Great Vein and Right Atrial Thrombosis in Critically Ill Infants and Children with Central Venous Lines

Great Vein and Right Atrial Thrombosis in Critically Ill Infants and Children with Central Venous Lines* William Berman, Jr., M.D.; Raymond R. Fripp, M.D.; Steven M. Yabek, M.D.; jorge Wernly, M.D. , F.C.C.P.; and Sue Corlew, R.D. M.S .

We performed a retrospective review of echocardiographic

data files of infants and children hospitalized in the Newborn and Pediatric Intensive Care Units. Echocardiograms were examined to detect the presence and evolution of great vein and right atrial thrombosis in patients with central venous lines. Thirty-seven patients were identified over a five-year period. Echocardiograms were performed, not routinely, but in response to specific indications including catheter malfunction, thrombocytopenia, persistent chylothorax, bacterial or fungal sepsis, and superior vena cava syndrome. Fifteen of 37 patients died, 13 of them during the hospitalization in which the thrombus was discovered. Thrombolytic agents and surgery were used to

Echocardiography now provides a noninvasive means for assessing the presence of intracardiac thrombi in critically ill infants and children. Thrombus formation within the great veins and the right atrium is a known complication of central venous catheterization. •.a Because medical treatment of intracardiac and intravascular thrombosis is now possible,3-6 an understanding of the course of this disease entity becomes important. We performed a retrospective review based on our echocardiography data file to examine the frequency, progression, response to treatment, and eventual outcome of intracavitary thrombosis of the right heart and the veins leading to it in hospitalized infants and children. METHODS

Echocardiographic re<:ords for the period of Au~st 1983, to August 1988, were reviewed. This six-year retrospective analysis was performed on pediatric echocardiographic studies only. The population included critically ill infants and children in either the Newhorn Intensive Care Unit or Pediatric Intensive Care Unit of the University of New Mexico Hospital. The Newborn Intensive Care Unit, over the past six years, has maintained a capacity of 18 to 20 beds, averages a 90 percent census, and accepts 550 to 600 new patient admissions per year. The Pediatric Intensive Care Unit capacity has varied between eight and ten beds, has an average census of 95 percent, and accepts 500 to 600 admissions per year, about 20 percent of which are postoperative cardiac patients. *Fmm the Pediatric Cardiology Associates of New Mexico, and the Department of Pediatrics and Surgery, University of New Mexi<:o School of Medicine, Albuquerque. Manuscript received May 24; revision a(:cepted November 9. Re,Jrint requests: Dr. Berman, 4-North, Department of Pediatrics, University of New Mexico, Albuquerque 87131

treat selected patients, with mixed results. Two of the 22 survivors have significant disability related to the thrombus or complications arising from it. We conclude that great vein and/or right atrial thrombosis is a common complication of central venous catheterization in small infants and children; moreover, the morbidity and mortality relating to this complication is substantial. (Chut 1991; 99:963-61) BPD =bronchopulmonary dysplasia; CHD =congenital heart disease; CVP=c:entral venous pressure; NEC=necrotizing enterocolitis; PDA =patent ductus arteriosus; SBE = subac:ute bacterial endocanlitis; SVC =superior vena cava; tPA =tissue plasminogen activatori TPN =total parenteral nutrition; VSD=ventricular septal defect

Echocardiograrns were performed for a number of speci6c indications: superior vena cava syndrome; sepsis; "rule out SBE;" unexplained thrombocytopenia in a patient with a central venous catheter; documented SBE; and central venous catheter malfunction (either inability to withdraw blood or inability to record a phasic wave form from the central venous line). Some echocardiograms were performed for hemodynamic indications and thrombi were detected incidentally. A total of 37 patients with thrombus were identi6ed by this review. Extensive descriptions of the thrombi are not included in this review. The thrombus was identi6ed as de6nitely being present if an echo dense mass could he seen around the catheter shaft or tip near a venous junction with the right atrium, whether or not the thrombus extended into the atrial cavity. Whenever possible, the relationship of the thrombus to the catheter was described. When evidence for thn>mbus was e
963

Table 1-lbtient Study Group-Death. Precipitatin~t

Age

DialtJlOSiS

fustop

"Cause

Cause of Death

Death Related to Thrombus

Yes

CVP line

Chronic respiratory failure

Nc1

1 mo

Complex cyanotic CHD with heart block VSD, interrupted arch

Yes

CVPiine

Chylous effusicms., bacterial sepsis

Yes

11 mo

VSD

Yes

CVPiine

fustimmunization

Nn

4mo

VSD, coarctation

Yes

CVPiine

No

3mo

VSD, coarctation

Yes

CVPiine

Hypertrophic cardiomyopathy Empyema, bacterial sepsis

12 yr

Asplenia, complex CH D

Yes

"CVP" line to venous baffle

Baffie thrombus, low cardiac output

Yes

1 mo

Tricuspid atresia

Yes

CVP line

Chylous effusions, bacterial sepsis

Yes

2wk

Disseminated herpes

No

CVP line

Disseminated herpes

No

2mo

BPD&NEC

No

Silastic TPN line

Yes

3wk

Tetralogy of Fallot Tracheoesophageal fish1la BPD

Yes

Bmviac catheter

No

CVPiine

Bacterial sepsis, low cardiac output & necrotizing enteroc'Oiitis Low cardiac output, superior vena cava syndrome Chronic respiratory failure

Yes

Silastic TPN line

Respi.ratory failure

No

1 yr

Hirschsprungs's, Ondines curse BPD

No

Broviac cathete r

Candida sepsis

Yes

1 wk

Anomalous pulmonary

Yes

CVPiine

Chylous effusions, bacteria.! sepsis

Yes

14 mo

Pulmonary atresia, VSD

Yes

CVPiine

Postoperative low cardiac output

No

3wk

4mo

3mo

RESULTS

Patient age varied from four days to 17 years at the time of diagnosis ('Thble 1). The mean and median ages at the time of thrombus diagnosis were 13.0 and 2.0 months, respectively, in the patients who survived and 12.7 and 2.0 months, respectively, in those who died. Structural congenital heart disease was present in 20 of the 37 patients. Five of the 17 patients without heart disease died. In eight of the 37 cases, the catheter was a Broviac; in 20, it was a Cook 5 French double lumen line; in seven, a Cook 5 French triple lumen line; and in two, a Silastic catheter. Thirteen of the 37 patients died during the hospitalization in which the thrombus was discovered; two died during a subsequent hospitalization unrelated to the throm-

Yes

Outcome of Thrombus Persisted after catheter removal Partial lysis after urokinase Rx x3; s urgical removal of VSD patch, residual dut&mnduit Resolved after catheter removal (LATE DEATH) Persisted after catheter removal Persisted until death 10 days pustop Persisted after urokinase and TPA

Rx Persisted after urokinase Rx; surgical excision of thrombus Persisted after catheter re moval Persisted after catheter removal

Yes

Persisted after urokinase Rx

No

Resolved after urokinase Rx (LATE DEATH) Resolved after catheter removal Persisted after catheter removal; t'Oai(Uiopathy Persisted until death 4 wks postop; <.'03gulopathy Persisted after urokinase Rx

bus (Late death noted in Table 1); 22 of the 37 are alive currently (see Table 2). The mean duration of venous catheterization prior to recognition of the thrombus was 16 days in the patients who survived and 17 days in the patients who died; the range of time, however, was broad, from 2 to 90 days. A spectrum of findings was associated with great vein and/or right atrial thrombus. Thrombocytopenia was noted in 16 patients, five who died and 11 who lived; apersistent chylothorax, in two cases significant enough to warrant thoracic duct ligation, was present in nine patients, four who died and five who lived; documented bacterial or fungal sepsis was present in ten of the patients, four who died and six who lived; a

Thrombosis in Crtlicaly IM lnlants and Childr8n with Central Venous Lhls (Berman et Ill}

Table 2-Survioora Age

Diagnosis

Postop

Precipitating Causes

Outcome of Thrombus

4mo

Tetralogy of Fallot

Yes

CVPiine

2wk 2mo 1 wk

Yes Yes Yes

CVPiine CVPiine CVPiine

Yes

CVP line

Resolved after catheter removal

Yes

CVP line

Cerebral embolus; residual lei\ hemiparesis

1 wk 1wk 17 yr 6 mo Swk 7wk 15mo Smo

Aortic stenosis PDA/Lef\SVC Critical pulmonic stenosis Aortic stenosis coarctation A-V canal, Pulmonic stenosis, Left SVC VSD/coarctation Coarctation/A· V canal Lymphoma Hirscbspnmg's Colonic atresia BPD Near drowning Sepsis

Persisted after catheter removal; residual superior vena cava syndrome Resolved after catheter removal Surgical excision & thoracic duct ligation Resolved after catheter removal

Yes Yes No No Yes No No No

CVPline CVPiine Broviac catheter CVPline Broviac catheter CVPline CVPiine CVPline

1 wk

Gastroschisis

Yes

Broviac catheter

11 mo 13mo 2mo 3mo 3mo 6mo Smo

Hydrocephalus PneumoniaiBPD BPDINEC VSDIBPD BPD/apnea BPD C{)af"Ctation

Yes No Yes Yes No Yes Yes

CVP line Broviac catheter Silastic TPN line CVPiine Brovlac catheter Bmviac catheter CVP line

Resolved after urokinase Rx Surgical clot removal Resolved after catheter removal Resolved after catheter removal Resolved after catheter removal Persisted after catheter removal Resolved after catheter removal Resolved after heparin infusion & catheter removal Persisted after urokinase Rx & resolved after catheter removal Resolved after catheter removal Resolved after catheter removal Resolved after catheter removal Resolved after streptokinase Rx Resolved after catheter removal Resolved after urokinase and catheter removal Resolved after catheter removal

2mo 1 wk

clinical superior vena cava syndrome was present in 12 patients, four who died and eight who lived. The thrombus was noted fortuitously on echocardiograms performed for cardiac structure or function in nine of the 37 patients. Thrombus resolution occurred in 20 of the 37 patients. Anticoagulant therapy with tPA, streptokinase, urokinase, or heparin was instituted in 11 patients, six of whom died and five of whom lived. Echocardiographic demonstration of thrombus resolution was found in two of the six treated patients who eventually died and four of the five treated patients who lived. Of those patients who did not receive specific thrombolytic therapy, 2 of the 9 who died and 12 of the 17 who lived showed clot resolution after catheter removal during the hospitalization when thrombus was shown. Twenty-one of the 37 patients received concomitant antibiotic therapy during the time the clot was known to be present. Two of the 22 patients who survived, and two of the 15 patients who died underwent surgical excision of the thrombus at a time when thrombolytic therapy was contraindicated. In 8 of the 15 patients who died, death was related directly to presence of the thrombus or complications (sepsis, emboli) arising from it (Table 1). Intractable sepsis unresponsive to antibiotic therapy was the cause of death in six patients, three of whom had associated large chylous pleural effus~ons and one of whom had

a bacterial empyema; in two cases, major venous occlusion (atrial bafBe, one and superior vena cava, one) resulted in low cardiac output and death. Two surviving patients have disability related to their episode of venous thrombosis. The first, with repaired tetralogy of Fallot and 4 months old at the time of superior vena cava thrombosis, has now, at age 20 months, residual SVC syndrome with facial swelling and upper extremity edema. The second, a 2 1/2 year old with Down's syndrome, an atrioventricular septal defect (AV canal), pulmonic stenosis, and an aortopulmonary shunt placed at one week of age, had a cerebral embolus/infarction postoperatively at a time when thrombus was noted in the coronary sinus, around a CVP line inserted through the left subclavian vein into a persistent left superior vena cava. DISCUSSION

Venous thrombosis is now a known complication of central venous catheterization. In 1983, Katz et al8 reviewed their experience with pulmomary artery catheterizations in children and commented that "aseptic thrombi" can be a source of distant (pulmonary) embolization in patients with indwelling pulmonary artery catheters traversing the right heart. In 1982, Chastre et al 1 reported a prospective series of thrombosis detection in adult patients with indwelling pulmonary artery (Swan-Ganz) catheters. These auCHEST I 99 I 4 I APRIL. 1991

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thors reported that in 22 of 33 patients, thrombus was detected prospectively by contrast dye techniques at a mean of3.3 days after catheter insertion. An autopsy study of 142 adult patients in whom Swan-Ganz catheters had been placed revealed that 20 percent had sterile thrombi and an additional 4 percent had hemorrhage and thrombus in the right heart related in some way to the catheter's presence.8 Kinney and Wrighfl reviewed the literature from 1966 to 1989; in 71 reports involving 119 patients, central venous catheterization was found to he a significant risk factor for the presence of thrombus within the great veins or the right heart. The compiled mortality was 31 percent. Experience specific to intravascular thrombosis in pediatric patients accumulated rapidly in the late 1970s and early 1980s following recognition of aortic thrombosis as a complication of umbilical artery catheterization. 1o-13 Most reports suggest that extensive aortic thrombosis is associated with poor outcome; the variable response to thrombolytic agents has raised as yet unsettled questions about the appropriate dose of urokinase or streptokinase to use in the neonate with intravascular thrombosis. This issue is raised specifically by Corrigan et al 10 and referred to again by Emami et al. 12 Moreover, a recent study of neonates with aortic thrombosis by Caplan et al13 suggests that the long-term outcome in surviving patients who were untreated with thrombolytic agents is not universally poor. Articles specific to venous occlusion and right atrial thrombosis in pediatric patients are less numerous than those dealing with neonatal aortic thrombosis. Not even the most recent New England journal of Medicine Medical Progress sections reviewing the status of thrombolytic therapy mention application to the patient with thrombosis of the great veins or a right heart chamher.M In 1982, Delaplane et al, 4 reported the use of urokinase for treatment of a catheter-related right atrial thrombosis in a prematurely horn infant who had also undergone cardiac surgery. A silastic catheter had been used for parenteral nutrition, and a catheter-related clot was noted on "routine" two-dimensional echocardiography. Following infusion of doses of urokinase comparable on a weight related basis to those used in adults, the clot lysed over a period of 10 hours, hut recurred 4 weeks later. Clot lysis on the second occasion was guided by measurements of prothrombin time, partial thromboplastin time, fibrinogen levels, fibrin degradation products, and plasminogen levels; very high doses (52,800 IU/kglh) were required to affect the clotting system according to the measured lab values. Clot lysis was apparently effective, as following death from an unrelated cause at six months of age, no emboli were found at post mortem examination.

In 1983, Dhande et al14 reported the association of bilateral chylothorax with superior vena cava obstruction complicating central venous catheterization. The report focused on five prematurely horn infants who presented management problems related to recurring pleural effusions that become chylous following oral feeding. All of the patients had sepsis complicating the venous occlusion, four with Staphylococcus epidermidis and one with Candida albicans; four of the five infants died. In 1988, Marsh et al 2 reported two patients who developed right atrial thrombosis as a complication of central venous catheterization used during and after extracorporeal membrane oxygenation. In one patient, urokinase at an unspecified dose caused thrombus resolution; the other patient required surgery to remove the thrombus. These authors included in their report a recommendation that weekly echocardiograms he performed to detect thrombi in children with chronic indwelling venous catheters. A report by Bagnall et al, tS in 1989, emphasizes that the problem of great vein and right atrial thrombosis is not specific to the very small infant. These authors reported a surveillance study of 227 pediatric hematology/oncology patients. A total of254 right atrial catheters placed for administration of chemotherapy agents were associated with 81 occurrences of partial or complete vascular occlusion involving 58 of the 254 catheters. Also in 1989, Ross et al16 reported a two-part analysis of central venous catheterization with silicone catheters in infants and children. In the retrospective segment of 350 patients, catheter thrombi were detected in 16, 12 of whom were premature infants. Continuous catheter use and the administration of parenteral nutrition were thought to he risk factors. Ten of the 16 patients died within three months, hut none of the deaths was thought to he catheter-related. Forty-seven patients were screened prospectively. The majority of these were children receiving chemotherapy. None was symptomatic, ten were receiving parenteral nutrition, and none had thrombus detected. We cannot report precisely on the incidence ofgreat vein or right atrial thrombosis with indwelling central venous lines because of the retrospective nature of this report. Estimates from the number of cases and from the number of admissions handled yearly in our intensive care units suggest that the incidence of hemodynamically significant venous thrombosis approximates 5 to 10 percent of patients with central venous lines. This number is not significantly different from that reported in two other series. 17• 18 In our series, clinical and laboratory findings associated with presence of a thrombus were relatively frequent, due in large part to the fact that the study was not prospective, but instead was responsive to findings suggestive of a hemodynamic problem. In addition to

the finding of persistent chylothorax in 9 patients, .. 16 of the 37 patients had thrombocytopenia, 10 had positive blood cultures, and 12 had superior vena cava syndrome. The benefits of treatment are equivocal in this series. Overall, 6 of 10 patients treated with thrombolytic agents showed resolution of thrombus. Marder and SherrY' suggest that for established thrombi, "fibrin selective" agents, such as tPA or single chain urokinase plasminogen activator may be more effective. We did not monitor a panel of coagulation variables to determine whether or not the thrombolytic therapy had its desired effect on the blood clotting system. In this regard, it is noteworthy that early experience in neonates with aortic thrombosis raised questions about whether or not thrombolytic therapy was effective in that circumstance; moveover, the appropriate dose for use in the pediatric age range has never been established with certainty. The report mentioned previously by Delaplane et al• showed that to achieve laboratory evidence of fibrinolysis, a dose fully ten times higher than that employed by most clinicians was used to treat the second episode of thrombosis in their patient. Lastly, little attention has been paid to catheter construction or composition as those factors relate to initial thrombus formation or dissolution with therapy. 19 Surgery was performed on four occasions in patients felt not to be candidates for thrombolytic therapy, but with clear hemodynamic compromise due to thrombus. The two patients who died following surgery had relentless courses of pleural Ouid drainage and bacterial sepsis after surgery. The two who survived are now clot-free, but one has moderate tricuspid valve incompetence following repair of an atrioventricular septal defect (AV canal) and the other is ventilato~ dependent at age 13 months with severe BPD. In conclusion, we report a retrospective study of pediatric patients in whom great vein and/or right atrial thrombosis was found by echocardiography. The venous occlusion was associated not infrequently with thrombocytopenia, recurrent chylothorax, sepsis, and the superior vena cava syndrome. The episode of thrombosis was a morbid event-13 of the 37 patients died during the hospitalization in which the thrombus was discovered, and 8 of the deaths were thought to be related directly to the presence of thrombus or complications arising from it. Superior vena cava or right atrial thrombosis or both should be considered a

significant risk of central venous catheterization in critically ill infants and children. REFERENCES 1 Chastre J, Comud F, Bouchama A, Viau F, Benacerraf R, Gibert C. Thrombosis as a complication of pulmonary-artery catheter· ization via the internal jugular vein. N Eng) J Med 1982; 306:278-80 2 Marsh 0 , Wilkerson S, Cook L, Pietsch J. Right atrial thrombosis in neonates receiving central venous lines after extracorporeal membrane oxygenation. Crit Care Med 1988; 16:202-03 3 Kinney EL, Wright RJ. Efficacy of treatment of patients with echocardiographically detected right-sided heart thrombi: a meta-analysis. Am Heart J 1989; 118:569-73 4 Delaplane 0 , Scott P. Riggs Tw, Silverman BL, Hunt CE. Urokinase therapy for acatheteNelated right atrial thrombus. J Pediatr 1982; 100:149-52 5 Bell WR, Meek AG. Guidelines for the use of thrombolytic agents. N Engl J Med 1979; 301:1266-70 6 Marder VJ, Sherry S. Thrombolytic therapy: current status. N Engl J Med 1988; 318:1512-95 7 Suarez CR. Ow EP, Lambert GH, Anderson CL, Purewal NS. Urokinase therapy for a central venous catheter thrombus. Am J Hematol1989; 31:269-72 8 Katz Rw, fullaclc MM, ~ibley RE. Pulmonary artery catheterization in pediatric intensive care. Adv Pediatr 1983; 30:169-90 9 Rowley KM, SoniClubb K, Walker Smith GJ, Cabin HS. Rightsided infective endocarditis as a consequence of flow-directed pulmonary-artery catheterization. N Eng) J Med 1984; 311:115256 10 Corrigan JJ, Allen HD, Jeter M, Malone JM. Aortic thrombosis in a neonate: failure of urokinase thrombolytic therapy. Am J Pediatr Hematol Oncol1982; 4:243-47 11 Vailas GN, Brouillette RT, Scott JP, Shkolnik A, Conway J, Wiringa K. Neonatal aortic thrombosis: recent experience. J Pediatr 1986; 109:101-M 12 Emami A, Saldanha R, Knupp C, KodroffM . Failure of systemic thrombolytic and heparin therapy in the treatment of neonatal aortic thrombosis. Pediatrics 1987; 79:773-77 13 Caplan MS, Cohn RA, Langman CB, Conway JA, Shkolnik A, Brouillette RT. Favorable outcome of neonatal aortic thrombosis and renovascular hypertension. J Pediatr 1989; 115:291-95 14 Dhande V. Kattwinkel J, Alford B. Recurrent bilateral pleural effusions secondary to superior vena cava obstruction as a complication of central venous catheterization. Pediatrics 1983; 72:109-13 15 Bagnall HA, Gomperts E, Atkinson JB. Continuous infusion of low-dose urokinase in the treatment of central venous catheter thrombosis in infants and children. Pediatrics 1989; 83:963-M 16 Ross P Jr, Ehrenkranz R, Kleinman CS, Seashore JH. Thrombus associated with central venous catheters In infants and children. J Pediatr Surg 1989; 24:253-56 17 Ahmed N, Payne NF. Thrombosis afier central venous cannulation. Med J Aust 1976; 1:217-20 18 Kanter RK, Zimmerman JJ, Strauss RH , Stoeckel K.A. Central venous catheter insertion by femoral vein: safety and effectiveness for the pediatric patient. Pediatrics 1986; 77:842-47 19 Borow M, Crowley JG. Evaluation of central venous catheter thrombogenicity. Acta Anaesth Scand 1985; 81:~

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