Clinical Toxicology Downloaded from informahealthcare.com by McMaster University on 12/11/14 For personal use only.
CLINICAL TOXICOLOGY, 15(l),pp. 39-44 (1979)
Generalized Arterial and Venous Thrombosis Following Intra-Arterial Paraldehyde
W. M. GOOCH 111, M.D., J. KENNEDY, B.A., W. BANNER, JR., M.D., and H. J. McGUIRE, B.A.
Departments of Pathology and Pediatrics University of Tennessee Center for the Health Sciences Memphis, Tennessee 38103
INTRODUCTION Despite i t s known toxicity and the availability of effective alternative anticonvulsants, paraldehyde continues to be recommended for acute seizure control [l'l Fatalities and other toxic manifestations following administration of this drug have been reported since 1890. The following case demonstrates the thrombogenic potential of intra-arterial paraldehyde.
.
CASE R E P O R T Baby Boy G was admitted. to the intensive care nursery with respiratory distress following tracheal intubation and assisted ventilation for the first 10 min of life. Estimated gestational age was 42 weeks, and delivery was complicated by cesarean section for fetal d i s t r e s s and partial abruptio placentae. Physical examination upon admission revealed: heart rate 160/m in, respiratory rate 84/min, systolic blood p r e s s u r e 58 t o r r , rectal temperature 98.6"F, weight 3590 gm, 39 Copyright 0 1979 by Marcel Dekker, Inc All Rights Reserved. Neither this work nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying. microfilming, and recordirNg, or by any information storage and retrieval system, withouf permission in writing from the publisher.
Clinical Toxicology Downloaded from informahealthcare.com by McMaster University on 12/11/14 For personal use only.
40
GOOCH ET AL.
barrel chest, scaphoid abdomen, decreased subcutaneous fat, complete Moro reflex. Admission laboratory data included: hematocrit 61%; hemoglobin 19.3 gm/dl; WBC 20,1OO/pl with 35 nucleated red blood cells/100 WBC, 10% bands, 52% segmented neutrophils, 28% lymphocytes, 6% monocytes, 3% eosinophils, and 1% metamyelocytes; sodium 146 mEq/l; potassium 3.5 mEq/l; calcium 7.6 mg/dl; arterial pH 7.24 with POZ of 63 torr; and PCOZ of 42 t o r r in room air. Cerebrospinal fluid glucose, protein, and cells were normal. Gram stain of tracheal aspirate revealed numerous Gram-positive cocci, and Group B P-hemolytic streptococci eventually grew in the admission blood culture. A n umbilical arterial catheter was inserted, and therapy with intermittent hypertonic sodium bicarbonate, ampicillin ( 100 mg/kg/24 h r ) , gentamicin (5 mg/kg/24 h r ) , and continuous 10% glucose water was begun. Although the child initially was oliguric despite adequate fluids, he responded to mannitol therapy. At 2 h r of age, because of multiple apneic episodes, tracheal intubation and positive pressure ventilation were reinstituted. Phenobarbital and diazepam therapy was administered at 3 h r of age because of intermittent generalized seizure activity. When seizure activity persisted, undiluted intramuscular paraldehyde was given at a dose of 0.15 mg/kg. This dose was repeated 3 h r later; however, inadvertently, it was administered via the umbilical artery. Immediately after the injection, both legs became mottled pink and gray and the left femoral pulse became weak. Larger areas of purple discoloration developed on the left leg within hours and spread to the periumbilical region. Over the next 4 days the feet became edematous, indurated, and cool, and on the 4th day the right dorsal pedal pulse was barely palpable and the right toes were necrotic. The entire hospital course was characterized by gradual neurologic deterioration, and on the 7th day an acute episode of hypotension and bradycardia was followed by cardiac a r r e s t which was resident to resuscitation. G a s chromatographic and infrared analysis of two ampules of the same lot of paraldehyde stored under identical conditions revealed no acetaldehyde. Postmortem examination revealed dry gangrene of the toes of the right foot and an occlusive thrombus which extended from the right iliac artery into the popliteal artery (Fig. 1). Multifocal, small hemorrhages were noted i n the cerebral cortex and the spinal cord, and there was hemorrhagic necrosis of the anterior pituitary gland. Extensive microscopic thrombi were seen in the arterioles and venules of the right leg and foot and the toes of the left foot, intrahepatic branches of the hepatic artery, glomerular capillaries, and pulmonary arteries and arterioles (Fig. 2). Portions of all thrombi except those in renal glomeruli were undergoing organization. No thrombi were observed i n the pulmonary venous system, and the heart was normal. Multiple foci of coagulation necrosis were observed in the soft tissues of the legs and feet.
Clinical Toxicology Downloaded from informahealthcare.com by McMaster University on 12/11/14 For personal use only.
INTRA-ARTERIAL PARALCEHYDE
41
FIG. 1. Iliac artery containing thrombus.
DISCUSSION Paraldehyde is a colorless, transparent, inflammable polymer of acetaldehyde which is rapidl], absorbed when administered by the oral, rectal, o r parenteral rcute, but which is extremely irritating to soft tissues including mucous membranes, nerves, muscles, blood vessels, and skin [2, 31. The safety margin of paraldehyde is quite narrow. The minimal anesthetic dose for dogs, cats, and rabbits is 0.3 mg/kg while the mean lethal dose is 0.45 ml/kg for cats and rabbits and 0.5 ml/kg for dogs [4]. Toxic manifestations include esophagitis, gastritis, proctitis, metabolic acidosis, severe pain at the injection site, sciatic nerve damage, sterile abscess, skin slough, severe pulmonary congestion and hemorrhage, acute right heart failure, shock, coma, and death [2, 4, 51. Catastrophic toxic manifestations
Clinical Toxicology Downloaded from informahealthcare.com by McMaster University on 12/11/14 For personal use only.
42
GOOCH ET AL.
FIG. 2. Section of a pulmonary artery containing an organizing thrombus. may be seen with any route of administration. Some of the reported toxic effects actually may have been due to decomposition products, as paraldehyde spontaneously decomposes to acetaldehyde and is further oxidized to acetic acid i n the presence of air [2, 6-81. In one study almost one-half of the hospitals and pharmacies surveyed had stocks of paraldehyde which contained excess acetic acid [2]. Decomposition products were not present in the lot of paraldehyde from which the drug was taken in this case. The immediate blanching and mottling of the skin which occurred following intra-arterial injection of paraldehyde in this case is a logical extension of its known irritating potential. The thrombotic events which occurred may be explained by the effect upon circulating blood by exposed collagen following endothelial damage [9]. Irritating o r hypertonic solutions administered via intravascular catheter a r e known to be thrombogenic [lo, 111. Decreased blood flow caused by the combination of intravascular catheter, vasospasm, and poor peripheral and visceral perfusion in this compromised neonate may well have countered the usual tendency of the bloodstream to dilute the drug and to disrupt early
Clinical Toxicology Downloaded from informahealthcare.com by McMaster University on 12/11/14 For personal use only.
INTRA-ARTERIAL PARALDEHYDE
43
mural thrombi. In addition, the administered drug was undiluted, and the child's ability to excrete the drug via the lungs was reduced. Although no liver studies wero performed in this case, immaturity of many hepatic functions in the neonate is well known [12]. While paraldehyde i s metabolized and excreted primarily via the liver, i n the presence of hepatic compromise, pulmonary excretion increases [2]. Toxic manifestations in the side of the circulation opposite that of the injection a r e unique to this case. Although intra-arterial injection has not been reported, published instances of intravenous injections have not described toxicity of the arterial system. It is unlikely that the pulmonary arterial lesions a r e due to a separate episode of disseminated intravascular coagulation (DIC). Although acidosis and bacterial sepsis a r e known I:O be associated with DIC, there was no clinical evidence of defective hemostasis, multiple visceral hemorrhages were not seen, and both arterial and venous thrombi were i n similar stages of evolution, ,SUMMARY
A neonate with pulmonary hypoventilation, metabolic acidosis, streptococcal bacteremia, oliguria, and generalized convulsions r e ceived 0.54 ml of paraldehyde inadvertently via an umbilical a r t e r i a l catheter. Immediately after the injection, the infraumbilical abdominal wall and the legs became discolored and cold. Thereafter, the distal right leg became necrotic; necropsy revealed thrombosis of the right iliac, right femoral, hepatic, bronchial, and pulmonary arteries, glomerular capillaries, and microvasculature of the right leg. Generalized thrombosis i s a. potential toxic manifestation of intravascular administration of garaldehyde. RIC F E R E N C E S
[l] J. M. Freeman and A. W. Brand, Jr., "Central nervous system disturbances," i n Neonatal-Perinatal Medicine, 2nd ed. (R E. Behrman, J. M. Driscoll, Jr. and W. E. Seeds, eds.), Mosby, St. Louis, 1977, p. 82f. 21 J. Kittel, Paraldehyde toxicity, Hosp. Pharm., 8, 263 (1973). 31 New England Journal of Medicine, Sedative-hypnotic drugs. HI. Paraldehyde and methylparafynol, 255, 909 ( 1956). C. L. Burstein, The hazard of paraldehyde administration, J. [4] . . Am. Med. ASSOC., 121, 187 (1943). r51 F. G. Woodson. Sciatic: nerve iniurv due to the intramuscular injection of paraldehyde, J. Am. Med. ASSOC., 121, 1343 (1943).
t
L
J
Clinical Toxicology Downloaded from informahealthcare.com by McMaster University on 12/11/14 For personal use only.
44
GOOCH E T AL.
[6] R. P. Bell and R. LeG. Burnett, Acid-base catalysis in g a s reactions. I. The depolymerization of paraldehyde, Trans. Faraday SOC., 33, 355 (1937). [7] A. L. Agranat and W. H. D. Trubshaw, The danger of decomposed paraldehyde, S. Afr. Med. J., 29, 1021 (1955). 2, 1114 [8] Death from decomposed paraldehydeTBr. Med. J., (1954). [9] H. J. Wigger, B. R. Bransilver, and W. A. Blanc, Thromboses due to catheterization in infants and children, J. Pediatr., 1976, 1 (1970). [lo] J. M. Gupta, N. R. C. Roberton, and J. S. Wigglesworth, Umbilical a r t e r y catheterization in the newborn, Arch. Dis. Child., 43, 382 (1968). [ll] J. M. Scott, Iatrogenic lesions in babies following umbilical vein catheterization, Arch. Dis. Child., 40, 426 (1965). [ 121 A. Rane and F. Sjoqvist, Drug metabolism in the human fetus 19, 37 ( 1972). and newborn infant, Pediatr. Clin. North Am., -
_ .
CLINICAL TOXICOLOGY, 15(l),pp. 39-44 (1979)
Generalized Arterial and Venous Thrombosis Following Intra-Arterial Paraldehyde
W. M. GOOCH 111, M.D., J. KENNEDY, B.A., W. BANNER, JR., M.D., and H. J. McGUIRE, B.A.
Departments of Pathology and Pediatrics University of Tennessee Center for the Health Sciences Memphis, Tennessee 38103
INTRODUCTION Despite i t s known toxicity and the availability of effective alternative anticonvulsants, paraldehyde continues to be recommended for acute seizure control [l'l Fatalities and other toxic manifestations following administration of this drug have been reported since 1890. The following case demonstrates the thrombogenic potential of intra-arterial paraldehyde.
.
CASE R E P O R T Baby Boy G was admitted. to the intensive care nursery with respiratory distress following tracheal intubation and assisted ventilation for the first 10 min of life. Estimated gestational age was 42 weeks, and delivery was complicated by cesarean section for fetal d i s t r e s s and partial abruptio placentae. Physical examination upon admission revealed: heart rate 160/m in, respiratory rate 84/min, systolic blood p r e s s u r e 58 t o r r , rectal temperature 98.6"F, weight 3590 gm, 39 Copyright 0 1979 by Marcel Dekker, Inc All Rights Reserved. Neither this work nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying. microfilming, and recordirNg, or by any information storage and retrieval system, withouf permission in writing from the publisher.
Clinical Toxicology Downloaded from informahealthcare.com by McMaster University on 12/11/14 For personal use only.
40
GOOCH ET AL.
barrel chest, scaphoid abdomen, decreased subcutaneous fat, complete Moro reflex. Admission laboratory data included: hematocrit 61%; hemoglobin 19.3 gm/dl; WBC 20,1OO/pl with 35 nucleated red blood cells/100 WBC, 10% bands, 52% segmented neutrophils, 28% lymphocytes, 6% monocytes, 3% eosinophils, and 1% metamyelocytes; sodium 146 mEq/l; potassium 3.5 mEq/l; calcium 7.6 mg/dl; arterial pH 7.24 with POZ of 63 torr; and PCOZ of 42 t o r r in room air. Cerebrospinal fluid glucose, protein, and cells were normal. Gram stain of tracheal aspirate revealed numerous Gram-positive cocci, and Group B P-hemolytic streptococci eventually grew in the admission blood culture. A n umbilical arterial catheter was inserted, and therapy with intermittent hypertonic sodium bicarbonate, ampicillin ( 100 mg/kg/24 h r ) , gentamicin (5 mg/kg/24 h r ) , and continuous 10% glucose water was begun. Although the child initially was oliguric despite adequate fluids, he responded to mannitol therapy. At 2 h r of age, because of multiple apneic episodes, tracheal intubation and positive pressure ventilation were reinstituted. Phenobarbital and diazepam therapy was administered at 3 h r of age because of intermittent generalized seizure activity. When seizure activity persisted, undiluted intramuscular paraldehyde was given at a dose of 0.15 mg/kg. This dose was repeated 3 h r later; however, inadvertently, it was administered via the umbilical artery. Immediately after the injection, both legs became mottled pink and gray and the left femoral pulse became weak. Larger areas of purple discoloration developed on the left leg within hours and spread to the periumbilical region. Over the next 4 days the feet became edematous, indurated, and cool, and on the 4th day the right dorsal pedal pulse was barely palpable and the right toes were necrotic. The entire hospital course was characterized by gradual neurologic deterioration, and on the 7th day an acute episode of hypotension and bradycardia was followed by cardiac a r r e s t which was resident to resuscitation. G a s chromatographic and infrared analysis of two ampules of the same lot of paraldehyde stored under identical conditions revealed no acetaldehyde. Postmortem examination revealed dry gangrene of the toes of the right foot and an occlusive thrombus which extended from the right iliac artery into the popliteal artery (Fig. 1). Multifocal, small hemorrhages were noted i n the cerebral cortex and the spinal cord, and there was hemorrhagic necrosis of the anterior pituitary gland. Extensive microscopic thrombi were seen in the arterioles and venules of the right leg and foot and the toes of the left foot, intrahepatic branches of the hepatic artery, glomerular capillaries, and pulmonary arteries and arterioles (Fig. 2). Portions of all thrombi except those in renal glomeruli were undergoing organization. No thrombi were observed i n the pulmonary venous system, and the heart was normal. Multiple foci of coagulation necrosis were observed in the soft tissues of the legs and feet.
Clinical Toxicology Downloaded from informahealthcare.com by McMaster University on 12/11/14 For personal use only.
INTRA-ARTERIAL PARALCEHYDE
41
FIG. 1. Iliac artery containing thrombus.
DISCUSSION Paraldehyde is a colorless, transparent, inflammable polymer of acetaldehyde which is rapidl], absorbed when administered by the oral, rectal, o r parenteral rcute, but which is extremely irritating to soft tissues including mucous membranes, nerves, muscles, blood vessels, and skin [2, 31. The safety margin of paraldehyde is quite narrow. The minimal anesthetic dose for dogs, cats, and rabbits is 0.3 mg/kg while the mean lethal dose is 0.45 ml/kg for cats and rabbits and 0.5 ml/kg for dogs [4]. Toxic manifestations include esophagitis, gastritis, proctitis, metabolic acidosis, severe pain at the injection site, sciatic nerve damage, sterile abscess, skin slough, severe pulmonary congestion and hemorrhage, acute right heart failure, shock, coma, and death [2, 4, 51. Catastrophic toxic manifestations
Clinical Toxicology Downloaded from informahealthcare.com by McMaster University on 12/11/14 For personal use only.
42
GOOCH ET AL.
FIG. 2. Section of a pulmonary artery containing an organizing thrombus. may be seen with any route of administration. Some of the reported toxic effects actually may have been due to decomposition products, as paraldehyde spontaneously decomposes to acetaldehyde and is further oxidized to acetic acid i n the presence of air [2, 6-81. In one study almost one-half of the hospitals and pharmacies surveyed had stocks of paraldehyde which contained excess acetic acid [2]. Decomposition products were not present in the lot of paraldehyde from which the drug was taken in this case. The immediate blanching and mottling of the skin which occurred following intra-arterial injection of paraldehyde in this case is a logical extension of its known irritating potential. The thrombotic events which occurred may be explained by the effect upon circulating blood by exposed collagen following endothelial damage [9]. Irritating o r hypertonic solutions administered via intravascular catheter a r e known to be thrombogenic [lo, 111. Decreased blood flow caused by the combination of intravascular catheter, vasospasm, and poor peripheral and visceral perfusion in this compromised neonate may well have countered the usual tendency of the bloodstream to dilute the drug and to disrupt early
Clinical Toxicology Downloaded from informahealthcare.com by McMaster University on 12/11/14 For personal use only.
INTRA-ARTERIAL PARALDEHYDE
43
mural thrombi. In addition, the administered drug was undiluted, and the child's ability to excrete the drug via the lungs was reduced. Although no liver studies wero performed in this case, immaturity of many hepatic functions in the neonate is well known [12]. While paraldehyde i s metabolized and excreted primarily via the liver, i n the presence of hepatic compromise, pulmonary excretion increases [2]. Toxic manifestations in the side of the circulation opposite that of the injection a r e unique to this case. Although intra-arterial injection has not been reported, published instances of intravenous injections have not described toxicity of the arterial system. It is unlikely that the pulmonary arterial lesions a r e due to a separate episode of disseminated intravascular coagulation (DIC). Although acidosis and bacterial sepsis a r e known I:O be associated with DIC, there was no clinical evidence of defective hemostasis, multiple visceral hemorrhages were not seen, and both arterial and venous thrombi were i n similar stages of evolution, ,SUMMARY
A neonate with pulmonary hypoventilation, metabolic acidosis, streptococcal bacteremia, oliguria, and generalized convulsions r e ceived 0.54 ml of paraldehyde inadvertently via an umbilical a r t e r i a l catheter. Immediately after the injection, the infraumbilical abdominal wall and the legs became discolored and cold. Thereafter, the distal right leg became necrotic; necropsy revealed thrombosis of the right iliac, right femoral, hepatic, bronchial, and pulmonary arteries, glomerular capillaries, and microvasculature of the right leg. Generalized thrombosis i s a. potential toxic manifestation of intravascular administration of garaldehyde. RIC F E R E N C E S
[l] J. M. Freeman and A. W. Brand, Jr., "Central nervous system disturbances," i n Neonatal-Perinatal Medicine, 2nd ed. (R E. Behrman, J. M. Driscoll, Jr. and W. E. Seeds, eds.), Mosby, St. Louis, 1977, p. 82f. 21 J. Kittel, Paraldehyde toxicity, Hosp. Pharm., 8, 263 (1973). 31 New England Journal of Medicine, Sedative-hypnotic drugs. HI. Paraldehyde and methylparafynol, 255, 909 ( 1956). C. L. Burstein, The hazard of paraldehyde administration, J. [4] . . Am. Med. ASSOC., 121, 187 (1943). r51 F. G. Woodson. Sciatic: nerve iniurv due to the intramuscular injection of paraldehyde, J. Am. Med. ASSOC., 121, 1343 (1943).
t
L
J
Clinical Toxicology Downloaded from informahealthcare.com by McMaster University on 12/11/14 For personal use only.
44
GOOCH E T AL.
[6] R. P. Bell and R. LeG. Burnett, Acid-base catalysis in g a s reactions. I. The depolymerization of paraldehyde, Trans. Faraday SOC., 33, 355 (1937). [7] A. L. Agranat and W. H. D. Trubshaw, The danger of decomposed paraldehyde, S. Afr. Med. J., 29, 1021 (1955). 2, 1114 [8] Death from decomposed paraldehydeTBr. Med. J., (1954). [9] H. J. Wigger, B. R. Bransilver, and W. A. Blanc, Thromboses due to catheterization in infants and children, J. Pediatr., 1976, 1 (1970). [lo] J. M. Gupta, N. R. C. Roberton, and J. S. Wigglesworth, Umbilical a r t e r y catheterization in the newborn, Arch. Dis. Child., 43, 382 (1968). [ll] J. M. Scott, Iatrogenic lesions in babies following umbilical vein catheterization, Arch. Dis. Child., 40, 426 (1965). [ 121 A. Rane and F. Sjoqvist, Drug metabolism in the human fetus 19, 37 ( 1972). and newborn infant, Pediatr. Clin. North Am., -
_ .
![[Mechanisms of arterial and venous thrombosis].](/assets/img/hold.png)
