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Murmurs heard at a distance from the patient: Report of an unusual case
LETTERS
TO T H E E D I T O R
Clinical notes
"Clinical notes" represent clinical and/or laboratory experiences which can be presented in 200 to 400 words, 3 or 4 references, and, if contributory, one illustration or short table. "Clinical notes" are subject to the same critical peer review and editing as papers published in other sections of ThE JOURNAL.
Murmurs heard at a distance from the patient: Report of an unusual case
T
SM
Fr
To the Editor: A previously unreported acoustic phenomenon associated with congenital heart disease was recently encountered.
ii
CASE REPORT Patient J.B.,-a 16-year-old female, has been followed since the age of 16 months because of congenital heart disease. At the age of 19 months, a diagnosis o f tetralogy of Fallot with stenosis of both branches of the pulmonary artery was established by cardiac catheterization and cineangiography. At 6 years of age, corrective surgery was attempted; a large ventricular septal defect and a malformed, stenotic pulmonary valve were observed. The ventricutar septal defect was closed with an ivalon patch. The pulmonary valve was completely resected, and the pulmonary outflow tract was enlarged with an Ivalon gusset. The coarctation of the right pulmonary artery was incised longitudinally at the area of stenosis and then closed using the Heinecke-Mikulicz procedure; a significant degree of obstruction remained; the main pulmonary artery pressure measured 70 mm Hg at the end of the procedure. Following the operation, the patient's course has been uneventful. A grade 3 systolic and grade 2 diastolic murmurs were heard over the pulmonic area. The systolic murmur was transmitted to the neck vessels, to both axillae, and to the back. There were no palpable thrills. The patient casually remarked that when she opened her mouth, he r mother could hear the murmur. This was confirmed: A murmur could faintly, but clearly, be heard when the examiner was within three feet of the patient's open mouth. With the stethoscope at the oral orifice, the murmur was considerably louder. It was synchronous with the heart beat. A phonocardiographic tracing with the microphone at the open mouth of the patient documented the presence of a loud systolic murmur (Fig. 1). Subsequent catheterization of the right and left sides of the heart showed pulmonic insufficiency with stenosis of both ~he right and left pulmonary arteries: Catheterization of the left side of the heart showed no evidence of abnormality of the left ventricular chamber, the aortic valve, or the aorta. Cineangiocardiograms showed a greatly dilated main pulmonary artery with
852
The Journal o f P E D 1 A T R I C S VoL 89, No. 5, pp. 852-865
i
x
SM ', / .
MOUTH
Fig. 1. Shown are the electrocardiogram (ECG) and the phonocardiographic tracings obtained in the second left interspace ( 2 L I S ) and at the mouth. The murmur at the mouth was recorded with the microphone placed between the upper and lower incisors. I = first heart sound; II = second heart sound; SM = systolic murmur. moderate pulmonic regurgitation and severe coarctation of the right pulmonary artery just distal to the bifurcation. The left pulmonary artery was not clearly visualized. DISCUSSION Only one other reference to the type of transmitted sound described here could be found. In a review of precordial noises heard at a distance from the chest, Bean 1refers to an unpublished instance in which the heart sounds could be heard several inches from the open mouth of a healthy man. He speculated that the esophagus may have been patulous with the mouth open and thus served as a megaphone. The mechanism of production of the unusual acoustic phenomenon described in our patient is entirely speculative. The hemodynamic findings indicate that the major area of turbulent blood flow is in the area of bifurcation of the main pulmonary artery. This region along with the right and left branches are in
Volume 89 Number 5
Letters to the Editor
direct contact with the mainstem bronchi; sound waves arising from these vessels conceivably could be transmitted to the airways. Perhaps the tracheobronchial tree with only one opening to the atmosphere, in this instance provides the acoustic amplification. Arthur J. Moss, M.D. UCLA School of Medicine Department of Pediatrics Los Angeles, Calif. 90024 REFERENCE 1. Bean WB: Precordial noises heard at a distance from the chest, JAMA 152:1293, 1953.
Experimental toxicologic studies on a phenol detergent associated with neonatal hyperbilirubinemia To the Editor: Recently, the Center for Disease Control, Atlanta, Georgia, reported ~ two unusual hospital nursery outbreaks of severe idiopathic neonataI unconjugated hyperbilirubinemia. Investigation revealed that, in both instances, a phenolic disinfectantdetergent (Vestal LpH, Division of Chemed Corporation, St. Louis, Mo.) in excess of the recommended concentrations had been used to clean nursery equipment. After discontinuation of the disinfectant, the frequency of neonatal jaundice abated in the nurseries. No acute hemolysis or hepatic dysfunction could be appreciated as the cause of the jaundice, but impairment of the hepatic glucuronidation process could not be excluded. To determine if phenolic inhibition of hepatic bilirubin glucuronyl transferase activity (EC 2.4.1.17) might be a mechanism responsible for the unconjugated hyperbilirubinemia, several in vitro and in vivo animal experiments were performed. MATERIALS
AND METHODS
In vitro inhibition study. Dilutions of phenolic detergent ranging in concentrations from 1:2 to 1:2048 were added in 0.2 ml volumes to the reaction mixture of the assay for hepatic bilirubin glucuronyI transferase ~ to determine inhibition of activity as previously described for human breast milk. :~Hepatic bilirubin glucuronyl transferase activity was estimated in 8% homogenates of liver according to the method of DeLeon and associates" as later modified by Gartner. In this nrodification 2% digitonin in 0.154M KCI is added to the liver homogenate in a 1:1 dilution just prior to the addition of 0, t ml of uridine diphosphate glucuronic acid (6.6 x I 0 - 3. All enzyme assays were performed immediately. In vivo experiments. Eight hon-tozygote and heterozygote 14week-old Gunn rats were brush "painted" or placed in cages whose walls were "painted" with undiluted phenol detergent on each of three successive days. Serum specimens were obtained from tail veins, and bilirubin concentrations were determined by
853
T a b l e I. P e r c e n t a g e i n h i b i t i o n o f bilirubin g l u c u r o n y l t r a n s f e r a s e activity u p o n the a d d i t i o n o f various dilutions o f 0.2 ml Of p h e t m l i c d e t e r g e n t to the r e a c t i o n m i x t u r e ; a significant d e g r e e o f i n h i b i t i o n is n o t e d t h r o u g h a 1:128 dilution,
Dilution of phenolic detergent
Percentage inhibition
No dilution 1:2 1:4 1:8 1:32 1:64 1:128 1:256 1:512 1: 1,024
100 98 100 94 100 100 46 15 9 5 0
1:2,048
the method of Malloy and Evelyn ~ before and after phenolic exposure. Five homozygote and heterozygote Gunn rats were exposed to physiologic saline under similar conditions as control animals. Additionally, five heterozygote rats received a single 0.5 ml intraperitoneal injection of either phenolic disinfectant or physiologic saline. The phenol-treated rats consisted of three subgroups of five animals each injected with the disinfectant in dilutions of 1:48, 1:64, and 1:128. Serum bilirubin concentrations were measured prior to and eight, 24, and 48 hours after injection. Lastly, five heterozygote Gunn rats exposed for three days, as noted above, to phenolic detergent or physiologic saline were sacrificed by decapitation and their liver tissue analyzed to determine the activity of hepatic bilirubin glucuronyl transferase.-' The results are expressed as /*g of bilirubin glucuronide formed per gram of liver per 40 minutes. RESULTS In vitro inhibition studies. Significant inhibition of enzyme activity was evident when phenolic detergent in dilutions of 1:128 or less was added to the in vitro assay system (Table l). In vivo experiments. There were no significant differences in serum bilirubin concentrations noted in phenol-detergent treated homozygote and heterozygote Gunn rats from those given saline. Similarly, bilirubin glucuronyl transferase activity determined in liver homogenates from heterozygote Gunn rats treated with phenolic detergent was not significantly different from that in saline-treated control animals (974 _+ 124 versus 857 _+ 9 p,g hilirubin glucuronide formed/gin Iiver/40 minutes, respectively). DISCUSSION Although the Gunn rat represents an excellent animal model to study certain aspects of bilirubin metabolism, it was not a useful model in this in vivo toxicologic appraisal. Failure to demon-
TO T H E E D I T O R
Clinical notes
"Clinical notes" represent clinical and/or laboratory experiences which can be presented in 200 to 400 words, 3 or 4 references, and, if contributory, one illustration or short table. "Clinical notes" are subject to the same critical peer review and editing as papers published in other sections of ThE JOURNAL.
Murmurs heard at a distance from the patient: Report of an unusual case
T
SM
Fr
To the Editor: A previously unreported acoustic phenomenon associated with congenital heart disease was recently encountered.
ii
CASE REPORT Patient J.B.,-a 16-year-old female, has been followed since the age of 16 months because of congenital heart disease. At the age of 19 months, a diagnosis o f tetralogy of Fallot with stenosis of both branches of the pulmonary artery was established by cardiac catheterization and cineangiography. At 6 years of age, corrective surgery was attempted; a large ventricular septal defect and a malformed, stenotic pulmonary valve were observed. The ventricutar septal defect was closed with an ivalon patch. The pulmonary valve was completely resected, and the pulmonary outflow tract was enlarged with an Ivalon gusset. The coarctation of the right pulmonary artery was incised longitudinally at the area of stenosis and then closed using the Heinecke-Mikulicz procedure; a significant degree of obstruction remained; the main pulmonary artery pressure measured 70 mm Hg at the end of the procedure. Following the operation, the patient's course has been uneventful. A grade 3 systolic and grade 2 diastolic murmurs were heard over the pulmonic area. The systolic murmur was transmitted to the neck vessels, to both axillae, and to the back. There were no palpable thrills. The patient casually remarked that when she opened her mouth, he r mother could hear the murmur. This was confirmed: A murmur could faintly, but clearly, be heard when the examiner was within three feet of the patient's open mouth. With the stethoscope at the oral orifice, the murmur was considerably louder. It was synchronous with the heart beat. A phonocardiographic tracing with the microphone at the open mouth of the patient documented the presence of a loud systolic murmur (Fig. 1). Subsequent catheterization of the right and left sides of the heart showed pulmonic insufficiency with stenosis of both ~he right and left pulmonary arteries: Catheterization of the left side of the heart showed no evidence of abnormality of the left ventricular chamber, the aortic valve, or the aorta. Cineangiocardiograms showed a greatly dilated main pulmonary artery with
852
The Journal o f P E D 1 A T R I C S VoL 89, No. 5, pp. 852-865
i
x
SM ', / .
MOUTH
Fig. 1. Shown are the electrocardiogram (ECG) and the phonocardiographic tracings obtained in the second left interspace ( 2 L I S ) and at the mouth. The murmur at the mouth was recorded with the microphone placed between the upper and lower incisors. I = first heart sound; II = second heart sound; SM = systolic murmur. moderate pulmonic regurgitation and severe coarctation of the right pulmonary artery just distal to the bifurcation. The left pulmonary artery was not clearly visualized. DISCUSSION Only one other reference to the type of transmitted sound described here could be found. In a review of precordial noises heard at a distance from the chest, Bean 1refers to an unpublished instance in which the heart sounds could be heard several inches from the open mouth of a healthy man. He speculated that the esophagus may have been patulous with the mouth open and thus served as a megaphone. The mechanism of production of the unusual acoustic phenomenon described in our patient is entirely speculative. The hemodynamic findings indicate that the major area of turbulent blood flow is in the area of bifurcation of the main pulmonary artery. This region along with the right and left branches are in
Volume 89 Number 5
Letters to the Editor
direct contact with the mainstem bronchi; sound waves arising from these vessels conceivably could be transmitted to the airways. Perhaps the tracheobronchial tree with only one opening to the atmosphere, in this instance provides the acoustic amplification. Arthur J. Moss, M.D. UCLA School of Medicine Department of Pediatrics Los Angeles, Calif. 90024 REFERENCE 1. Bean WB: Precordial noises heard at a distance from the chest, JAMA 152:1293, 1953.
Experimental toxicologic studies on a phenol detergent associated with neonatal hyperbilirubinemia To the Editor: Recently, the Center for Disease Control, Atlanta, Georgia, reported ~ two unusual hospital nursery outbreaks of severe idiopathic neonataI unconjugated hyperbilirubinemia. Investigation revealed that, in both instances, a phenolic disinfectantdetergent (Vestal LpH, Division of Chemed Corporation, St. Louis, Mo.) in excess of the recommended concentrations had been used to clean nursery equipment. After discontinuation of the disinfectant, the frequency of neonatal jaundice abated in the nurseries. No acute hemolysis or hepatic dysfunction could be appreciated as the cause of the jaundice, but impairment of the hepatic glucuronidation process could not be excluded. To determine if phenolic inhibition of hepatic bilirubin glucuronyl transferase activity (EC 2.4.1.17) might be a mechanism responsible for the unconjugated hyperbilirubinemia, several in vitro and in vivo animal experiments were performed. MATERIALS
AND METHODS
In vitro inhibition study. Dilutions of phenolic detergent ranging in concentrations from 1:2 to 1:2048 were added in 0.2 ml volumes to the reaction mixture of the assay for hepatic bilirubin glucuronyI transferase ~ to determine inhibition of activity as previously described for human breast milk. :~Hepatic bilirubin glucuronyl transferase activity was estimated in 8% homogenates of liver according to the method of DeLeon and associates" as later modified by Gartner. In this nrodification 2% digitonin in 0.154M KCI is added to the liver homogenate in a 1:1 dilution just prior to the addition of 0, t ml of uridine diphosphate glucuronic acid (6.6 x I 0 - 3. All enzyme assays were performed immediately. In vivo experiments. Eight hon-tozygote and heterozygote 14week-old Gunn rats were brush "painted" or placed in cages whose walls were "painted" with undiluted phenol detergent on each of three successive days. Serum specimens were obtained from tail veins, and bilirubin concentrations were determined by
853
T a b l e I. P e r c e n t a g e i n h i b i t i o n o f bilirubin g l u c u r o n y l t r a n s f e r a s e activity u p o n the a d d i t i o n o f various dilutions o f 0.2 ml Of p h e t m l i c d e t e r g e n t to the r e a c t i o n m i x t u r e ; a significant d e g r e e o f i n h i b i t i o n is n o t e d t h r o u g h a 1:128 dilution,
Dilution of phenolic detergent
Percentage inhibition
No dilution 1:2 1:4 1:8 1:32 1:64 1:128 1:256 1:512 1: 1,024
100 98 100 94 100 100 46 15 9 5 0
1:2,048
the method of Malloy and Evelyn ~ before and after phenolic exposure. Five homozygote and heterozygote Gunn rats were exposed to physiologic saline under similar conditions as control animals. Additionally, five heterozygote rats received a single 0.5 ml intraperitoneal injection of either phenolic disinfectant or physiologic saline. The phenol-treated rats consisted of three subgroups of five animals each injected with the disinfectant in dilutions of 1:48, 1:64, and 1:128. Serum bilirubin concentrations were measured prior to and eight, 24, and 48 hours after injection. Lastly, five heterozygote Gunn rats exposed for three days, as noted above, to phenolic detergent or physiologic saline were sacrificed by decapitation and their liver tissue analyzed to determine the activity of hepatic bilirubin glucuronyl transferase.-' The results are expressed as /*g of bilirubin glucuronide formed per gram of liver per 40 minutes. RESULTS In vitro inhibition studies. Significant inhibition of enzyme activity was evident when phenolic detergent in dilutions of 1:128 or less was added to the in vitro assay system (Table l). In vivo experiments. There were no significant differences in serum bilirubin concentrations noted in phenol-detergent treated homozygote and heterozygote Gunn rats from those given saline. Similarly, bilirubin glucuronyl transferase activity determined in liver homogenates from heterozygote Gunn rats treated with phenolic detergent was not significantly different from that in saline-treated control animals (974 _+ 124 versus 857 _+ 9 p,g hilirubin glucuronide formed/gin Iiver/40 minutes, respectively). DISCUSSION Although the Gunn rat represents an excellent animal model to study certain aspects of bilirubin metabolism, it was not a useful model in this in vivo toxicologic appraisal. Failure to demon-