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Acquired palatal groove after prolonged orotracheal intubation
5 12
Editorial correspondence
agers are in jails, lockups, and detention facilities on any one day and several hundred thousand are detained yearly on a national basis. These young people represent some health risk both to themselves and as a reservoir for others. Therefore, screening of this high-risk group appears quite appropriate but in no way could we disagree with Dr. Buttery that treatment facilities and counselling services complement the former activity. Indeed, in our youth detention program we offer all three services. Karen Hein, M.D. Andrea Marks, M.D. Michael L Cohen, M.D. Montefiore Hospital and Medical Center 111 E. 210th St. Bronx, N Y 10467
Hyposplenic septicemia and adrenal hemorrhage To the Editor: The recent article by Waldman et aP reviewing sepsis in congenitally asplenic children contributed substantial data about the natural history of this syndrome. They record two patients dying with pneumococcal sepsis and the Waterhouse-Friderichsen syndrome and suggest a predilection of pneumococci for the adrenal glands and spleen based on an animal model. A detailed study by Perry and Cluff~in a rabbit model of pneumococcemia revealed rather constant organ concentrations of bacteria. In their model the spleen did have per gram concentrations in excess of the blood concentrations, consistent with the finding that in the nonimmune animal the spleen is the most efficient organ of phagocytosis for encapsulated organisms? However, in Perry and Cluff's model, the adrenal concentration of bacteria was generally lower than blood concentration. Schulkind et al 3, using l~I-labelled pneumococci, demonstrated significant concentrations of bacteria only in the spleen and liver. The associatio~ of postsplenectomy or hyposplenic sepsis with disseminated intravascular coagulation (DIC) and adrenal hemorrhage is well documented. Postsplenectomy sepsis has uniquely high levels of bacteria i n the blood reaching 106/ml compared to 200/ml in the usual bacteremia. 4 High levels of pneumococci in the blood have been implicated in initiating DIC? DIC, rather than adrenal concentrating of bacteria, would appear to be a more likely explanation for the observed Waterhouse-Friderichsen syndome; any observed increase of bacteria in the adrenal gland may represent adrenal hemorrhage of blood heavily laden with bacteria. J. C. Dearth, M.D. G. S. Gilchrist, M.D. Mayo Clinic Rochester, M N 55901 REFERENCES
1. Waldman JD, Rosenthal A, Smith AL, Shurin S, and Nadas AS: Sepsis and congenital asplenia, J PED~ATR~90:555, 1977.
The Journal of Pediatrics March 1978
2.
Perry JE, and Cluff, LE: Clinical and bacteriological events in experimental lethal pneumococcal infection, Tex Rep Biol Med 24:125, 1960. 3. Schulkind ML, Ellis EF, and Smith RT: Effect of antibody upon clearance of I12~-labelled pneumococci by the spleen and liver, Pediatr Res 1:178, 1967. 4. Tortes J, and Bisno AL: Hyposplenism and pneumococcemia, Am J Med 55:851, 1973. 5. Rytel MW, Dee TH, Ferstenfeld JE, and Hensley GT: Possible pathogenetic role of capsular antigens in fulminant pneumococcal disease with disseminated intravascular coagulation (DIC), Am J Med 57:889, 1974.
Reply To the Editor: Drs. Dearth and Gilchrist wish to suggest an explanation for the Waterhouse-Friderichsen syndrome and with their view we have no argument. In our paper, we queried what the adrenal concentration of pneumococci might be in the absence of a spleen. Nowhere did we speculate as to pathogenesis. Our clinical study resulted in three conclusions which we hope will remain clear and simple: (1) congenitally asplenic patients are at high risk for overwhelming bacterial sepsis, (2) this risk is primarily related to lack of a spleen rather than presence of cyanotic heart disease, and (3) we give continuous antibiotic prophylaxis to asplenic patients commencing at three months of age. J. Deane Waldrnan, M.D. Pediatric Cardiology Medical Group, Inc. 7920 Frost St. San Diego, CA 92123
Acquired palatal groove after prolonged orotracheal intubation To the Editor: Saunders et al 1 and Duke et aF in the December, 1976, issue of THE JOURNAL describe acquired palatal defects in neonates secondary to prolonged orotracheal intubation. We would like to add a similar case.
CASE REPORT Birth asphyxia and subsequent idiopathic respiratory distress syndrome required a premature infant to be intubated immediately after birth. Intubation and ventilatory assistance were needed for a total of 44 days. The endotracheal tubes, all of polyvinyl chloride,: were replaced three times because of accidental extubation, and always secured to the upper lip in the midline. The initial and replacement tubes varied from 2.5 to 3.0 mm in diameter. Initial physical examination revealed no palatal abnormality, but at the time of extubation a deep palatal groove was noted extending slightly.left of the midline behind the upper alveolar ridge to the soft palate. No communication with the nasal cavity was present.
Vo&me 92 Number 3
Editorial correspondence
Unfortunately no follow-up examination has been possible to assess resolutiop of this acquired defect. ADDENDUM
After this letter was written the patient was seen in the Outpatient Clinic by one of us (E. K. B.). Examination revealed almost complete resolution of the palatal groove. Evanthia K. Biskinis, M.D. Director, Neonatal Intensive Care Unit Michael Herz, M.D. Resident, Obstetrics-Gynecology Kern Medical Center 1830 Flower St. Bakersfield, CA 93305 REFERENCES
1. Saunders BS, Easa D, and Slaughter, RJ: Acquired palatal groove in neonates, J PEDIATR 89:988, 1976. 2. Duke PM, Coulson JD, Santos JI, and Johnson JD: Cleft palate associated with prolonged orotracheal intubation in infancy, J PEDIATR 89:990, 1976.
Intrapatient variability in theophylline kinetics To the Editor: The manuscript by Walson et all claims to have demonstrated intrapatient variability in theophylline kinetics but more likely is simply demonstrating excessive sampling variability. The authors utilized a bare minimum of data points, and the first data point at one hour may have occurred during the distribution phase of the degradation curve in some patients. Given normal variability in theophyltine measurement and the special problems of the Schack and Waxler method for assaying theophylline, ~ this minimum number of data points will result in variability of the slope of the regression line which will alter the extrapolated zero time level (C~) used to calculate the volume of distribution (Vd). Errors i n Cp and subsequently in Vd and clearance will be amplified because of the logarithmic relationship between serum concentration and time. Thus, half-lives (a function of the slope of the degradation curve) will vary excessively as a result of experimental error in theophylline measurements compounded by the small number of data points over a relatively short time interval, and the V~ (used for the calculation of clearance) will vary as a result in an accentuated manner. The resulting clearance calculation (C1 = Vd X 0.693/tJA) will reflect this sampling variability. Additional errors are created by the authors' methods for calculating the Vd. The method of extrapolation used assumes a one-compartment model and predictably overestimates the volume of distribution when the drug has distribution and elimination characteristics that are best described by a two compartment open system modelY This explains the authors' deviant V~ calculations, which were initially 0.64 • 0.05 (mean _+ SE) and were subsequently 0.71 _+ 0.141/kg. Both means were
5 13
considerably higher than other reports of Vd which have consis~ averaged less than 0.51/kg with a range of from 0.3 to 0.71/ kg. 4-~ Alterations of drug elimination characteristics affect clearance as a function of an altered rate of degradation rather than an altered Vd.7 Therefore, the high Vd's and associated clearances reported by Walson et al I are most likely factitious as a result of the authors' inappropriate methods rather than any physiologic peculiarities of their patients. Two of their seven subjects (3 and 4) had Vd's and associated clearances much higher than any found among more than 50 patients previously examined. "-7 When clearance was calculated in a more direct manner by determining the steady-state concentration resulting from a constant infusion rate, changes in clearance were much smaller than those reported by Walson et al 1 and, in fact, were not clinically important among 16 patients examined over an average interval of five months. ~Akhough the authors are correct in their statement that "single determination of theophylline kinetics cannot be safely used to predict future dosage requirements...," their methods and data analysis do not validly support that "significant intrapatient variability in kinetic measurements can occur." Other data, in fact, argue the opposite. Rather, pharmacokinetic factors for theophylline based on first-order elimination characteristics are not valid forpredicting dosage requirements because theophyUine, like many other drugs, has dose-dependent kinetics probably better described by a Michaelis-Menton model than first order elimination. ~ Miles Weinberger, M.D. Associate Professor of Pediatrics and Pharmacology Chairman of the Pediatric Allergy and Pulmonary Division Leslie Hendeles, Pharm. D. Assistant Pivfessor, College of Pharmacy Clinical Pharmacist, Pediatric Allergy Clinic The University of lowa Iowa Cit)5 IA 52242 REFERENCES
1. Walson PD, Strunk RC, and Taussig LM: Intrapatient variability in theophylline kinetics, J PEDIATR 91:321, 1977. 2. Matheson LE, Bighley L, and Hendeles L: Drug interference with the Schack and Waxler plasma theophylline assay, Am J Hosp Pharm 34:496, 1977. 3. Riegelman S, Loo J, and Rowland M: Concept of a volume of distribution and possible errors in evaluation of its parameter, J Pharm Sci 57:I28, 1968. 4. Jenne JW, Wyze MS, Rood FS, et al: Pharmacokinetics of theophylline. Application of adjustment of the clinical dose of anainophylline, Clin Pharmacol Ther 13:349, 1972. 5. Mitenko PA, and Ogilvie RI: Rational intravenous doses of theophylline, N Engl J Med 289:600, 1973. 6. Ellis E, Koysooko R, and Levy G: Pharmacokinetics of theophylline in children with asthma, Pediatrics 58:542, 1976. 7. Piafsky KM, Sitar D, and Rangno RE: Theophyltine disposition in patients with hepatic cirrhosis, N Engl J Med 296:1495, 1977.
Editorial correspondence
agers are in jails, lockups, and detention facilities on any one day and several hundred thousand are detained yearly on a national basis. These young people represent some health risk both to themselves and as a reservoir for others. Therefore, screening of this high-risk group appears quite appropriate but in no way could we disagree with Dr. Buttery that treatment facilities and counselling services complement the former activity. Indeed, in our youth detention program we offer all three services. Karen Hein, M.D. Andrea Marks, M.D. Michael L Cohen, M.D. Montefiore Hospital and Medical Center 111 E. 210th St. Bronx, N Y 10467
Hyposplenic septicemia and adrenal hemorrhage To the Editor: The recent article by Waldman et aP reviewing sepsis in congenitally asplenic children contributed substantial data about the natural history of this syndrome. They record two patients dying with pneumococcal sepsis and the Waterhouse-Friderichsen syndrome and suggest a predilection of pneumococci for the adrenal glands and spleen based on an animal model. A detailed study by Perry and Cluff~in a rabbit model of pneumococcemia revealed rather constant organ concentrations of bacteria. In their model the spleen did have per gram concentrations in excess of the blood concentrations, consistent with the finding that in the nonimmune animal the spleen is the most efficient organ of phagocytosis for encapsulated organisms? However, in Perry and Cluff's model, the adrenal concentration of bacteria was generally lower than blood concentration. Schulkind et al 3, using l~I-labelled pneumococci, demonstrated significant concentrations of bacteria only in the spleen and liver. The associatio~ of postsplenectomy or hyposplenic sepsis with disseminated intravascular coagulation (DIC) and adrenal hemorrhage is well documented. Postsplenectomy sepsis has uniquely high levels of bacteria i n the blood reaching 106/ml compared to 200/ml in the usual bacteremia. 4 High levels of pneumococci in the blood have been implicated in initiating DIC? DIC, rather than adrenal concentrating of bacteria, would appear to be a more likely explanation for the observed Waterhouse-Friderichsen syndome; any observed increase of bacteria in the adrenal gland may represent adrenal hemorrhage of blood heavily laden with bacteria. J. C. Dearth, M.D. G. S. Gilchrist, M.D. Mayo Clinic Rochester, M N 55901 REFERENCES
1. Waldman JD, Rosenthal A, Smith AL, Shurin S, and Nadas AS: Sepsis and congenital asplenia, J PED~ATR~90:555, 1977.
The Journal of Pediatrics March 1978
2.
Perry JE, and Cluff, LE: Clinical and bacteriological events in experimental lethal pneumococcal infection, Tex Rep Biol Med 24:125, 1960. 3. Schulkind ML, Ellis EF, and Smith RT: Effect of antibody upon clearance of I12~-labelled pneumococci by the spleen and liver, Pediatr Res 1:178, 1967. 4. Tortes J, and Bisno AL: Hyposplenism and pneumococcemia, Am J Med 55:851, 1973. 5. Rytel MW, Dee TH, Ferstenfeld JE, and Hensley GT: Possible pathogenetic role of capsular antigens in fulminant pneumococcal disease with disseminated intravascular coagulation (DIC), Am J Med 57:889, 1974.
Reply To the Editor: Drs. Dearth and Gilchrist wish to suggest an explanation for the Waterhouse-Friderichsen syndrome and with their view we have no argument. In our paper, we queried what the adrenal concentration of pneumococci might be in the absence of a spleen. Nowhere did we speculate as to pathogenesis. Our clinical study resulted in three conclusions which we hope will remain clear and simple: (1) congenitally asplenic patients are at high risk for overwhelming bacterial sepsis, (2) this risk is primarily related to lack of a spleen rather than presence of cyanotic heart disease, and (3) we give continuous antibiotic prophylaxis to asplenic patients commencing at three months of age. J. Deane Waldrnan, M.D. Pediatric Cardiology Medical Group, Inc. 7920 Frost St. San Diego, CA 92123
Acquired palatal groove after prolonged orotracheal intubation To the Editor: Saunders et al 1 and Duke et aF in the December, 1976, issue of THE JOURNAL describe acquired palatal defects in neonates secondary to prolonged orotracheal intubation. We would like to add a similar case.
CASE REPORT Birth asphyxia and subsequent idiopathic respiratory distress syndrome required a premature infant to be intubated immediately after birth. Intubation and ventilatory assistance were needed for a total of 44 days. The endotracheal tubes, all of polyvinyl chloride,: were replaced three times because of accidental extubation, and always secured to the upper lip in the midline. The initial and replacement tubes varied from 2.5 to 3.0 mm in diameter. Initial physical examination revealed no palatal abnormality, but at the time of extubation a deep palatal groove was noted extending slightly.left of the midline behind the upper alveolar ridge to the soft palate. No communication with the nasal cavity was present.
Vo&me 92 Number 3
Editorial correspondence
Unfortunately no follow-up examination has been possible to assess resolutiop of this acquired defect. ADDENDUM
After this letter was written the patient was seen in the Outpatient Clinic by one of us (E. K. B.). Examination revealed almost complete resolution of the palatal groove. Evanthia K. Biskinis, M.D. Director, Neonatal Intensive Care Unit Michael Herz, M.D. Resident, Obstetrics-Gynecology Kern Medical Center 1830 Flower St. Bakersfield, CA 93305 REFERENCES
1. Saunders BS, Easa D, and Slaughter, RJ: Acquired palatal groove in neonates, J PEDIATR 89:988, 1976. 2. Duke PM, Coulson JD, Santos JI, and Johnson JD: Cleft palate associated with prolonged orotracheal intubation in infancy, J PEDIATR 89:990, 1976.
Intrapatient variability in theophylline kinetics To the Editor: The manuscript by Walson et all claims to have demonstrated intrapatient variability in theophylline kinetics but more likely is simply demonstrating excessive sampling variability. The authors utilized a bare minimum of data points, and the first data point at one hour may have occurred during the distribution phase of the degradation curve in some patients. Given normal variability in theophyltine measurement and the special problems of the Schack and Waxler method for assaying theophylline, ~ this minimum number of data points will result in variability of the slope of the regression line which will alter the extrapolated zero time level (C~) used to calculate the volume of distribution (Vd). Errors i n Cp and subsequently in Vd and clearance will be amplified because of the logarithmic relationship between serum concentration and time. Thus, half-lives (a function of the slope of the degradation curve) will vary excessively as a result of experimental error in theophylline measurements compounded by the small number of data points over a relatively short time interval, and the V~ (used for the calculation of clearance) will vary as a result in an accentuated manner. The resulting clearance calculation (C1 = Vd X 0.693/tJA) will reflect this sampling variability. Additional errors are created by the authors' methods for calculating the Vd. The method of extrapolation used assumes a one-compartment model and predictably overestimates the volume of distribution when the drug has distribution and elimination characteristics that are best described by a two compartment open system modelY This explains the authors' deviant V~ calculations, which were initially 0.64 • 0.05 (mean _+ SE) and were subsequently 0.71 _+ 0.141/kg. Both means were
5 13
considerably higher than other reports of Vd which have consis~ averaged less than 0.51/kg with a range of from 0.3 to 0.71/ kg. 4-~ Alterations of drug elimination characteristics affect clearance as a function of an altered rate of degradation rather than an altered Vd.7 Therefore, the high Vd's and associated clearances reported by Walson et al I are most likely factitious as a result of the authors' inappropriate methods rather than any physiologic peculiarities of their patients. Two of their seven subjects (3 and 4) had Vd's and associated clearances much higher than any found among more than 50 patients previously examined. "-7 When clearance was calculated in a more direct manner by determining the steady-state concentration resulting from a constant infusion rate, changes in clearance were much smaller than those reported by Walson et al 1 and, in fact, were not clinically important among 16 patients examined over an average interval of five months. ~Akhough the authors are correct in their statement that "single determination of theophylline kinetics cannot be safely used to predict future dosage requirements...," their methods and data analysis do not validly support that "significant intrapatient variability in kinetic measurements can occur." Other data, in fact, argue the opposite. Rather, pharmacokinetic factors for theophylline based on first-order elimination characteristics are not valid forpredicting dosage requirements because theophyUine, like many other drugs, has dose-dependent kinetics probably better described by a Michaelis-Menton model than first order elimination. ~ Miles Weinberger, M.D. Associate Professor of Pediatrics and Pharmacology Chairman of the Pediatric Allergy and Pulmonary Division Leslie Hendeles, Pharm. D. Assistant Pivfessor, College of Pharmacy Clinical Pharmacist, Pediatric Allergy Clinic The University of lowa Iowa Cit)5 IA 52242 REFERENCES
1. Walson PD, Strunk RC, and Taussig LM: Intrapatient variability in theophylline kinetics, J PEDIATR 91:321, 1977. 2. Matheson LE, Bighley L, and Hendeles L: Drug interference with the Schack and Waxler plasma theophylline assay, Am J Hosp Pharm 34:496, 1977. 3. Riegelman S, Loo J, and Rowland M: Concept of a volume of distribution and possible errors in evaluation of its parameter, J Pharm Sci 57:I28, 1968. 4. Jenne JW, Wyze MS, Rood FS, et al: Pharmacokinetics of theophylline. Application of adjustment of the clinical dose of anainophylline, Clin Pharmacol Ther 13:349, 1972. 5. Mitenko PA, and Ogilvie RI: Rational intravenous doses of theophylline, N Engl J Med 289:600, 1973. 6. Ellis E, Koysooko R, and Levy G: Pharmacokinetics of theophylline in children with asthma, Pediatrics 58:542, 1976. 7. Piafsky KM, Sitar D, and Rangno RE: Theophyltine disposition in patients with hepatic cirrhosis, N Engl J Med 296:1495, 1977.