Letters to the Editor
Statements appearing here are those of the writers and do not represent the official position of the American Academy of Pediatrics, Inc. or its Committees. Comments on any topic, including the contents ofPediatrics,are invited from all members of the profession: those accepted for publication will not be subject to major editorial revision but generally must be no more than 400 words in length. The editors reserve the right to publish replies and may solicit responses from authors and others.
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Letters should be submitted in duplicate in double-spaced typing on plain white paper with name and address of sender(s) on the letter. Send them to Jerold F. Lucey, MD, Editor, Pediatrics Editorial Office, University of Vermont College of Medicine, 89 Beaumont Ave, Given Building, Room D201, Burlington, VT 05405-0068.
Respiratory Instability of Term and Near-Term
Healthy Newborn Infants in Car Safety Seats
To the Editor.—
The uncontrolled study by Merchant et al1raises disturbing questions. But contrary to what the authors state in the abstract, their data does not support the current AAP recommendations that all infants who are born at⬍37 weeks’ gestation be observed for respiratory instability and secure fit in their car seats before hospital discharge. Oxygen desaturation occurred equally in the preterm and term infants, and without unrestrained controls ob-served for the same period of time, we don’t know if the brady-cardic events observed in the preterm infants were greater than expected.
Harry A. Ackley, MD Department of Pediatrics
University of California, San Francisco San Francisco, CA
REFERENCE
1. Merchant JR, Worma C, Porter S, Coleman JM, deRegnier R-AO. Respi-ratory instability of term and near-term infants in car safety seats. Pediatrics.2001;108:647– 652
In Reply.—
We appreciate Dr Ackley’s interest in our study.1The study’s purpose was to determine if the AAP recommendation, to perform a predischarge car seat evaluation on all premature infants⬍37 weeks, applies to healthy infants in a normal nursery setting.2The results of our study showed that a significant number of these minimally premature infants could not be securely positioned in their car seats, and that 12% of these infants had significant apnea and/or bradycardia that did not occur in the term infants. Oxygen desaturation occurred similarly in term and preterm infants. The incidence of abnormal events was similar to what has been neo-natal intensive care unit graduates.3–5These studies led the AAP to develop the current recommendations, and given that our study had similar findings, we concluded that preterm infants hospital-ized in normal newborn nurseries should also have a car seat evaluation.
The issue Dr Ackley raises, of whether the events are attribut-able to the positioning in the car seat, is a separate issue that was previously addressed by Willett and colleagues.3,4These authors demonstrated that the incidence of apnea and bradycardia was increased in the seated position compared with the recumbent position in convalescent premature infants. Our study was not intended to readdress the issue of the pathophysiology behind the events. The fact that episodes of apnea and/or bradycardia could have other causes (apnea of prematurity, severe gastroesophageal reflux) aside from those related to the seated position is not disputed and was addressed in the “Discussion” section of our article. As we also stated, if an infant from the newborn nursery experiences events in their car seat, our clinical practice is to place them in a car bed and continue monitoring for an additional
period of time. If events continue, the infant is admitted to the neonatal intensive care unit and additional evaluation is per-formed. If no additional events occur, the infant is discharged home with a car bed, as recommended by the AAP.1Given that the seated position appears to identify those infants with imma-ture control of breathing, a car seat evaluation appears to be the minimal respiratory evaluation that a healthy preterm infant should undergo before discharge from the hospital.
Jennifer Reetz Merchant, MD Mountain States Neonatology Neonatal Intensive Care Unit
St Alphonsus Regional Medical Center Boise, ID
Raye-Ann O. deRegnier, MD Associate Professor of Pediatrics
Northwestern University School of Medicine Chicago, IL
REFERENCES
1. Merchant JR, Worwa C, Porter S, Coleman JM, deRegnier R-AO. Respi-ratory instability of term and near-term infants in car safety seats. Pediatrics.2001;108:647– 652
2. American Academy of Pediatrics, Committee on Injury and Poison Prevention and Committee on Fetus and Newborn. Safe transportation of premature and low birth weight infants.Pediatrics.1996;97:758 –760 3. Willett LD, Leuschen P, Nelson LS, Nelson RM. Risk of hypoventilation
in premature infants in car seats.J Pediatr.1986;109:245–248 4. Willett LD, Leuschen P, Nelson LS, Nelson RM. Ventilatory changes in
convalescent infants positioned in car seats.J Pediatr.1989;15:451– 455 5. Bass JL, Mehta KA, Camara J. Monitoring premature infants in car seats:
implementing the American Academy of Pediatrics policy in a commu-nity hospital.Pediatrics.1993;91:1137–1141
CHOICE Study Group Trial
To the Editor.—
Oral rehydration therapy with the WHO formulation has saved millions of lives,1 but has yet to achieve universal acceptance because, although it performs the essential function of maintain-ing water and electrolyte balance durmaintain-ing acute watery diarrhea, it does not reduce diarrhea volume. It has been proposed that a lower osmolar formula might achieve this aim by substituting rice for glucose or reducing the concentrations of sodium and glucose.2 To that end, the CHOICE Study Group compared the WHO standard oral rehydration solution (311 mmol/L) with a reduced osmolar solution (245 mmol/L) to try and reduce stool output, vomiting, and the need to return to intravenous therapy (“un-scheduled”).3 Based on results from this and 14 other trials,4 recommendations may be offered either to stay with the standard formula worldwide or to propose changes.
The results from this double-blind study at 5 centers with a total of 675 children were unambiguous: scarcely a whisper of
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difference between study and control groups in stool output and duration or vomiting; and a marginally significant difference in the need for unscheduled intravenous therapy in the first 24 hours (34/341 and 50/334, odds ratio 0.6, confidence interval [0.4, 1.0]). Since the criterion for unscheduled IV was intended to be clinical observation of dehydration or failure to become rehydrated on oral rehydration salt (the actual observations leading to the clinical decisions were not presented), a shift in just 1 or 2 decisions in either direction would have negated the statistical significance. What was observedequallyin both groups, however, was a dou-bling of stool output in those requiring extra IV. This may be explained by transient glucose malabsorption, a well-known phe-nomenon in children with diarrhea,5and apparently not elimi-nated by the lower osmolar solution.
Another limitation of the CHOICE study was that it considered only a single episode of diarrhea per child, whereas an annual incidence in children under 2 years of age is likely to be 5 or more.6 Thus, a substantial concern arises with respect to sodium balance, not measured in any study of lower osmolar (and reduced so-dium) solutions to date: an ORS solution lower in sodium than the standard may lead to an accumulated sodium deficit, which would then prompt potassium loss via renal retention of sodium.5 In the CHOICE study, twice as many in the group receiving the reduced osmolar solution developed serious hyponatremia, less than 125 mmol/L (4%), compared to those receiving standard solution (2%), odds ratio 1.9, confidence interval (0.7, 5.6). One child in the former group had seizures. If a lower sodium formu-lation becomes the standard, then the treatment of millions of children could lead to an unacceptable number of such adverse reactions, with potential for permanent sequelae and increased fatalities. This would be especially likely to affect children with frequent episodes or high-output diarrhea from whatever cause, or with hyponatremia of malnutrition, that can be aggravated by hypoosmolar solutions used to treat the malnourished.7–11
From our reading of the data, we strongly recommend no change be made to the standard WHO formulation, a conclusion also reached by Fuchs.2
Norbert Hirschhorn, MD New Haven, CT 06510
David R. Nalin, MD West Chester, PA
Richard A. Cash, MD Cambridge, MA
REFERENCES
1. Victora CG, Bryce J, Fontaine O, Monasch R. Reducing deaths from diarrhoea through oral rehydration therapy. Bull WHO 2000;78: 1246 –1255
2. Fuchs G. A better oral rehydration solution? An important step, but not a leap forward.BMJ.2001;323:59 – 60
3. CHOICE Study Group. Multicenter, randomized, double-blind clinical trial to evaluate the efficacy and safety of a reduced osmolarity oral rehydration salts solution in children with acute watery diarrhea. Pedi-atrics.2001;107:613– 618
4. Hahn S, YaeJean K, Garner P. Reduced osmolarity oral rehydration solution for treating dehydration due to diarrhoea in children: system-atic review.BMJ.2001;323:81– 85
5. Hirschhorn N. The treatment of acute diarrhea in children. An historical and physiological perspective.Am J Clin Nutr.1980;33:637– 663 6. Miller P, Hirschhorn N. The effect of a national control of diarrheal
diseases program on mortality: the case of Egypt.Soc Sci Med.1995;40: S1–S30
7. Uysal G, Sokmen A, Vidinlisan S. Clinical risk factors for fatal diarrhea in hospitalized children.Indian J Pediatr.2000;67:329 –333
8. Nagpal A, Aneja S. Oral rehydration therapy in severely malnourished children with diarrheal dehydration.Indian J Pediatr.1992;59:313–319 9. Glaser GH. Neurologic symptoms with electrolyte and water
imbal-ance.Postgrad Med.1971;50:170 –175
10. Goulon M, Babinet P, Raphael JC, Grosbuis S, Gajdos P. Les manifes-tations neurologiques des hyponatremies.Rev Neurol (Paris).1971;125: 219 –237
11. Samadi AR, Wahed MA, Islam MR, Ahmed SM. Consequences of hyponatremia and hypernatremia in children with acute diarrhea in Bangladesh.BMJ (Clin Res Ed.)1983;286:671– 673
In Reply.—
Drs Hirschorn, Nalin, and Cash, noted pioneers in oral rehy-dration salt (ORS) research, question the significance of our find-ing of reduced need for unscheduled intravenous (IV) fluids, express concern about the possibility of chronic sodium deficits, and raise the question of whether the findings from the CHOICE trial provide adequate justification for changing the composition of WHO ORS.
The need for unscheduled IV therapy was defined as the clin-ical requirement for IV infusion after oral rehydration had been started. This outcome is based on clinical judgment and represents failure of oral treatment either to correct dehydration or to main-tain hydration. The criteria used in the trial for instituting un-scheduled IV fluids were agreed on in a protocol development workshop, validated in an exercise there, and adhered to through-out the trial, as noted by repeated exercises and site monitoring visits. In many diarrhea treatment sites in developing countries, IV therapy is not readily available, so reducing the need for unsched-uled IV therapy means reducing the risk of death from dehydra-tion. The finding of a 33% reduction in IV fluid use, therefore, has significant health and economic implications for areas of the world where the majority of diarrheal deaths occur, and has been con-firmed in several other trials of reduced osmolarity ORS.1–3 Al-though it is true that our trial did not find a significant difference in stool output between the study groups, a recent meta-analysis did find that reduced osmolarity ORS was associated with a significant reduction in stool output and vomiting.4Clearly, the published data support a record of improved efficacy of this solution for children.
Although nonsignificant increased rates of hyponatremia were seen in children receiving the reduced osmolarity ORS, the clinical significance of these results is unclear. The mean (standard devi-ation) serum sodium concentration at 24 hours was 1376mEq/L in the WHO group and 1366in patients receiving reduced osmolarity ORS (NS). One of the participants in the reduced osmolarity group did have a brief generalized seizure, but he also had a fever. No other symptoms of hyponatremia were noted. In addition, the 24-hour serum potassium concentration were 3.9 (0.8) mEq/L in the WHO ORS group and 4.0 (0.7) in the reduced osmolarity group. These data do not support the concerns of hypokalemia expressed by Hirschhorn et al.
In a previous trial of reduced osmolarity ORS in adult patients with cholera infection,5no patients were noted to have symptoms of hyponatremia. Although cholera stool sodium losses can be as high as 120 to 150 mEq/L, it should be noted that even the current formulation of WHO ORS contains less sodium than may be needed to prevent negative sodium balance. Patients with diar-rhea should continue to receive food during their oral therapy, so it seems likely that they will receive sodium from sources other than ORS.
Whether a change in the formulation of ORS should be under-taken should not depend solely on the results of the CHOICE study or for that matter any single study. An evaluation of the risks and benefits of a prospective change in ORS composition, the desire to promote and distribute a single solution for worldwide use, and the analysis of economic, cultural as well as health variables should be undertaken. The WHO and UNICEF began this process this summer with an expert consultation on ORS formulation, and the recommendations of this meeting will be forthcoming.
Shinijini Bhatnagar, MD
Centre for Diarrheal Diseases and Nutrition Research Department of Paediatrics
All India Institute od Medical Sciences Ansari Nagar, New Delhi—110 029, India
Olivier Fontaine, MD
Division of Child Health and Development World Health Organization
Geneva, Switzerland
Christopher Duggan, MD, MPH Children’s Hospital
Harvard Medical School Boston, MA
REFERENCES
1. Santosham M, Fayad I, Abu Zikri M, et al. A double-blind clinical trial comparing World Health Organization oral rehydration solution with a reduced osmolarity solution containing equal amounts of sodium and glucose.J Pediatr.1996;128:45–51
2. International Study Group on Reduced-Osmolarity ORS Solutions. Multicentre evaluation of reduced-osmolarity oral rehydration salts solution.Lancet.1995;345:282–285
3. Bernal C, Velaquez C, Garcia G, Uribe G, Palacio C. Oral hydration with a low osmolarity solution in children dehydrated by diarrhetic diseases. Saludarte.2000;1:6 –23
4. Hahn S, Kim Y, Garner P. Reduced osmolarity oral rehydration solution for treating dehydration due to diarrhoea in children: systematic re-view.BMJ.2001;323:81– 85
5. Alam NH, Majumder FN, Fuchs GJ, CHOICE Study Group. Efficacy and safety of oral rehydration solution with reduced osmolarity in adults with cholera: a randomised double-blind clinical trial.Lancet. 1999;354:296 –299
Role of Carbon Monoxide and Nitric Oxide in
Newborn Infants With Postasphyxial
Hypoxic-Ischemic Encephalopathy
To the Editor.—
We read with interest the recent article by Shi et al.1However, we believe that any conclusions drawn from the report, as well as from an earlier study,2must be interpreted with caution.
The authors found plasma carbon monoxide (CO) concentra-tions ranging from 53 to 140mol/L (Tables 2 and 3), which are theoretically impossible. Furthermore, the error appeared to have originated in their methodology, which is based on a previously published method.3
Because the solubility of CO in water is directly proportional in the CO concentration in the gas phase at a given temperature and pressure, one can calculate the volume of CO in plasma water using the following physical relationships. The solubility of pure CO (106L/L) at one atmosphere of pressure in water is 18.3 mL/L at 37°C.4 Furthermore, the volume of CO dissolved in plasma water (“x”L/L) is in equilibrium with lung air, which contains approximately 2 L CO/L as measured in end-tidal breath from neonates.5 Thus, in a neonate at steady state, the highest concentration that should be measurable (ignoring the affinity of hemoglobin towards CO) is:
18.3 mL CO/L water 106gL CO/L CO ⫽
“x”mL CO/L plasma 2L CO/L breath
or “x” mL CO/L plasma⫽2L CO/L breath106L CO/LCO⫻18.3 mL CO/L water
or 36.6⫻10⫺6mL CO/L water or 36.6 nL/L water
Finally, at 22.4 nL/nmol, this translates to 1.6 nmol CO/L plasma. Similar concentrations (2 to 10 nmol/L) in equilibrium with 0.87 to 3.8% carboxyhemoglobin (COHb) have been reported earlier for extravascular CO in humans6and ocean water in equilibrium with ambient CO.7Thus, the plasma CO concentrations reported by Shi are approximately 104- to 105-fold too high.
These high values could be possibly attributable to an invisible degree of plasma contamination with hemolyzed blood. Indeed, most of the blood’s CO (approximately 1.8 mL/L or 80M) is transported in the red blood cells (RBCs) as COHb.8This CO concentration in blood is, however, within the range of plasma concentrations reported by Shi et al. Thus RBC-derived CO from minimal hemolysis cannot account for the measured plasma CO concentrations.
Furthermore, using a sensitive (1 pmol CO) gas chromato-graphic method8, we also have attempted to quantitate CO con-centrations in fresh plasma from normal humans and in mice with COHb levels of 10% and found⬍1 pmol CO per 40L plasma or ⬍25 mmol/L in both instances.
We concluded that a methodologic error must be responsible for the overestimation. Shi et al used a previously reported method of Chalmers,3who hypothesized that unbound CO, rather than COHb, is responsible for the toxic effects of CO. The principle
of the method entailed trapping plasma CO with hemoglobin to form COHb, which is then measured spectrophotometrically after reduction with dithionite. Using this method, Chalmers reported finding a mean plasma CO reference value for males and females of 0.36 mg/L. This translates to 12 857 nmol CO/L [(0.36⫻106 ng/L) (nmol/ 23 ng)], again some 103- to 104-fold greater than the calculated maximum possible concentration. Curiously, in two lines on page 1444, right-hand column, Chalmers referred to find-ing plasma CO concentrations of “0.36 mg/L or 13 nmol/L.” These CO concentrations are not equivalent, and the latter, but not the former, value is relatively close to the theoretical solubility of CO in water. Thus, we assume that an incorrect conversion of CO concentration units was the major source of error. Fundamental to Chalmers’ method and physiologic reality is the simple, but per-tinent question, of how plasma in equilibrium with hemoglobin-loaded RBCs, could release any CO into the assay medium, which contains a 20-fold lower hemoglobin concentration. Interestingly, Chalmers also observed that the reported plasma CO concentra-tions were markedly in excess of what would be predicted from the measured COHb concentrations in the same subjects. This statement indicates that Chalmers recognized the existence of a problem, but was not able to resolve the discrepancy. Clearly, more rigorous work is needed to validate this method.
Hendrik J. Vreman, PhD Ronald J. Wong, MD David K. Stevenson, MD
Divison of Neonatal and Developmental Medicine Department of Pediatrics
Stanford University School of Medicine Stanford, CA 94305-5208
Rolf R. Engel, MD
Department of Perinatal Pediatrics Hennepin County Medical Center Minneapolis, MN 55415
REFERENCES
1. Shi Y, Pan F, Li H, et al. Role of carbon monoxide and nitric oxide in newborn infants with postasphyxial hypoxic-ischemic encephalopathy. Pediatrics.2000;106:1447–1451
2. Shi Y, Pan F, Li H, et al. Plasma carbon monoxide levels in term newborn infants with sepsis.Biol Neonate.2000;78:230 –232
3. Chalmers AH. Simple, sensitive measurement of carbon monoxide in plasma.Clin Chem.1991;37:1442–1445
4. Kimmel EC, Caprenter RL, Reboulet JE, Still KR. A physiological model for predicting carboxyhemoglobin formation from exposure to carbon monoxide in rats.J Appl Physiol.1999;86:1977–1893
5. Vreman HJ, Baxter LM, Stone RT, Stevenson DK. Evaluation of a fully automated end-tidal carbon monoxide instrument for breath analysis. Clin Chem.1996;52:50 –56
6. US Environmental Protection Agency. Air Quality Criteria for Carbon Monoxide. Research Triangle Park, NC: Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Office of Research and Development, US Environmental Protection Agency; 2000;5–16
7. Swinnerton JW, Linnenbom VJ, Lamontagne RA. The ocean: a natural source of carbon monoxide.Science.1970;167:984 –986
8. Vreman HJ, Kwong LK, Stevenson DK. Carbon monoxide in blood: an improved microliter blood sample collection system, with rapid analy-sis by gas chromatography.Clin Chem.1984;30:1382–1386
In Reply.—
We thank Vreman et al for their letter about our article. Because of the increasing interest in the role of endogenously produced carbon monoxide (CO), some basic problems, especially the assay for CO levels in the blood, should be discussed and solved.
In our article, we used a simple method described by Chalm-ers.1There was an incorrect conversion of CO concentration units in the assay based on the previously published article. The error was on page 1448, left-hand column. The right CO concentration in x mL of the sample should be given:
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DOI: 10.1542/peds.109.4.713-a
2002;109;713
Pediatrics
Norbert Hirschhorn, David R. Nalin and Richard A. Cash
CHOICE Study Group Trial
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DOI: 10.1542/peds.109.4.713-a
2002;109;713
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Norbert Hirschhorn, David R. Nalin and Richard A. Cash
CHOICE Study Group Trial
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