well as possible changes in the timing of death, we identified all deaths in a cohort of infants,1500 g in an ongoing study at six neonatal intensive care units in New England.2Of these 849
in-fants, 355 (42%) were,1000 g at birth. Mortality rates for birth weight strata are shown in Table 1, and distribution of mortality over the first 2 weeks of life is shown in Table 2. We calculated the odds of subsequent mortality for infants who survived to 4 days of life, examining the contributions of birth weight and severity of illness on day of life 3 as measured by the Score for Neonatal Acute Physiology (Table 3).
We found mortality rates at less than half the levels reported by the authors for the cohort from the previous era (53% vs 25%). In addition, we found a pattern of deferred mortality, with only 44% of infants,750 g who died before discharge (within the first 3 days of life). In contrast, Meadow et al found 85% of the deaths occurred within the first 3 days of life, a fraction not approached in our cohort until after 2 weeks of life. We also found that both birth weight and severity of illness contribute to risk of mortality for survivors to day 4 with the extremes of both birth weight and severity of illness each powerfully affecting mortality risk.
The differences in risk and timing of mortality between our cohort and Meadow et al is probably attributable to enhanced survival in the “surfactant era” and possibly the contribution of more prevalent use of antenatal glucocorticoids. In addition, there may be differences in institutional practices of resuscitation and withdrawal of support for ELBW infants that might explain dif-ferences in the timing and extent of mortality between the cohorts. Nevertheless, our cohort is drawn from six neonatal intensive care units and probably represents a broader, more recent experience with early mortality risk and timing of deaths. Perhaps the respi-ratory survival to day 4 (due to surfactant) now leaves extremely immature infants succumbing more unpredictably to other organ system failures? The issues the authors raise about trials of treat-ment and resource allocation to nonsurvivors are, we feel, still valid, but are certainly less clear-cut than in the earlier era.
Marty Ellington, Jr, MD, MPH Douglas K. Richardson, MD, MBA James E. Gray, MD, MS
DeWayne M. Pursley, MD, MPH Joint Program in Neonataology Harvard Medical School Boston, MA 02115
REFERENCES
1. Meadow W, Reimshisel T, Lantos J. Birth weight-specific mortality for extremely low birth weight infants vanishes by four days of life: epi-demiology and ethics in the neonatal intensive care unit. Pediatrics. 1996;97:636 – 643
2. Ellington M Jr, Richardson DK, Gray JE, Gortmaker S, Frantz I III, and the SNAP-II Study Group. Variation in neonatal illness severity among neonatal intensive care units (NICUs) at days 1, 3, and 14. Pediatr Res. 1996;39:263. Abstract
In Reply.—
We thank Dr Ellington and colleagues for their interest in our study and its implications for health care decisions in the neonatal intensive care unit (NICU). We would like to make a few points in response to their letter, and propose a synthesis:
First, technologic improvements in NICU care during the past 7 years (surfactant, oscillators, etc) did not unduly influence our data. Our initial report was derived from 1989 to 1991, a period of time when surfactant was already widely used in our NICU. We have recently published our experience with 498 ELBW infants through 19931and reconfirmed the phenomenon of early death in
the highest risk infants. Spurred by Dr Ellington’s data on 355 patients from six centers in New England, we recently evaluated our experience with an additional 233 extremely low birth weight (ELBW) infants admitted to our NICU from January 1994 to July 1996. The phenomenon persists—for infants at the greatest risk of death (birth weight,750 g), the majority (66%) had died by day of life 3. For infants who were less likely to die (birth weight 750 –1000 g), the timing of death was delayed. For both birth weight groups, as we and Dr Ellington demonstrate to no one’s great surprise, illness severity continued to influence survival for infants at least as old as 4 days.
In our view, two common themes emerge from our data and Dr Ellington’s. First, overwhelmingly NICU death is a phenomenon of the smallest infants in the first days of life. In our NICU in Chicago, infants weighing,750 g accounted for 81% of all ELBW deaths; in New England they accounted for 73% of ELBW deaths. Nevertheless, for infants weighing,750 g who remained alive on day of life 4 the likelihood of ultimate survival had risen to 75% in New England and 66% in Chicago. Consequently, it appears that in both of these regions (and likely for the rest of the country as well), the usefulness of birth weight as a prognostic indicator wanes after 72 hours. Survival for larger ELBW infants (birth weight 750 –1000 g; 87% in New England, 87% in Chicago) is already too good to invoke ethical concerns based on birth weight alone. We tried to call attention to the fact that, even for smaller infants, survival is quite good for those infants who reach 4 days old.
Second, in both Chicago and New England, the health care resources attributed to dying ELBW infants before their demise are negligible— compared with either the resources devoted to surviving ELBW infants or to dying adult patients. In both Chi-cago and New England,15% of all NICU bed-days are devoted to patients who will not survive, even for the lowest birth weight populations with the highest mortality. In contrast, we have re-cently demonstrated1 that the comparable figure for ventilated
adults in a general medicine ICU is 55%, and for adults.85 years old the figure rises to 90%!
The differences between Chicago and New England raise some interesting questions about the care of these infants in the first days of life. To the extent that death is predictable, continued intensive care only prolongs dying and ought to be curtailed. To the extent that death is not predictable except by a trial of therapy, current NICU practices may be as good as it gets.
William Meadow, MD, PhD John Lantos, MD
Laura Frain, MD Yaya Ren, MD
Department of Pediatrics
MacLean Center for Clinical Medical Ethics University of Chicago
Chicago, IL 60637
REFERENCE
1. Meadow WL, Lantos JD, Mokalla M, Reimschisel T. Distribution justice across generations: epidemiology of ICU care for the very young and the very old. Clin Perinatol. 1996;23:597– 608
Obesity and Penicillin Dosage
To the Editor.—
I enjoyed the supplement to Pediatrics (1996;97:945–998) con-cerning group A streptococcal infections. In a “Review of the Rationale and Advantages of Various Mixtures of Benthazine TABLE 2. Cumulative Percent of Deaths by Day of Life
#3 Days #4 Days #1 Week #2 Weeks
,750 g 43% 49% 62% 77%
750–999 g 42% 50% 58% 67%
1000–1499 g 79% 79% 86% 86%
TABLE 3. Risk of Subsequent Mortality for Infants Surviving at Day 4*
Odds Ratio Confidence Interval P Value
,750 g 26.7 7.6–94 0.0001
750–999 g 9.7 2.7–35.3 0.0005
SNAP3† 10–19 2.2 1.07–4.7 0.0315
SNAP3†.20 27.9 8.2–94 0.0001
Abbreviation: SNAP, Score for Neonatal Acute Physiology. Referent group infants 1000–1499 g with SNAP3,10 surviving.3 days. * Independent effect adjusted in multiple logistic model. † SNAP3: Score for Neonatal Acute Physiology measured on day 3 of life.
Penicillin G,” Dr Bass concludes that the combination of 900 000 units of benzathine penicillin G plus 300 000 units of procaine penicillin offers optimal parenteral treatment for streptococcal pharyngitis in all children who weigh ,140 lb. Does Dr Bass reconcile this recommendation with the 1994 “Report of the Com-mittee on Infectious Diseases” of the American Academy of Pedi-atrics, which on page 435 states, “Although supporting data are limited, the combination of 900 000 units benzathine penicillin G and 300 000 units of procaine penicillin G will satisfactorily be used for children who weigh,60 lb.” In review of this recom-mendation, much to the distress of my plumper patients, I have returned to using 1.2 million units of benzathine penicillin G as a single intramuscular shot. Thank you for reviewing this contra-diction.
Gary Preiser, MD, FAAP
Departments of Pediatrics and Adolescent Medicine Delaware Valley Hospital Health Centers
Walton, NY 13856
In Reply.—
Dr Preiser has observed a discrepancy between what is consid-ered the upper weight limit for children (up to 140 lb, or 64 kg, in my article)1who are treated with the combination of 900 000 units
of benzathine penicillin G (BPG) plus 300 000 units of procaine penicillin G (PPG) intramuscularly for group A beta-hemolytic streptococci (GABHS) and the figure of 60 lb, or 27 kg, according to the current American Academy of Pediatrics Red Book Report of the Committee on Infectious Diseases.2I will try to resolve this
discrepancy.
From the 1950s well into the 1970s intramuscular BPG was the “standard of care for treatment of streptococcal pharyngitis.” To help reduce the incidence of pain and tenderness around the site of injection, a combination of BPG and PPG was developed. The only combination that was available from the 1950s through the mid-1970s was 600 000 units of BPG with 600 000 units of PPG in a 2-mL injection. The 600 000 units of BPG had been shown to be adequate for treatment of children up to 60 lb but with a 2-mL volume limit, this left no BPG/PPG-containing combination for older, heavier children. These studies were reviewed in my report1
cited by Dr Preiser.
In a statement by the American Heart Association in 1972 on the treatment of streptococcal pharyngitis in children, 600 000 units of BPG was recommended for children up to 60 lb, and 900 000 units for children of all ages.3In the 1970 Red Book, 600 000
units of BPG was likewise recommended for children up to 60 lb, but 900 000 to 1.2 million units was recommended for children weighing more.4With these recommendations in mind a
combi-nation of 900 000 units of BPG with 300 000 units of PPG in a single 2-mL injection should suffice for treatment of streptococcal phar-yngitis in children of all ages, and the pain and untoward reac-tions seen with BPG could be reduced to no more than that seen with PPG alone.
These statements by two authoritative sources prompted our group to investigate such a product in the early 1970s. As detailed in the original report in 19765and in my recent review1of 400
children with acute GABHS pharyngitis, 100 each received by randomization one of four BPG regimens: 600 000 units BPG in 1 mL, 1.2 million units BPG in 2 mL, 600 000 units BPG plus 600 000 units PPG in 2 mL, and 900 000 units BPG plus 300 000 units PPG in 2 mL. Our findings supported the following conclusions. The investigational product (900 000 units BPG plus 300 000 units PPG) effected a cure rate equal to 1.2 million units of BPG alone and was significantly superior to that achieved with 600 000 units of BPG alone. Although the formulations including the procaine component did not hasten resolution of signs and symptoms compared with the BPG component alone, the two formulations of BPG plus PPG did clear the throat of streptococci more rapidly (48 hours vs 72 hours) and decreased the incidence and severity of reaction at the injection site. In 49 children with documented GABHS pharyngitis who received the investigational product, serum penicillin levels were measured. The mean 10-day level was 0.038 units/mL; this concentration was four times the mean and five times the median minimal inhibitory (MIC) concentration of 204 strains of GABHS that were isolated from the study patients. We concluded that the 900 000-unit BPG/300 000-unit PPG
com-bination fulfilled the recommendation of the American Heart As-sociation for the treatment of streptococcal pharyngitis in children. On the basis of these studies and findings, this product was licensed for this purpose in 1976.
In another study utilizing this product, published in 1982,613
children ages 1.8 to 10.7 years and weighing an average of 36.5 lb (16.6 kg) demonstrated 10-day serum levels of penicillin similar to those observed in our study.
Neither authority cites reference data to document the change in their recommendation, with 900 000 units of BPG no longer listed as an option for treatment of children with streptococcal pharyngitis for any weight above 60 lb.
Previous recommendations and study data mentioned the 140-lb upper limit of weight, with the 900 unit BPG/300 000-unit PPG formulation providing adequate treatment for children with streptococcal pharyngitis. The approved package insert for this product indicates usage for treatment of streptococcal phar-yngitis in children of all ages.7With childhood defined as birth to
onset of puberty, the overwhelming majority of prepubertal chil-dren weigh,100 lb (45 kg). Regarding older, heavier children, the package insert observes that individuals weighing 100 to 140 lb (45– 64 kg) have mean blood levels of penicillin of 0.24, 0.039, and 0.024 units/mL at 24 hours and 7 and 10 days, respectively, after receiving an injection of this product. The mean 10-day level of 0.024 units/mL and the mean 10-day level of 0.038 units/mL in our study patients are both significantly above the MIC of all 303 isolates of GABHS reported in 1965,8204 isolates from our study
in the 1970s,5and 474 isolates in a more recent study published in
1981.9 This exquisite susceptibility of GABHS to penicillin has
remained constant with no evidence of emerging resistance after 50 years of use of this drug for treatment of infections caused by this organism.10Finally, these penicillin blood levels achieved in
individuals who weigh 100 to 140 lb are comparable to those achieved in adults who receive 1.2 million units of BPG alone.11
In conclusion, the 900 000-unit BPG/300 000-unit PPG 2-mL injection offers optimal injection treatment for all children with streptococcal pharyngitis with the exceptions of those weighing greater than 140 lb (64 kg). Heavier children (such as teenagers) and adults require 1.2 million units of BPG. The 900 000-unit BPG/300 000-unit PPG 2-mL injection has never been recom-mended for treatment of adults with streptococcal pharyngitis, or for the monthly prophylaxis of rheumatic heart disease.
James W. Bass, MD, COL, MC
Pediatrics/Pediatric Infectious Diseases Department of Pediatrics
Tripler Army Medical Center Honolulu, HI 96959-5000
REFERENCES
1. American Academy of Pediatrics, Committee on Infectious Diseases.
Red Book: Report of the Committee on Infectious Diseases. 23rd ed. Elk Grove
Village, IL: American Academy of Pediatrics; 1994
2. Bass JW. A review of the rational and advantages of various mixtures of benzathine penicillin G. Pediatrics. 1995;97(suppl):960 –963
3. Rheumatic Fever Committee of the Council on Rheumatic Fever and Congenital Heart Disease of the American Heart Association. Statement (Circular). Dallas, TX: American Heart Association; 1972
4. American Academy of Pediatrics, Committee on Infectious Diseases.
Red Book: Report of the Committee on Infectious Diseases. 16th ed. Evanston,
IL: American Academy of Pediatrics; 1970
5. Bass JW, Crast FW, Knowles R, Onufer CN. Streptococcal pharyngitis in children: a comparison of four treatment schedules with intramuscular benzathine penicillin G. JAMA. 1976;235:1112–1116
6. Ginsburg CM, McCracken JH Jr, Zweighaft TC. Serum penicillin con-centrations after intramuscular administration of benzathine penicillin G in children. Pediatrics. 1982;69:452– 454
7. Medical Economics Company, Inc. Physicians’ Desk Reference. 49th ed. Montvale, NJ: Medical Economics Data, Division of Medical Economics Company Inc; 1995:2652
8. Eickoff TC, Finland M. In vitro susceptibility of group beta-hemolytic streptococci to 18 antibiotics. Am J Med Sci. 1965;248:261–268 9. Istre GR, Welch DF, Marks MI, Moyer N. Susceptibility of group A
beta-hemolytic streptococcus isolates to penicillin and erythromycin.
Antimicrob Agents Chemother. 1981;20:244 –246
10. Bass JW. Treatment of streptococcal pharyngitis resisted. JAMA. 1986; 256:740 –743
LETTERS TO THE EDITOR 755
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11. Wright WW, Welch H, Wilner J, Robert EF. Body fluid concentrations of penicillin following intramuscular injection of a single dose of benza-thine penicillin G and/or procaine penicillin G. Antibiot Med Clin Ther. 1959;6:232–241
Pulmonary Alveolar Proteinosis
To the Editor.—
I wish to congratulate Dr Mahut and colleagues1 for their
excellent review. The authors report the necessity to use extracor-poreal oxygenation to perform successful massive lung lavage in infants.
My colleagues and I have successfully used total lung lavage in infants and pediatric patients with pulmonary alveolar proteino-sis.2–5Two unrelated infants experienced symptoms at 1 month of
age, and at 7 months diagnosis of pulmonary alveolar proteinosis was made. Before lavage our patients weighed only 5 kg and manifested severe hypoxemia.
At 9 months of age both infants had successful total bilateral lung lavage using the single lumen endotracheal tube technique.6,7
A brief description of this technique follows: In a hyperbaric chamber with ketamine anesthesia and Pancuronium, a 4-mm uncuffed nasotracheal tube was secured in horizontal left lateral decubitus position. The lavage was performed by repeat infusion and drainage of 30-mL tidal volume of saline during apnea, fol-lowed by ventilation of both lungs with oxygen. Apnea never exceeded 1 minute and ventilation was at least 2 minutes. The patient was then placed in a supine position and both lungs were ventilated with 100% oxygen. Subsequently, the patient was se-cured in a horizontal right lateral decubitus position and the lavage procedure was repeated. Lavage was discontinued when the effluent was clear or when the residual fluid was equal to the total lung capacity of the lavaged lung. Using a volume of 1500 mL of saline, the procedure was completed in 3 hours. Hyperbaric
conditions prevented serious hypoxemia during the therapeutic lung lavage.
The infants tolerated the initial and repeat lavages without sequelae and are living and well at age 14 and 21 years. The first patient treated with this procedure at age 8 is currently asymp-tomatic at age 30 years. Under hyperbaric conditions the single lumen endotracheal lung lavage technique obviates the need for extracorporeal oxygenation and provides a safe and effective mode of therapy for the infants and perhaps the newborn with pulmonary alveolar proteinosis.
Alexander Spock, MD Department of Pediatrics Duke University Medical Center Durham, NC 27710
REFERENCES
1. Mahut B, Delacourt C, Scheinmann P, et al. Pulmonary alveolar proteinosis: experience with eight pediatric cases and a review.
Pediat-rics. 1996;97:117–122
2. Spock A, Lanning CF, Kylstra J. Lavage of both lungs of a nine month infant with alveolar proteinosis. Clin Res. 1977;25:84. Abstract 3. Spock A, Kylstra J, Lanning C, Comporersi E. Lung lavage in two
infants with alveolar proteinosis. Pediatr Res. 1983;17:390. Abstract 4. Kariman K, Spock A, Kylstra J. Pulmonary alveolar proteinosis:
pro-spective clinical experience in 23 patients for 15 years. Lung. 1984;162: 223–231
5. Spock A. Treatment of congenital alveolar proteinosis. J Pediatr. 1993; 123:495– 496
6. Muggenburg BA, Manderly JL. Lung lavage using a single-lumen en-dotracheal tube. J Appl Physiol. 1975;38:922–926
7. Spock A. State of the art of lung lavage in patients with cystic fibrosis. In: Warwick WJ, ed. 1,000 Years of Cystic Fibrosis. Minneapolis, MN: University of Minnesota Press; 1981:113–117
DOI: 10.1542/peds.99.5.754
1997;99;754
Pediatrics
Gary Preiser
Obesity and Penicillin Dosage
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DOI: 10.1542/peds.99.5.754
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