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Continuous versus intermittent heparin infusion of umbilical artyery catheters in the newborn infant
Volume 108 Number 1
Intensive care in the newborn. New York: Masson Publishing, 1978;331-345. 6. Mathieu J, Looze Y, Deconinck M. Comparative study of the
Clinical and laboratory observations
14 1
binding to human serum albumin of bitiscopine (a new cholangiographic contrast medium) and five other contrast media. Fortschr Roentgenstr 1979;130:4l 8.
Continuous versus intermittent heparin infusion of umbilical artery catheters in the newborn infant E l e n a B o s q u e , R.N., M S . , a n d L i n d a W e a v e r , R.N., M.S. From the Departments of Pediatrics, Children's Hospital of San Francisco, and Mount Zion Hospital and Medical Center, San Francisco
Both continuous infusion of heparin and intermittent heparinized flushes have been suggested to prevent clot formation and to maintain patency of umbilical artery catheters) We compared the two methods in terms of their effects on patency, complications, and clotting. METHODS Infants admitted to the neonatal intensive care unit between November 1983 and September 1984 who had umbilical artery catheters placed were eligible for the study, which was approved by the Human Experimentation Committee of Children's Hospital of San Francisco. Written consent was obtained from parents. A 3.5 or 5 Fr Argyle polyvinyl, radiopaque catheter was placed in the umbilical artery to the level of L-3 or L-4. Placement was confirmed by radiography. Infants were stratified into three weight groups (~<1000 gm, 1001 to 1800 gm, >1800 gm), and infants within each group were randomly assigned to receive heparin either continuously or intermittently. A separate pad of paper was used for each weight group, and the assignments on each page were determined prospectively by table of random numbers. For infants in the continuous heparin group, sodium heparin (1 U/ml) was added to the infusate, but nonheparinized 0.9% saline solution was used to flush the catheter after blood sampiing. For infants in the intermittent heparin group, heparin was not added to the catheter infusate, but sodium heparin (1 U/ml) was added to the saline flush solution. The rate of infusion varied according to the infant's clinical Supported in part by a research grant from the Beta Gamma Chapter of Sigma Theta Tau. Submitted for publication May 31, 1985; accepted July 16, 1985. Reprint requests: Elena Bosque, R.N., M.S., Neonatal Clinical Specialist, Children's Hospital of San Francisco, Newborn Services, 3850 California St., San Francisco, CA 94118.
condition. The infusate consisted of amino acids, electrolytes, or a 5% to 13% dextrose solution. Between 0.5 and 1.0 ml 0.9% saline solution was used to clear the catheter after blood had been withdrawn. Information recorded included birth weight; catheter caliber; amount, rate, and type of fluids infused; duration of time the catheter remained in place, and reason for removal; and frequency of complications (e.g., cyanosis or blanching of the toes). Blood for PT and PTT was obtained before any heparin had been infused and at 24 and 72 hours after the catheter had been in place. Blood was obtained from a peripheral vein in infants weighing > 1250 gm. In infants weighing < 1250 gin, blood was obtained via catheter after 3 ml had been drawn back to clear the catheter of heparinized fluid? PT and PTT were considered abnormal at >17 and >70 seconds, respectively.3,4 Results were analyzed using the unpaired t test and PT PTT
Prothrombin time Partial thromboplastin time
chi-square test. The Fisher exact test was used when the expected frequency was <5 in any cell of the chi-square test. RESULTS Forty-seven infants were entered in the study. Of the 18 infants in the continuous heparin group, two weighed _<1000 gm, eight weighed 1001 to 1800 gin, and eight weighed >1800 gm (mean birth weight 1912 gin, range 940 to 3500 gin). Of the 29 infants in the intermittent heparin group, eight weighed _<1000 gin, 11 weighed 1001 to 1800 gm, and 10 weighed >1800 gm (mean birth weight 1568 gin, range 580 to 3765 gin). The discrepancy in number of patients in the lowest birth weight groups resulted from the system of randomization.
14 ]
Clinical and laboratory observations
The Journal of Pediatrics January 1986
T a b l e . PT and PTT in continuous and intermittent heparin groups PTT (sec)
PT (sec)
Continuous Mean Range Intermittent Mean Range
Initial
24 Hours
72 Hours
Initial
24 Hours
72 Hours
13.0 11.9-14.5
29.3 11.9-110
13.0 11.6-14.7
49.9 39.5-62.7
59.3 38-110
52.4 33.6-110
13.4 11.1-17.2
t 2.5 11.2-14.7
12.8 12.3-13.2
63.0 35.3-110
47.4 29.6-82
51.7 38.5-66.3
Catheters were removed because of occlusion in none of the 18 infants in the continuous heparin group and in eight of the 29 infants in the intermittent heparin group (P = 0.014). Catheters were removed because of complications in six of 18 infants in the continuous heparin group and in four of 29 infants in the intermittent heparin group; this difference was not statistically significant. The complications were cyanosis and blanching of the toes in eight infants, and visible clots, not causing obstruction, in the catheters of two infants in the group receiving heparin continuously. Twelve of the 18 catheters in the continuous heparin group and 17 of the 29 catheters in the intermittent group remained patent until they were removed electi~,ely when no longer needed; this difference was not statistically significant. The mean duration the catheters remained in place was 66.9 hours (range 8 to 167 hours) in the continuous heparin group and 61.6 hours (range 8 to 166 hours) in the intermittent heparin group. Occlusions occurred in eight of 29 infants weighing _<1800 gm, compared with none of 18 infants weighing >1800 gm (P = 0.014). Six of 20 of the 3.5 Fr catheters became occluded, compared with two of 27 of the 5 Fr catheters (P = 0.045). Nineteen of the 20 3.5 Fr catheters, compared with 10 of the 27 5 Fr catheters, were placed in infants weighing <1800 gm. Babies in the continuous heparin group received a mean of 120 U/kg/day (range 80 to 220 U/kg/day) heparin, and those in the intermittent heparin group received a mean of 3.9 U/kg/day (range 0.8 to 9.8 U/kg/day). There were no signs of bleeding in any of the babies. Because of technical difficulties and early removal of catheters, complete clotting studies were performed in only 21 infants. Two of seven infants in the continuous heparin group and one of 14 in the intermittent heparin group had abnormal PT or PTT after heparinization of the catheter (Table). There were no significant differences between the groups in gestational age, birth weight, Apgar scores, diagnoses, catheter size, or amount, rate, and type of fluids infused. DISCUSSION Heparinized umbilical artery catheters remain patent longer than those not heparinized?,6 Rajani et al. 5 showed
that continuous infusion of heparin (1 U/ml) maintained patency better, and David et al. 6 showed that continuous infusion of heparin (1 U/ml) plus heparin flush solutions (1 U / m l ) maintained patency better than solutions without heparin. In both of these studies, heparinized solutions were compared with nonheparinized solutions. The effects of continuous versus intermittent heparinization of umbilical artery catheters have not been compared. In our study, all of the occlusions occurred in the catheters in the intermittent heparin group, perhaps because they received less heparin or because they received it intermittently. The infants in the continuous heparin group received an average of 30 times more heparin per day than did those in the intermittent heparin group. We discontinued the study when we found that all of the occlusions were occurring in the group receiving heparin intermittently and that the difference was statistically significant. Because of concern about delivering too much heparin in newborn infants, intermittent flushes of heparinized solutions have been used to maintain patency of umbilical artery catheters. No baby in our study had any signs of bleeding, and there were no differences in the clotting studies despite a remarkable difference in the dose of heparin when the groups were compared. Some infants in the continuous heparin group received as much as 220 U / k g / d a y heparin, but this is considerably less than the 576 U/kg/day calculated by McDonald and Hathaway vto produce heparinization in infants. Our finding that occlusions were more likely to occur in catheters with the smaller lumen is not surprising and may explain why all occlusions occurred in infants weighing < 1800 gm, who were more likely to have smaller catheters. Inasmuch as equivalent numbers of 3.5 Fr catheters were placed in infants in both groups, the small lumen size may have contributed to but did not by itself cause occlusions in the intermittent heparin group. It is possible that occlusions occurred because of the smaller lumen in combination with less heparin. We conclude that continuous heparin infusion is a better way of maintaining patency of an umbilical artery catheter, even in the smallest premature infant.
Volume 108 Number 1
We thank all those who helped with the study, especially June P. Brady, M.D., Julien I. E. Hoffman, M.D., Ben Lloyd, M.D., Kathy Lewis, M.D., Ellen McCann, M.S., and Melva Averhart, R.N., B.S. REFERENCES
1. Kitterman JA, Phibbs RH, Tooley WH. Catheterization of umbilical vessels in newborn infants. Pediatr Ctin North Am 1970;17:895. 2. Merenstein GB. Heparinized catheters and coagulation studies. J PEDIATR 1971;79:117. 3. Hathaway WE. The bleeding newborn. Semin Hemato11975; 12:175. 4. Beverley DW, Inwood M J, Chance GW, Schaus M, O'Keefe
Clinical and laboratory observations
14 3
B. "Normal" haemostasis parameters: a study in a welldefined inborn population of preterm infants. Early Hum Dev 1984;9:249. 5. Rajani K, Goetzman BW, Wennberg RP, Turner E, Abildgaard C. Effect of heparinization on fluids infused through an umbilical artery catheter on catheter patency and frequency of complications. Pediatrics 1979;63:552. 6. David RJ, Merten DF, Anderson JC, Gross S. Prevention of umbilical artery catheter clots with heparinized infusates. Dev Pharmacol Ther 1981;2:117. 7. McDonald MM, Hathaway WE. Anticoagulant therapy by continuous heparinization in newborn and older infants. J PEDIATR 1982;101:451.
Intensive care in the newborn. New York: Masson Publishing, 1978;331-345. 6. Mathieu J, Looze Y, Deconinck M. Comparative study of the
Clinical and laboratory observations
14 1
binding to human serum albumin of bitiscopine (a new cholangiographic contrast medium) and five other contrast media. Fortschr Roentgenstr 1979;130:4l 8.
Continuous versus intermittent heparin infusion of umbilical artery catheters in the newborn infant E l e n a B o s q u e , R.N., M S . , a n d L i n d a W e a v e r , R.N., M.S. From the Departments of Pediatrics, Children's Hospital of San Francisco, and Mount Zion Hospital and Medical Center, San Francisco
Both continuous infusion of heparin and intermittent heparinized flushes have been suggested to prevent clot formation and to maintain patency of umbilical artery catheters) We compared the two methods in terms of their effects on patency, complications, and clotting. METHODS Infants admitted to the neonatal intensive care unit between November 1983 and September 1984 who had umbilical artery catheters placed were eligible for the study, which was approved by the Human Experimentation Committee of Children's Hospital of San Francisco. Written consent was obtained from parents. A 3.5 or 5 Fr Argyle polyvinyl, radiopaque catheter was placed in the umbilical artery to the level of L-3 or L-4. Placement was confirmed by radiography. Infants were stratified into three weight groups (~<1000 gm, 1001 to 1800 gm, >1800 gm), and infants within each group were randomly assigned to receive heparin either continuously or intermittently. A separate pad of paper was used for each weight group, and the assignments on each page were determined prospectively by table of random numbers. For infants in the continuous heparin group, sodium heparin (1 U/ml) was added to the infusate, but nonheparinized 0.9% saline solution was used to flush the catheter after blood sampiing. For infants in the intermittent heparin group, heparin was not added to the catheter infusate, but sodium heparin (1 U/ml) was added to the saline flush solution. The rate of infusion varied according to the infant's clinical Supported in part by a research grant from the Beta Gamma Chapter of Sigma Theta Tau. Submitted for publication May 31, 1985; accepted July 16, 1985. Reprint requests: Elena Bosque, R.N., M.S., Neonatal Clinical Specialist, Children's Hospital of San Francisco, Newborn Services, 3850 California St., San Francisco, CA 94118.
condition. The infusate consisted of amino acids, electrolytes, or a 5% to 13% dextrose solution. Between 0.5 and 1.0 ml 0.9% saline solution was used to clear the catheter after blood had been withdrawn. Information recorded included birth weight; catheter caliber; amount, rate, and type of fluids infused; duration of time the catheter remained in place, and reason for removal; and frequency of complications (e.g., cyanosis or blanching of the toes). Blood for PT and PTT was obtained before any heparin had been infused and at 24 and 72 hours after the catheter had been in place. Blood was obtained from a peripheral vein in infants weighing > 1250 gm. In infants weighing < 1250 gin, blood was obtained via catheter after 3 ml had been drawn back to clear the catheter of heparinized fluid? PT and PTT were considered abnormal at >17 and >70 seconds, respectively.3,4 Results were analyzed using the unpaired t test and PT PTT
Prothrombin time Partial thromboplastin time
chi-square test. The Fisher exact test was used when the expected frequency was <5 in any cell of the chi-square test. RESULTS Forty-seven infants were entered in the study. Of the 18 infants in the continuous heparin group, two weighed _<1000 gm, eight weighed 1001 to 1800 gin, and eight weighed >1800 gm (mean birth weight 1912 gin, range 940 to 3500 gin). Of the 29 infants in the intermittent heparin group, eight weighed _<1000 gin, 11 weighed 1001 to 1800 gm, and 10 weighed >1800 gm (mean birth weight 1568 gin, range 580 to 3765 gin). The discrepancy in number of patients in the lowest birth weight groups resulted from the system of randomization.
14 ]
Clinical and laboratory observations
The Journal of Pediatrics January 1986
T a b l e . PT and PTT in continuous and intermittent heparin groups PTT (sec)
PT (sec)
Continuous Mean Range Intermittent Mean Range
Initial
24 Hours
72 Hours
Initial
24 Hours
72 Hours
13.0 11.9-14.5
29.3 11.9-110
13.0 11.6-14.7
49.9 39.5-62.7
59.3 38-110
52.4 33.6-110
13.4 11.1-17.2
t 2.5 11.2-14.7
12.8 12.3-13.2
63.0 35.3-110
47.4 29.6-82
51.7 38.5-66.3
Catheters were removed because of occlusion in none of the 18 infants in the continuous heparin group and in eight of the 29 infants in the intermittent heparin group (P = 0.014). Catheters were removed because of complications in six of 18 infants in the continuous heparin group and in four of 29 infants in the intermittent heparin group; this difference was not statistically significant. The complications were cyanosis and blanching of the toes in eight infants, and visible clots, not causing obstruction, in the catheters of two infants in the group receiving heparin continuously. Twelve of the 18 catheters in the continuous heparin group and 17 of the 29 catheters in the intermittent group remained patent until they were removed electi~,ely when no longer needed; this difference was not statistically significant. The mean duration the catheters remained in place was 66.9 hours (range 8 to 167 hours) in the continuous heparin group and 61.6 hours (range 8 to 166 hours) in the intermittent heparin group. Occlusions occurred in eight of 29 infants weighing _<1800 gm, compared with none of 18 infants weighing >1800 gm (P = 0.014). Six of 20 of the 3.5 Fr catheters became occluded, compared with two of 27 of the 5 Fr catheters (P = 0.045). Nineteen of the 20 3.5 Fr catheters, compared with 10 of the 27 5 Fr catheters, were placed in infants weighing <1800 gm. Babies in the continuous heparin group received a mean of 120 U/kg/day (range 80 to 220 U/kg/day) heparin, and those in the intermittent heparin group received a mean of 3.9 U/kg/day (range 0.8 to 9.8 U/kg/day). There were no signs of bleeding in any of the babies. Because of technical difficulties and early removal of catheters, complete clotting studies were performed in only 21 infants. Two of seven infants in the continuous heparin group and one of 14 in the intermittent heparin group had abnormal PT or PTT after heparinization of the catheter (Table). There were no significant differences between the groups in gestational age, birth weight, Apgar scores, diagnoses, catheter size, or amount, rate, and type of fluids infused. DISCUSSION Heparinized umbilical artery catheters remain patent longer than those not heparinized?,6 Rajani et al. 5 showed
that continuous infusion of heparin (1 U/ml) maintained patency better, and David et al. 6 showed that continuous infusion of heparin (1 U/ml) plus heparin flush solutions (1 U / m l ) maintained patency better than solutions without heparin. In both of these studies, heparinized solutions were compared with nonheparinized solutions. The effects of continuous versus intermittent heparinization of umbilical artery catheters have not been compared. In our study, all of the occlusions occurred in the catheters in the intermittent heparin group, perhaps because they received less heparin or because they received it intermittently. The infants in the continuous heparin group received an average of 30 times more heparin per day than did those in the intermittent heparin group. We discontinued the study when we found that all of the occlusions were occurring in the group receiving heparin intermittently and that the difference was statistically significant. Because of concern about delivering too much heparin in newborn infants, intermittent flushes of heparinized solutions have been used to maintain patency of umbilical artery catheters. No baby in our study had any signs of bleeding, and there were no differences in the clotting studies despite a remarkable difference in the dose of heparin when the groups were compared. Some infants in the continuous heparin group received as much as 220 U / k g / d a y heparin, but this is considerably less than the 576 U/kg/day calculated by McDonald and Hathaway vto produce heparinization in infants. Our finding that occlusions were more likely to occur in catheters with the smaller lumen is not surprising and may explain why all occlusions occurred in infants weighing < 1800 gm, who were more likely to have smaller catheters. Inasmuch as equivalent numbers of 3.5 Fr catheters were placed in infants in both groups, the small lumen size may have contributed to but did not by itself cause occlusions in the intermittent heparin group. It is possible that occlusions occurred because of the smaller lumen in combination with less heparin. We conclude that continuous heparin infusion is a better way of maintaining patency of an umbilical artery catheter, even in the smallest premature infant.
Volume 108 Number 1
We thank all those who helped with the study, especially June P. Brady, M.D., Julien I. E. Hoffman, M.D., Ben Lloyd, M.D., Kathy Lewis, M.D., Ellen McCann, M.S., and Melva Averhart, R.N., B.S. REFERENCES
1. Kitterman JA, Phibbs RH, Tooley WH. Catheterization of umbilical vessels in newborn infants. Pediatr Ctin North Am 1970;17:895. 2. Merenstein GB. Heparinized catheters and coagulation studies. J PEDIATR 1971;79:117. 3. Hathaway WE. The bleeding newborn. Semin Hemato11975; 12:175. 4. Beverley DW, Inwood M J, Chance GW, Schaus M, O'Keefe
Clinical and laboratory observations
14 3
B. "Normal" haemostasis parameters: a study in a welldefined inborn population of preterm infants. Early Hum Dev 1984;9:249. 5. Rajani K, Goetzman BW, Wennberg RP, Turner E, Abildgaard C. Effect of heparinization on fluids infused through an umbilical artery catheter on catheter patency and frequency of complications. Pediatrics 1979;63:552. 6. David RJ, Merten DF, Anderson JC, Gross S. Prevention of umbilical artery catheter clots with heparinized infusates. Dev Pharmacol Ther 1981;2:117. 7. McDonald MM, Hathaway WE. Anticoagulant therapy by continuous heparinization in newborn and older infants. J PEDIATR 1982;101:451.