Atlas of Procedures in Neonatology, 4th Edition

Vascular Access

33

Management of Vascular Spasm and Thrombosis

Jayashree Ramasethu

Thromboembolism (TE) is being increasingly recognized as a significant complication of intravascular catheters in sick newborn infants. About 90% of neonatal venous thromboses are associated with central venous catheters, although additional risk factors may be present (1). This chapter focuses on catheter-related vascular spasm and thrombosis.

  1. Definitions
  2. Vascular spasm is transient, reversible arterial constriction, triggered by intravascular catheterization or arterial blood sampling. The clinical effects of vascular spasm usually last less than 4 hours from onset, but the condition may be difficult to differentiate from more serious thromboembolic (TE) disease. The diagnosis of vasospasm of arteries may only be made retrospectively, after documentation of the transient nature of ischemic changes and complete recovery of circulation.
  3. Thrombosis is the complete or partial obstruction of arteries or veins by blood clot(s).
  4. Assessment
  5. Clinical diagnosis (Fig. 33.1)
  6. The clinical signs associated with arterial or venous TE are shown in Table 33.1.
  7. Vascular spasm of peripheral arteries is characterized by transient pallor or cyanosis of the involved extremity with diminished pulses and perfusion.
  8. Persistent bacteremia or thrombocytopenia are nonspecific signs associated with vascular thrombosis at any site.
  9. Clinical signs may be subtle or absent in many cases of thrombosis.
  10. Diagnostic imaging
  11. Contrast angiography is the “gold standard.” It gives the best definition of thrombosis, but it is difficult to perform in critically ill neonates and requires infusion of radiocontrast material that may be hypertonic or cause undesired increase in vascular volume (2).
  12. Doppler ultrasonography is portable, noninvasive, and can be used to monitor progress over time. It is useful for follow-up of aortic and peripheral arterial obstruction, but it may give both false positive and false negative results compared with contrast angiography (3).
  13. Additional diagnostic tests
  14. Obtain detailed family history in all cases of unusual or extensive TE.
  15. In the absence of predisposing risk factor for thrombosis, consider investigations for the diagnosis of thrombophilic disorders: anticardiolipin, antithrombin III, protein C, protein S deficiency, etc. (4,5).
  16. Management of Vascular Spasm
  17. Warm contralateral extremity (reflex vasodilation).
  18. Maintain neutral thermal environment for affected extremity, i.e., keep heat lamps away from the area.
  19. Maintain limb in horizontal position.
  20. If necessary, restore circulating volume with blood, albumin, or plasma.
  21. Consider removing catheter.

If mild cyanosis of the fingers or toes is noted after insertion of an arterial catheter, but peripheral pulses are still palpable, a trial of reflex vasodilation with close observation is reasonable, because vasospasm may resolve. Continually assess the need for keeping the catheter in place (i.e., the benefits of arterial access vs. the risk of thrombosis and further complications). A white or “blanched”-appearing extremity is an indication for immediate removal of the catheter.

  1. Topical nitroglycerine has been demonstrated to reverse peripheral and umbilical artery catheter–induced ischemia in isolated case reports. Maintain good circulatory volume. Monitor for hypotension and be prepared to treat it immediately.
  2. Topical application of 2% nitroglycerine ointment at a dose of 4 mm/kg body weight, applied as a thin film over the affected areas; may be repeated after 8 hours (6,7 and 8).
  3. Application of a nitroglycerine patch has also been described (9).

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FIG. 33.1. Skin necrosis associated with an umbilical artery catheter. Such lesions develop after vasospasm or embolization. A: Spinal injury may be present when ischemia involves this region. B: The distal part of an extremity is a common site for embolic arterial loss. The full extent of loss is unpredictable at this stage. (From 

Fletcher MA. Physical Diagnosis in Neonatolgy. Phildelphia: Lippincott-Raven; 1998:127

.)

TABLE 33.1 Diagnosis of Vascular Thrombosis

Site

Clinical Signs

Diagnostic Imaging

CVL-associated venous thrombosis

Malfunction of CVL, SVC syndrome, chylothorax, swelling and livid discoloration of extremity, dilatation of collateral veins over trunk or abdomen in chronic cases

Contrast angiography
Doppler ultrasonography
Real time 2-D ultrasonography

Inferior vena cava thrombosis

Lower limbs cool, cyanotic, edematous

Superior vena cava thrombosis

Swelling of upper limbs and head, chylothorax

Renal vein thrombosis

Flank mass, hematuria, thrombocytopenia, hypertension

Aortic or renal arterial thrombosis

Systemic hypertension, hematuria, oliguria

Peripheral or central (aorta or iliac) arterial thrombosis

Pallor, coldness, weak or absent peripheral pulse(s), discoloration, gangrene

Right atrial thrombosis

Congestive heart failure

Echocardiography

Pulmonary thromboembolism

Respiratory failure

Lung perfusion scan

CVL, central venous line; SVC, superior vena cava.

  1. Management of Catheter-Related Thromboembolism
  2. General principles
  3. Thrombolysis to restore catheter patency is described in Chapter 31.
  4. Management of vascular TE may involve one or more of the following: supportive care, anticoagulation, fibrinolytic therapy, surgical intervention (4,5,10).
  5. Treatment for neonates is highly individualizedand is determined by the extent of thrombosis and the degree to which diminished perfusion to the affected extremity or organ affects function (4,5).
  6. The infant should be managed in an appropriately staffed and equipped neonatal intensive care unit, where anticoagulant or thrombolytic therapy can be administered and monitored, and supportive and surgical care are readily available. Consultation

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with pediatric hematology is recommended. Plastic or vascular surgical consultation may be required.

  1. The International Children's Thrombophilia Network, based in Canada, is a free consultative service, maintained 24 hours a day, for physicians worldwide who are caring for children with thromboembolic disease. The toll-free line in North America is 1-800-NO-CLOTS; the number for physicians elsewhere is 1-905-573-4795. The service provides current management protocols as well as links to the network and its services (11).
  2. Initial management
  3. Initiate management as for vascular spasm for peripheral arterial ischemia.
  4. Removal of catheter is advocated (5).

Peripheral arterial and umbilical catheters should be removed immediately if an extremity appears white or “blanched.” Intravascular catheters are left in place even in the presence of thrombosis only if local thrombolysis through the catheter is planned (12).

  1. Supportive care: correct volume depletion, electrolyte abnormalities, anemia, and thrombocytopenia; treat sepsis.
  2. Anticoagulant/thrombolytic therapy (4,5)

The risk of serious bleeding associated with antithrombotic therapy in neonates must be balanced against the possibility of organ or limb loss or death without appropriate treatment. Adequate randomized controlled trials to guide therapy in neonates are not available (12,13). The following guidelines are based on published protocols used in small case series.

  1. Contraindications
  2. Major surgery within the last 10 days
  3. Major bleeding: intracranial, pulmonary, or gastrointestinal
  4. Pre-existing cerebral ischemic lesions
  5. Relative contraindications: thrombocytopenia (platelet count <100 x 109/L), hypofibrinogenemia (fibrinogen <100 mg/dL), severe coagulation factor deficiency, hypertension. Anticoagulant/thrombolytic therapy may be given after correction of these abnormalities.
  6. Precautions
  7. No arterial punctures
  8. No subcutaneous or intramuscular injections
  9. No urinary catheterizations
  10. Avoid aspirin or other antiplatelet drugs.
  11. Monitor serial head ultrasound scans for intracranial hemorrhage.
  12. Anticoagulants
  13. Oral anticoagulants (Warfarin)

Warfarin is not recommended in neonates because its anticoagulant effects are altered significantly by diet, illness, and other medications.

  1. Standard or unfractionated heparin (14,15)
  2. Anticoagulant, antithrombotic effect limited by low plasma levels of antithrombin in neonates
  3. Dosage: Loading dose of standard heparin 75 U/kg IV over 10 minutes; maintenance dose 28 U/kg/hr for infants <1 year of age
  4. Monitoring: Check activated partial thromboplastin time (APTT) 4 hours after loading dose and 4 hours after every change in the infusion rate.
  5. Adjust heparin infusion to maintain APTT at 60 to 85 seconds, corresponding to an anti-FXa level of 0.3 to 0.7 U/mL.
  6. If APTT <60 seconds, increase infusion rate by 10%, and repeat APTT after 4 hours.

iii.      If APTT >85 seconds, decrease infusion rate by 10%, and repeat APTT after 4 hours.

  1. If APTT >96 seconds, hold heparin infusion for 30 to 60 minutes, and restart at lower infusion rate; repeat APTT after 4 hours.
  2. When APTT values are therapeutic and infusion rate is stable, obtain complete blood count and APTT daily.
  3. The optimal duration of anticoagulation with heparin is unknown, but therapy is usually continued for 5 to 14 days (4,5).
  4. Monitor thrombus closely both during and following treatment.
  5. Complications
  6. Bleeding
  7. Heparin-induced thrombocytopenia (16)
  8. Antidote: Protamine sulfate IV may be used for rapid reversal of bleeding caused by heparin.

Dosage: 1.0 mg/100 U heparin received if the time since the last heparin dose is <30 minutes. The dose of protamine decreases linearly with increasing time since the last heparin dose, dropping to 0.25 mg/100 U

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heparin if the time since the last heparin dose is >120 minutes (5).

TABLE 33.2 Guidelines for Adjusting LMWH Treatment Dosage (32)

Anti-Factor Xa Level

Dose Change

Repeat Anti-Factor Xa Level

<0.35 U/mL

↑ by 25%

4 h following dose adjustment

0.35–0.49 U/mL

↑ by 10%

4 h following dose adjustment

0.50–1 U/mL

No change

Weekly, 4 h following a dosea

1.1–1.5 U/mL

↓ by 20%

Before next dose and 4 h following dose adjustment

1.6–2.0 U/mL

Hold next dose for 3 h, then T by 30%

Before next dose and 4 h following dose adjustment

>2.0 U/mL

Hold dose until anti-factor Xa level 0.5 U/mL, then T by 40%

Q 12 h until anti-factor Xa level <0.5, then 4 h following reinstitution of therapy

aCheck level 4 h after next dose if there is a change in renal function, addition of antibiotics, or if any bleeding occurs.
Modified from Andrew M, deVeber G. Pediatric Thromboembolism and Stroke Protocols. Hamilton, Ont.: B.C. Decker; 1999, with permission.

  1. Low-molecular weight heparin (LMWH) (17,18)
  2. LMWHs have specific activity against factor Xa and less activity against thrombin, so therapy is monitored by anti-FXa assay and not by APTT.
  3. Different LMWH preparations (e.g., enoxaparin, dalteparin, reviparin) differ in their molecular weights and dosage regimens.
  4. Advantages: Subcutaneous administration.
  5. Dosage: starting dose 1.5 mg/kg subcutaneously every 12 hours. Therapeutic dose range may vary from 0.95 to 3.5 mg/kg/12h.
  6. Monitoring
  7. Adjust dose to maintain anti-factor Xa level between 0.5 and 1 unit/mL (Table 33.2).
  8. Although LMWHs have more predictable pharmacokinetics in adults, in neonates, prematurity, rapid growth, and liver and kidney dysfunction make dosage less predictable. Frequent adjustment of the dose is required to attain target anti-FXa levels.
  9. Draw blood sample for testing from fresh venipuncture. There must be no contamination from standard heparin, e.g., from an arterial line.
  10. Check levels 4 hours after subcutaneous administration of LMWH on day 1 and day 2 of treatment.
  11. If therapeutic, weekly check of anti-factor Xa levels is adequate.
  12. To discontinue anticoagulation, simply discontinue LMWH therapy. If an invasive procedure such as lumbar puncture is required, skip two doses of LMWH, and measure anti-factor Xa level prior to the procedure.
  13. If an immediate antidote is required, protamine is partially effective. Consult a hematologist. 1 mg of protamine neutralizes 100 U (1 mg) of Enoxaparin given within the last 3 to 4 hours. Protamine should be administered IV, over a 10-minute period, as rapid infusions may produce hypotension.
  14. Thrombolytic agents
  15. Thrombolytic agents should be considered in the presence of extensive or severe thrombosis when organ or limb viability is at risk.
  16. Agents work by enhancing the conversion of plasminogen to plasmin, which then proteolytically cleaves fibrin within the clot to fibrin degradation products.
  17. Supplementation with plasminogen in the form of fresh frozen plasma enhances the thrombolytic effect (19).
  18. Thrombi that have been present for several days may be resistant to thrombolysis. Failure rates may be as high as 50% (20).
  19. The administration of heparin, either concomitantly or following thrombolytic therapy, has not been adequately evaluated in neonates.
  20. A wide variety of dosage protocols have been used (12).
  21. Streptokinase
  22. Associated with allergic reactions in adults and older children; replaced largely by urokinase. Limited information in neonates.

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  1. Dosage regimens in neonates range from 50 U/kg/hr (directly into the thrombus) to intravenous infusions of 2,000 U/kg/hr (5,21,22).
  2. Urokinase
  3. Nonantigenic, but like streptokinase, has a low affinity for plasminogen bound to fibrin (clot-bound fibrin).
  4. Human-derived urokinase has been replaced by the recombinant form in the United States.

iii.      Dosage: Loading dose 4,400 U/kg over 20 minutes, followed by continuous IV infusion of 4,400 U/kg/hr for 6 to 12 hours (4,5). The dosage and duration of therapy is determined by the response. Doses up to 10,000 to 16,000 IU/kg/hr have been used (23). Smaller doses have been used for local treatment of thrombi without removal of central venous catheters.

  1. Recombinant tissue plasminogen activator (r-tPA)
  2. Nonantigenic, has specific affinity for plasminogen bound to fibrin, intensifying thrombolysis at the site of the clot; has a short half-life.
  3. Large number of case reports published, with varying dosage protocols (17)

iii.      Dosage protocol 1: Infusion, 0.1 mg/kg/hr. If no response after 6 hours, may increase infusion rate by 0.1 mg/kg/hr every 6 hours, to a maximum of 0.5 mg/kg/hr. Monitor fibrinogen levels every 4 hours and keep levels >100 mg/dL (24).

  1. Dosage protocol 2: Initial bolus, 0.1 mg/kg over 10 minutes, followed by infusion of 0.3 mg/kg/hr over a 3-hour period. Perform Doppler sonography at the end of each infusion. Fibrinogen assay 1 hour and 4 hours after each r-TPA infusion is initiated. If repermiabilization is not complete, up to four additional r-TPA infusions may be given at intervals of 12 to 24 hours (25).
  2. Catheter-directed thrombolysis: Infusion of low doses of r-tPA through a catheter with the tip adjacent to or within the thrombus; higher response rate with decreased risk of bleeding (12).

Initial bolus dose ranges from 0 to 0.5 mg/kg, followed by infusion of 0.015 to 0.2 mg/kg/hr.

  1. Monitoring
  2. Imaging studies every 4 to 12 hours during fibrinolytic therapy, to allow discontinuation of treatment as soon as clot lysis is achieved.
  3. Measure thrombin time, fibrinogen and plasminogen levels, and fibrin split products or d-dimers prior to therapy, 3 to 4 hours after initiation of fibrinolytic therapy and one to three times daily thereafter (2).

iii.      Fibrinolytic response is measured by a decrease in fibrinogen concentration and increase in levels of fibrin degradation products, but the correlation between these hemostatic parameters and efficacy of thrombolysis is poor. Maintain fibrinogen levels of at least 100 mg/dL to prevent bleeding.

  1. Complications of Anticoagulation/Fibrinolytic Therapy
  2. Hemorrhagic complications (12,26)
  3. Intracerebral hemorrhage: Incidence approximately 1% in term neonates, 13% in preterm neonates, increasing to 25% in preterm infants treated in the first week of life. Data in preterm infants are confounded by the risk of “spontaneous” intraventricular hemorrhage (26).
  4. Other major hemorrhages: Gastrointestinal, pulmonary
  5. Bleeding from puncture sites and recent catheterization sites
  6. Hematuria
  7. Embolization

Dislodgement of intracardiac thrombus, causing obstruction of cardiac valves or main vessels, pulmonary or systemic embolization (27,28).

  1. Surgical Intervention (10,29,30and 31)

Early consultation is recommended, because surgical management may be required concomitantly, particularly for life- or limb-threatening emergencies.

  1. Thrombectomy
  2. Microvascular reconstruction

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  1. Leech therapy
  2. Decompressive fasciotomy
  3. Mechanical disruption of thrombus using soft wires and balloon angioplasty in conjunction with continuous site-directed thrombolytic infusion into the clot.
  4. Amputation

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