american academy of pediatrics · ally related to the sudden cessation of the total parenteral...

PEDIATRICS (ISSN 0031 4005). Copyright © 1983 by the

American Academy of Pediatrics.

PEDIATRICS Vol. 71 No. 4 April 1983 547

AMERICAN ACADEMY OF PEDIATRICS

Committee on Nutrition

Commentary on Parenteral Nutrition

Clinical experience has demonstrated the value

of optimal nutritional status in resisting the effects

of trauma and disease as well as in improving

response to medical and surgical therapy. The met-

abolic demands of rapid growth and the low nutri-

tional reserves in infancy make the potential ben-

efit of good nutrition to critically ill pediatric pa-

tients even greater.

This statement is not meant to be a comprehen-

sive review of parenteral nutrition nor a guideline

for specific techniques. It is intended to provide an

update on the “state of the art” of parenteral ali-

mentation. Details concerning the physiology, tech-

niques for approach, and efficacy of parenteral nu-

trition are given elsewhere.”2

In spite of the many formulas and feeding tech-

niques available, several gastrointestinal and med-

ical problems arise in infants that preclude or se-

verely limit the use of the intestine for nutritional

support. Since the first successful use of total par-

enteral nutrition in a malnourished infant in 1944,

the use of total or supplemental parenteral nutri-

tion has become a common practice. Premature

infants with severe respiratory disease, congenital

anomalies of the gastrointestinal tract, or inflam-

matory disease of the intestinal mucosa (necrotiz-

ing enterocolitis) are frequently candidates for this

form of nutritional support. Older infants with

intractable diarrhea, short bowel syndrome, severe

malnutrition, or inflammatory bowel disease also

have been successfully rehabilitated with parenteral

feedings. Extensive body surface burns, malignan-

cies, cardiac failure, and renal failure are examples

of disorders outside the gastrointestinal tract in

which parenteral nutritional support has been use-

ful. Specific formulations and procedures are avail-

able for these latter situations and have been re-

viewed elsewhere.3

In certain settings, particularly larger hospitals

with increased numbers of more complicated pa-

tients receiving parenteral nutrition, a nutritional

support team may be beneficial in providing opti-

mal care. An interdisciplinary team consisting of

medical, nursing, dietary, pharmacy, and surgicalstaff with expertise in parenteral nutrition provides

invaluable consultative services in the management

of these patients.

CATHETERS

Parenteral nutrition can be carried out via pe-

ripheral veins using standard peripheral intrave-

nous catheters and solutions with an osmolarity of

300 to 900 mosm/L. When solutions of higher Os-

molarity are used, larger veins with a high blood

flow volume must be used to avoid sclerosis and

inflammation of the wall of the vein.

Strict asepsis is always mandatory during cathe-

ter placement. The catheters are made of a flexible

material such as silicone elastomer, polyurethane,

or stiffer polyethylene. They are generally placed,

under anesthesia, in the subclavian or internal jug-

ular vein and advanced toward the right atrium.

Certain of these catheters can be introduced per-

cutaneously into the subclavian vein. The more

flexible catheters must be introduced through a

hollow needle, or be placed by incising the skin and

subcutaneous tissue to expose the vein or by cre-

ating a subcutaneous tunnel into a superficial neck

vein and advancing the catheter toward the right

atrium. The placement of flexible catheters in the

premature infant has a lower incidence of vein

perforation and thrombosis.4 On occasion when

jugular or subclavian sites have been unavailable,

veins that run toward the inferior vena cava, such

as the inferior epigastric veins, are alternate

choices.5 Regardless of the site, roentgenographic

confirmation of the intravascular placement of the

catheter is mandatory before parenteral nutrition

solutions are infused.

A number of complications that are directly re-lated to the catheter may occur. Malposition of a

central venous catheter outside the vein, with in-

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548 PARENTERAL NUTRITION

fusion of hypertonic solutions into the pleural or

pericardial space, may be life threatening. A rapiddecrease in serum glucose or the acute onset of

circulatory or respiratory compromise should signalthis complication. Hemorrhage, associated with

erosion of central veins or of the wall of the right

atrium, also has been reported. Pneumothorax and

brachial plexus injuries are relatively common com-

plications of percutaneous subclavian line inser-

tion. Air embolus may occur. Air-eliminating filters

and properly secured tubing junctions may helpprevent this. Catheter emboli have occurred from

rupture of silicone elastomer catheters perfused

under extremely high pressures or from the tips ofpolyethylene catheters sheared off when the cath-

eter was pulled back through the hub of the needle

used to insert it. Thrombophlebitis may be observed

in peripheral veins receiving hypertonic solutions.

Skin slough is a rare but serious complication of

extravasation of the parenteral solution into the

interstitial space.A major complication is catheter-related sepsis.

Fever alone is not an indication for removal of aparenteral nutrition catheter. Other sources of in-

fection should be searched for; if none are found,removal of the catheter should then be considered.Signs of sepsis in the neonate include lethargy,hyperbilirubinemia, temperature instability, and

intolerance to previously tolerated glucose and lipid

loads. Careful placement of the central catheter andstrict adherence to established guidelines for cath-

eter care and maintenance considerably decrease

the incidence of catheter-related complications.

Metabolic complications caused by the composi-tion and administration of the infusate will beconsidered as the various caloric sources are dis-cussed. A suggested schedule for monitoring par-

enteral nutrition is shown in Table 1.

COMPOSITION OF SOLUTIONS FOR INFANTS

AND CHILDREN

Protein

Current solutions supply nitrogen requirementsas crystalline amino acids. Infants have demon-

strated adequate growth with this source of protein.

Commercial preparations are available as concen-trated 3.5% to 10% mixtures of crystalline amino

acids which can be diluted to meet nutritional re-

quirements of infants at different ages.6 None ofthe solutions available in the United States has a

composition that is qualitatively identical with thatof the amino acid composition of breast milk, whichhas been used as the standard for the formulation

of enteral mixtures promoting optimal growth in

healthy infants.7 Also, the commercial solutions do

TABLE 1. Suggested Monitoring Schedule DuringTotal Parenteral Nutrition*

Variable Monitored Suggested

Initial

Frequency

Later

Periodt Periods

3-4 times/wk 2-3 times/wk

3 times/wk 2 times/wk3 times/wk 2 times/wk

§ §

3-4 times/wk 2-3 times/wk

2 times/wk WeeklyWeekly Weekly

Weekly Weekly

2 times/wk 2 times/wkDaily DailyDaily Daily

As indicated As indicated



Serum electrolytes

Serum urea nitrogenSerum calcium, mag-

nesium, phosphorusSerum glucoseSerum acid-base sta-

tusSerum ammoniaSerum protein (elec-

trophoresis or albu-

mm/globulin)Liver function studiesHemoglobinUrine glucoseClinical observations

(activity, tempera-ture, etc)

WBC count and dif-ferential count

CulturesSerum triglyceride

* Adapted from Heird.2#{176}

t Initial period is period before full glucose intake isachieved, or any period of metabolic instability.:1:Later period is period during which patient is in ametabolic steady state.§ Blood glucose should be monitored closely during periodof glucosuria (to determine degree of hyperglycemia) andfor two to three days after cessation of parenteral nutri-tion (to detect hypoglycemia). In latter instance, frequentDextrostix determination constitutes adequate screening.

not contain cysteine, although separate prepara-

tions of cysteine, which can be added to the solu-

tions, are available. Cysteine may be an essential

amino acid in premature infants with low activity

of hepatic cystathionase, which converts methio-

nine to cysteine.8 Taurine, which is formed from

cysteine and is present in human milk, may also be

important for these premature infants and is absent

from commercial solutions. None of the available

solutions contains carnitine, which is required for

the optimal oxidation of fatty acids.9

In spite of the recently recognized potential de-

ficiencies, infants have tolerated the available so-

lutions and have grown well while using them. Most

metabolic complications related to amino acids in

the solutions, including azotemia and acidosis, have

occurred when the infants received more than 4 g/

kg/d ofprotein equivalent. Complications are rarely

encountered with the recommended intake of 2 to

3 g/kg/d of protein equivalent. Hyperammonemia,

seen with earlier solutions, now rarely occurs with

the increased amounts of arginine and decreased

quantities of glycine in the formulations. Hyper-

chloremic metabolic acidosis, another problem


AMERICAN ACADEMY OF PEDIATRICS 549

noted with earlier crystalline amino acid solu-

tions,1#{176}has been ameliorated by the substitution of

acetate for chloride in the salts of lysine and theuse of basic salts of histidine.

Carbohydrate

Glucose (dextrose), fructose, galactose, sorbitol,

glycerol, and ethanol all have been used as a source

of carbohydrate calories in infants. Presently,

nearly all centers use glucose as the principal car-

bohydrate. A small amount of glycerol present inlipid solutions contributes to carbohydrate calories.

The other carbohydrate sources have fallen out of

favor because they have no advantage over glucose

and can produce serious complications in prema-

ture infants.

The quantity of glucose in the infusate that pre-

mature infants will tolerate is variable. Infusing

glucose at 5 mg/kg/mm and advancing to 15 mgI

kg/mm over a two-day period may reduce the in-

tolerance seen when large amounts of glucose are

infused initially. This is accomplished by increasing

the concentration of glucose in the solution while

keeping the volume of infusate constant at between

100 to 150 mL/kg/d, depending on the infant’s fluid

requirements. A suggested protocol to gradually

increase the amount of glucose given the infant is

shown in Table 2. Acute consequences of glucose

intolerance are serum hyperosmolarity and osmoticdiuresis. Both of these situations can be avoided by

careful serum monitoring. Hypoglycemia is gener-

ally related to the sudden cessation of the total

parenteral nutrition solution. In adult postsurgical

patients, there appears to be no correlation between

glucose clearance and the rate of oxidation of glu-

cose.’1 An increase in the glucose infusion rate from

4 to 7 mg/kg/mm is associated with an increased

rate of glucose oxidation; but, at higher infusion

rates, fat is synthesized from the glucose without a

further increase in glucose oxidation or energy de-

rived therefrom. Although similar studies have not

been completed in infants, this suggests that higher

glucose loads delivered by solutions containing

more than 20% glucose at 150 mL/kg/d may not be

beneficial to infants and may contribute to the fatty

infiltration of the liver seen with prolonged paren-

teral nutrition. The use of added insulin is difficult

because of unpredictable responses to this hormone.

Lipids

The composition, use, and complications of in-travenously infused fat emulsions have been dis-

cussed.’2 Briefly, in addition to being a concen-

trated source of energy and providing essential fatty

acids, parenteral lipid solutions are iso-osmolar.

TABLE 2. Suggested Protocol for a 3-Kilogram Infanton Central Parenteral Nutrition*

Catheter is placed in central vein and dextrose 5% in water isinfused following roentgenographic confirmation that catheteris in proper position.

Formulation Volume Calories! Calories!(mL/kg/d) 24 h kg/d

Pediatric 10% dex- 100 126 42trose solution (122)t (40.6)

Pediatric 10% dex- 150 189 63trose solution (153) (51)

Pediatric solution 150 266 89

15% dextrose (230) (77)(central)

Pediatric solution 150 342 11420% dextrose (306) (102)

(central)Pediatric solution 150 419 140

25% dextrose (383) (128)(central)

* From Pediatric Parenteral Nutrition Manual.” If glu-

cose intolerance develops: (1) the rate of infusion can belowered, then increased slowly over several hours; (2)intravenous fat emulsion can be started. Ten percent fatemulsion supplies 1.1 kcal/mL (0.122 g/mL) and willallow use of lower glucose loads while maintaining ade-quate fluid volumes. Fat emulsion contains 87% wt/volwater, and this should be counted in total daily fluidintake. Twenty percent fat emulsion provides 0.222 g fatper milliliter, 2 kcal/mL, and is 77% wt/vol ofwater (20%fat emulsions should be used with care). Note: Beginintravenous fat emulsion at 0.5 g/kg/d, given over 20 to

24 hours, and increase volume over 96 hours to a maxi-mum of 4 g/kg/d or 45% of total calories, whichever is

reached first. Essential fatty acid requirements can bemet by 0.5 g/kg/d once to twice a week. All caloriccalculations use 3.4 calories/g of intravenous dextrose,due to water of hydration. Weight gain of more than 50g/d more likely represents edema than cell growth andsuggests need for a more concentrated solution to provideadequate calories while limiting fluid intake.t Values in parentheses are nonprotein calories.

When lipid and amino acid-glucose solutions are

infused simultaneously into the same vein, the pa-

tient receives a higher calorie, lower osmolar solu-

tion than with a glucose-amino acid solution alone.

The use of “Y” connector tubing proximal to the

Micropore filter to infuse lipids simultaneously

with, but separately from, the glucose-amino acid

solution (containing vitamins, minerals, electro-

lytes, and trace elements) has greatly improved theeffectiveness of peripheral intravenous nutrition’3

and increased its use substantially in nutritional

support.

The requirement for linoleic acid (essential fatty

acid requirement) can be achieved by supplying 0.5

to 1 g/kg/d of intravenous lipid. Premature infants

have adequate lipoprotein lipase to metabolize

serum triglyceride concentrations of 100 mg/dL.

When triglyceride levels exceed 100 mg/dL, depo-sition of lipid may occur in reticuloendothelial cells



or along vascular endothelial surfaces. The easierways of determining lipid tolerance, visual inspec-

tion and nephelometry, correlate well with serum

chylomicron concentration, but do not correlatewell with the glyceride or free fatty acid concentra-

tions. Unfortunately, the latter chemical determi-

nations are costly, require relatively large volumesof blood, or may not be readily available. The slow(20 to 24 hours) infusion of up to 4 g/kg/d of

intravenous lipid should minimize the chances of

lipid intolerance. Under certain circumstances (eg,sepsis, hyperbilirubinemia, pulmonary hyperten-

sion), the lowest dose that meets essential fatty acid

requirements should be used.

Vitamins, Minerals, and Trace Elements

Vitamins, minerals, and trace elements must be

supplied in parenteral solutions. Metabolic compli-

cations have been described for deficiencies andexcesses of some of these nutrients. Intravenousdose requirements are not fully known. Current

recommendations are derived from oral require-ments and knowledge of enteric absorption. Sug-

gested amounts for use in parenteral alimentation

solutions are given in Table 3. Guidelines for mul-

tivitamin and essential trace element preparations

for parenteral use have been established.’4”5

GASTROINTESTINAL EFFECTS OFPARENTERAL NUTRITION

The single most problematic gastrointestinal

complication of total parenteral nutrition is thedevelopment of liver disease, presenting clinically

as hepatomegaly and jaundice and histologically as

cholestasis, hepatocellular necrosis, and, in far ad-

vanced cases, as cirrhosis or hepatic failure.’� Since

1971, liver disease has been recognized in approxi-

mately one third of premature infants receiving

total parenteral nutrition. The etiology remains

obscure.’7 Toxic effects of the amino acid and lipid

solutions have been proposed, although not corrob-

orated on further study. The appearance of liver

disease with elevations in levels of transaminases,

bilirubin, and alkaline phosphatase usually occurs

after 2 weeks of total parenteral nutrition; it fre-quently is progressive and leads to fibrosis and, in

a few infants, hepatic failure. These infants fre-quently are compromised by a number of intercur-

rent illnesses, including sepsis and severe respira-

tory distress. It has been difficult to separate these

factors from the effects of parenteral nutrition on

the development of hepatic dysfunction. The longer

the infusions are administered, the greater the risk

of cholestasis.

TABLE 3. Recommended Safe and Adequate Intakes of

Vitamins, Minerals, and Trace Elements*

Component Infants Aged0.0 to 1.0 yr

ChildrenAged <11 yr

Fat-soluble vitaminsVitamin A (�zg retinol 400-420 400-700

equivalents)Vitamin D (�Lg) 10 10

Vitamin E (mg a-to- 3-4 5-8copherol

Vitamin K (�Lg) 12-20 15-60

Water-soluble vitamins

Ascorbic acid (mg) 35 45Thiamine (mg) 0.3-0.5 0.7-1.2Riboflavin (mg) 0.4-0.6 0.8-1.4Pyridoxine (mg) 0.3-0.6 0.9-1.6

Niacin (mg nicotina- 6-8 9-16

mide)Folacin (;1g) 30-45 100-300

B12 (jag) 0.5-1.5 2-3Biotin (�tg) 35-50 65-120

Pantothenic acid (mg) 2-3 3-5

MineralsZinc (mg) 3-5 10Iodine (jAg) 40-50 70-120Iron (mg) 10-15 10-15Magnesium (mg) 50-70 150-250

Trace elementsCopper (mg) 0.5-1.0 1.0-2.0Fluoride (mg) 0.1-1.0 0.5-2.5

Manganese (mg) 0.5-1.0 1.0-3.0Chromium (mg) 0.01-0.06 0.02-0.2Selenium (mg) 0.01-0.06 0.02-0.2

* Adapted from Recommended Dietary Allowances.22 In-

travenous requirements are derived from these enteralstandards. No currently available formulation meets all

recommendations. Therefore, a combination that mostclosely approaches these needs should be used. Certainnutrients are not available and/or approved for continu-ous intravenous administration in the United States(iron, B12, vitamin K). Therefore, intramuscular or bolusinfusions are necessary to meet needs until suitable, low-risk preparations are ave�lab1e.

Much less is known about the long-term effects

of total parenteral nutrition on gastric, pancreatic,

and small bowel structure and function. Studies in

animals have documented pancreatic hyposecretion

and intestinal mucosal atrophy, which are reversi-

ble on resumption of enteric feeding.’5 The few

studies from human subjects’ suggest that exocrine

pancreatic secretion and gastric parietal cell mass

are decreased and the mucosa of the small intestine

atrophies during total parenteral nutrition. How-

ever, amino acids infused intravenously stimulate

gastric acid secretion, but much less than if amino

acids are infused into the stomach. These effects

disappear over a variable period of time after a

return to enteral nutrition. Although similar studies

have not been done in premature infants, clinical

experience suggests that enteric functions in pre-

mature infants also return to normal with time.


REFERENCES

1. Goodgame JT: A critical assessment of the indications fortotal parenteral nutrition. Surg Gynecol Obstet 1980;151:433

2. Wretlind A: Parenteral nutrition. Nutr Rev 1981;39:2573. Fischer JE (ed): Total Parenteral Nutrition. Boston, Little,

Brown and Co, 1976

4. Riordan TP: Placement of central venous lines in the pre-mature infant. JPEN 1979;3:381

5. Donohoe PK, Kim SH: The inferior epigastric vein as an

alternate site for central venous hyperalimentation. J Pe-diatr Surg 1980;15:737

6. Ghadimi H: Newly devised amino acid solutions for intra-venous administration, in Ghadimi H (ed): Total ParenteralNutrition, Premises and Promises. New York, John Wiley& Sons, 1975, pp 393-442

7. Hornchen H, Neubrand W: Amino acids for parenteralnutrition in premature and newborn infants: Use of a moth-er’s milk-adapted solution. JPEN 1980;4:294

8. Sturman JA, Gaull G, Raiha NCR: Absence of cystathionasein human fetal liver: Is cystine essential? Science1970;169:74

9. Schiff D, Chan G, Seccombe D, et al: Plasma carnitine levelsduring intravenous feeding of the neonate. J Pediatr1979;95:1043

10. Heird WC, Dell RB, Driscoll JM Jr, et al: Metabolic acidosisresulting from intravenous alimentation mixtures contain-ing synthetic amino acids. N Engi J Med 1972;287:943

11. Wolfe RR, Alisop JR, Burke JF: Glucose metabolism in

man: Responses to intravenous glucose infusion. Metabolism1979;28:210

ACKNOWLEDGMENTS

The Committee thanks the following for assistance inthe preparation of this paper: Kristy Hendricks, RD, MS,and Ronald E. Kleinman, MD, Massachusetts GeneralHospital.

AMERICAN ACADEMY OF PEDIATRICS 551

ENTERAL FEEDINGS

Initiation of enteral feedings should begin as soon

as the gastrointestinal tract is functional. Initially,

enteral feedings may be a supplement to parenteral

nutritional support, which should not be discontin-

ued until the patient is tolerating enteral feedings

well enough to meet nutritional requirements.

SUMMARY

Nutritional requirements of young infants, both

premature and full-term, can be met better by

recognizing the absorptive and digestive limitations

present. When gastrointestinal disease is superim-

posed on an immature digestive system, special

support frequently is needed to maintain adequate

growth. This support can be offered as parenteral

nutrition or with specialized enteral feeding tech-

niques and formulations.

Because parenteral solutions are formulated to

provide complete nutritional support, they may be

used for short as well as extended periods of time.

Recommendations for use include:

1. Careful catheter placement and confirmation

of position by roentgenogram; strict adherence to

aseptic techniques and established guidelines of

catheter care; and laboratory and clinical monitor-

ing of patients for intolerance.

2. Protein, in the form of crystalline amino acids,should be provided at a rate of 2 to 3 g/kg/d. The

concentration of carbohydrate, as glucose (dex-

trose), should be advanced in a methodical manner

to ensure tolerance. Essential fatty acid require-

ments can be met by infusing 0.5 to 1 g/kg/d of

intravenous lipid. The slow infusion of up to 4 g/

kg/d of intravenous lipid should maximize toler-

ance. Vitamins, minerals, and trace elements are

essential nutrients and should be contained in par-

enteral nutrition solutions.

3. The transition to enteral nutrition should be-

gin as soon as possible, with continuation of par-

enteral nutrition until full nutritional support is

achieved via the gastrointestinal tract.

4. Continuous monitoring of nutritional status is

mandatory to assure the adequacy of nutritional

support. In some settings, a nutritional support

team with expertise in parenteral nutrition can help

provide optimal care.

COMMITTEE ON NUTRITION, 1982-1983

Alvin M. Mauer, MD, Chair

Platon Jack Collipp, MD

Harry S. Dweck, MD

Frederick C. Holmes, MDBuford L. Nichols, Jr, MD

John W. Reynolds, MD

Robert M. Suskind, MD

W. Allan Walker, MDCalvin W. Woodruff, MD

Technical Advisory Group

George A. Purvis, PhD, ChairJohn D. Benson, PhD

David A. Cook, PhD

Bruce R. Stillings, PhD

Rudolph M. Tomarelli, PhD

Liaison Representatives

Alice Smith, RD

Philip L. White, ScD

Mary C. Egan

Margaret Cheney, PhD

Paul Pencharz, MD

Mary Serdula, MD

Joginder Chopra, MD

Myrtle L. Brown, PhD

Thorsten J. Fjellstedt, PhD

William J. Darby, MD, PhD

L. J. Teply, PhD

Lynda Couvillion

AAP Section LiaisonStanley Hellerstein, MD



12. American Academy of Pediatrics, Committee on Nutrition:Use of intravenous fat emulsions in pediatric patients. Pe-diatrics 1981;68:738

13. Hoshal VL Jr: Total intravenous nutrition with peripherallyinserted silicone elastomer central venous catheters. ArchSurg 1975;1 10:644-646

14. American Medical Association, Department of Food andNutrition: Multivitamin preparations for parenteral use: Astatement by the Nutrition Advisory Group. JPEN1979;3:258

15. American Medical Association, Nutrition Advisory Group:Guidelines for essential trace element preparations for par-enteral use. JPEN 1979;3:263

16. Cohen MI: Changes in hepatic function in intravenous nu-trition, in Winters RW, Hasselmeyer E (eds): IntravenousNutrition in the High Risk Infant. New York, John Wiley &Sons, 1975, pp 293-313

17. Sondheimer JM, Bryan H, Andrews W, et al: Cholestatic

tendencies in premature infants on and off parenteral nu-trition. Pediatrics 1978;62:984

18. Feldman EJ, Dowling RH, McNaughton J, et al: Effects oforal versus intravenous nutrition on intestinal adaptationafter small bowel resection in the dog. Gastroenterology1976;70:712

19. Kotler DP, Levine GM: Reversible gastric and pancreatichyposecretion after long-term total parenteral nutrition. NEngI J Med 1979;300:241

20. Heird WC: Total parenteral nutrition, in Pediatric NutritionHandbook. Evanston, IL, American Academy of Pediatrics,1979, pp 392-408

21. Pediatric Parenteral Nutrition Manual. Boston, Children’sService, Massachusetts General Hospital, 1983

22. National Research Council, Food and Nutrition Board: Rec-ommended Dietary Allowances, ed 9. Washington, DC, Na-tional Academy of Sciences, 1980

A MAJOR PROBLEM

Two years after benoxaprofen (Opren) was launched in a blaze of publicity its

product licence [was suspended in Britain] on the grounds of concern aboutserious side effects. . . . The public has been alarmed by the total of 61 deaths in

patients, mostly elderly, taking benoxaprofen and by the admission of the

Committee on Safety of Medicines that it has received 3500 reports of adversereactions. . . . What are the lessons to be learnt?. . . A major unexpected side

effect (cholestatic jaundice) was first reported through a medical journal. Yet

benoxaprofen had full, careful clinical trials on over 3000 patients and was

monitored. . . on 5000 patients after marketing with no mention ofjaundice. The

problem remains one of numbers. Even if 20,000 patients had been monitorednothing untoward might have been detected. Among the classic side effects that

would evade detection by such a programme are the marrow aplasia associated

with chioramphenicol, the slow development of chioroqume retinopathy, and

the association between unopposed postmenopausal oestrogens and endometrialcarcinoma.

From Editorial: Benoxaprofen. Br Med J 1982;285:459-460

Submitted by Student


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