50 U/kg/h given directly into the clot was effective. Because of systemic side effects (allergic and toxic reactions and bleeding), its use has declined.

      3. Urokinase is no longer available in the United States but may be used in other countries. Dose: 4400 U/kg initial bolus dose IV over 10 minutes, then 4400 U/kg/h for 6–12 hours.

      4. Newer agents. Both bivalirudin and argatroban (direct thrombin inhibitors) have been approved in adults and use in infants is evolving.

   5. Catheter-directed thrombolysis (CDT). A sophisticated method in which the agent is injected into the thrombosis. In some reports it is superior to systemic thrombolytic therapy with fewer side effects. It is also used if neonates fail to respond to unfractionated heparin (UFH) therapy. For a blocked central venous access device, local thrombolysis is recommended after clinical assessment. For neonates with limb-threatening or organ-threatening femoral artery thrombosis who fail initial UFH therapy, thrombolysis is recommended. Drug of choice is tPA with a dose of 0.01–0.05 mg/kg/h.

   6. Surgery. Immediate surgery has been successfully performed in neonates and may be indicated in the presence of an occluding embolism if thrombolysis is contraindicated for peripheral arterial occlusion. Guidelines are not well established. Surgical options include thrombectomy, microvascular reconstruction, vascular decompression through the use of a fasciotomy, mechanical disruption of the thrombus (medical thrombectomy), and amputation. If antithrombotic therapy is contraindicated, arteriotomy, embolectomy, and microvascular reconstruction is an option.

   7. Specific treatment

      1. Peripheral arterial catheter–related thromboembolism. Remove the catheter immediately. Symptomatic peripheral arterial catheter–related thromboembolism: UFH anticoagulation with or without thrombolysis or surgical thrombectomy with microvascular repair with heparin therapy.

      2. Central venous lines thrombosis. Clinical assessment and local thrombolysis.

      3. Acute femoral thrombosis. Therapeutic doses of IV UFH as initial therapy or LMWH for a total of 5–7 days of anticoagulation. For infants with limb-threatening or organ-threatening femoral artery thrombosis who fail to respond to UFH therapy and there are no contraindications: thrombolysis. With contraindications: surgical intervention.

      4. Renal vein thrombosis

         1. Unilateral (no renal impairment, no IVC extension). Supportive care with close follow-up by radiology or anticoagulation in therapeutic doses for 6 weeks to 3 months. Unilateral (with extension into inferior vena cava [IVC]): anticoagulation for 6 weeks to 3 months.

         2. Bilateral (with renal impairment). Anticoagulation or initial thrombolytic therapy with tPA, then long-term anticoagulation.

      5. Cerebral sinovenous thrombosis (without significant intracranial hemorrhage). Anticoagulation for 6 weeks to 3 months. With significant intracranial hemorrhage: anticoagulation or supportive care with radiologic monitoring, and anticoagulation if extension of the thrombus occurs.

      6. First arterial ischemic stroke with no ongoing source of the cardioembolic source. Supportive care. With documented cardioembolic source: anticoagulation recommended. Recurrent arterial ischemic stroke: anticoagulant or aspirin therapy.

      7. Systemic air embolism. Use caution in setting up infusion lines with complex parts; use of IV fluid filters may decrease air embolism. Treatment is supportive cardiac care and supportive respiratory care, with 100% oxygen therapy. Hyperbaric oxygen has been used in some cases.

      8. Neonatal purpura fulminans/thrombophilias. See Chapter 87.