. . . . . . . . . . . . . . Reflections on Errors in Neonatology: II. The ‘‘Heroic’’ Years,
I remember, as an intern, having my obstetric rotation in thefactory town, Ypsilanti, MI. I was the only doctor staying in thehospital at night and was told what to do by a substantial nurse, a
This series errors in neonatology since the 1920s. Three historical periods
Swedish lady, who, apparently, thought I was as deaf as she. One
are defined: the ‘‘Hands-Off’’ years from 1920 to 1950, the ‘‘Heroic’’ years
night we delivered a baby who was depressed and needed
from 1950 to 1970, and the ‘‘Experienced’’ years from 1970 on. In this
resuscitation. I had no idea what to do other than suction the
article, the ‘‘Heroic’’ years, we discuss the Blossom air lock, sulfisoxazole,
mouth, blow oxygen toward the nose, and stimulate the baby by
chloramphenicol, novobiocin, hexachlorophene, Epsom salts enemas,
rubbing its back. The nurse brought in two pans, one containing
feeding gastrostomy, diaper laundering, and equipment cleaning.
warm water and the other containing ice water. She proceeded to
Journal of Perinatology (2003) 23, 154–161. doi:10.1038/sj.jp.7210843
resuscitate the baby by immersing the infant, alternately, in eachpan. Dr. Silverman mentions that using ice water was a favoriteresuscitation method of Dr. Virginia Apgar in the 1950s (Silverman,personal communication).
Blundell described endotracheal intubation and insufflation in
The first article of this series dealt with errors in neonatology,
1884.2 In 1871, Bernard Schultze described the ‘‘swinging’’ method
which occurred during the ‘‘Hands-Off’’ years, 1920 to 1970. In
of resuscitation.3 The Kreiselman resuscitator, which I used in
this period, premature infants were protected by the nurses who
early 1960 was described first in 1940.4 Since mouth-to-mouth
provided food, warmth, and isolation. The only routine treatments
ventilation was often unsuccessful and endotracheal intubation by
were silver nitrate eye drops to prevent ophthalmia neonatorum,
inexperienced personnel was dangerous, there was great variation
oxygen for apnea and cyanosis, and vitamin K to prevent
in resuscitation techniques in the 1950s.
hemorrhagic disease of the newborn. The introduction of the
The strangest resuscitation device was the Bloxsom air-lock
exchange transfusion in the 1940s for Rh isoimmunization was the
(Figure 1), introduced in 1950.5 This machine was a tightly closed
first remarkable intervention by pediatricians. Antibiotics (sulfas
chamber with humidified oxygen at B60%. To mimic uterine
developed in the 1930s and penicillin in the 1940s) were quickly
contractions, the pressure in the chamber was cycled regularly
incorporated into newborn infant care. The retrolental fibroplasia
between 1 and 3 lb/in2. The air lock was proposed as a method of
disaster and its explication led to research in blood gas monitoring
resuscitation; ‘‘The infant is placed gently in the lock, preferably
and the development of infant ventilators. These years were
not later than 30 seconds after failure to breathe or breathe
exciting. Silverman1 refers to ‘‘therapeutic exuberance’’; Baker
properly.’’ The machine received publicity in Newsweek and
describes a ‘‘great spirit of innovation, somewhat lacking in
became popular around the country. Kendig et al.6 have described
discipline’’ and refers to the ‘‘heroic’’ era (2). All treatments were
the brief life of this innovation. Subsequently, Apgar and
new, untested, and we marched on without fear! As a result of our
Kreiselman7 showed no improvement in oxygenation or CO2
uncritical enthusiasm for treatment, many errors occurred.
excretion in anesthetized dogs placed in the air lock. Dr. Bloxsom
This article details several unusual treatments, problems related
and Sister Mary Angelique responded.
to prophylaxis of infectious disease, and two episodes of poisoning.
In January, 1953, an adverse critical evaluation of the air lockfrom New York City appeared, based on attempts to make the airlock function as a barospirator for apneic adult dogs. Such afunction, of course, was never intended or claimed for the air lock.
Departments of Pediatrics, Brody School of Medicine, East Carolina University, Greenville, NC,
Bloxsom and Angelique8 suggested that the reduction in the 48-
hour neonatal death rate in term and premature infants at their
Address correspondence and reprint requests to Alex F. Robertson, MD, Department of Pediatrics,
hospital from 1949 to 1952 was because of the use of the air lock.
Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27858-
An appropriately designed study showed no beneficial effect of the
Journal of Perinatology 2003; 23:154–161
r 2003 Nature Publishing Group All rights reserved. 0743-8346/03 $25
(infants born after prolonged rupture of the placental membranesor premature infants).
As recounted by Dr. Silverman1 (pp. 79–81), when the prematurecenter at Babies Hospital in New York opened, all babies transferredin were treated with penicillin and oxytetracyclene orchloramphenicol. In 1953, a newly available sulfonamide,sulfisoxazole, was introduced and had the advantage of requiringless frequent dosing to maintain adequate blood levels. No
Figure 1. Bloxsom Air Lock Legend: Reproduced with permission:
problems were recognized with its use. When the use of
Pediatrics, Vol. 108, Page(s) e116, Figure 1, Copyedited 2001.
subcutaneous oxytetracyclene was suggested, a controlled study wasbegun comparing this drug to the accepted regimen of penicillinand sulfisoxazole. ‘‘Much to our amazement, the first trial gave a
air lock in 1956.9 In this study, all infants received adequate
definitive result. To our horror, the mortality rate was highest (and
resuscitation before entering either the Bloxsom air lock or an
strikingly so) in infants who received the established treatment!’’
Isolette. This study and the realization that RLF was caused by
The cause of the increased mortality rate was kernicterus which, at
oxygen led to the abandonment of the device. As the authors state,
autopsy, was nine times increased. There was, at that time, no
‘‘All too often the availability of such a device as the air lock
plausible explanation for this effect. The results of this study are
furnishes a panacea for the management of all infants with
shown in Table 1.11 The increased death rate (46 compared to 20)
respiratory difficulty. It may at times be substituted in place of a
and increased incidence of kernicterus (36% compared to 6%) in
careful diagnosis of the nature of the difficulty and for the use of
the sulfisoxazole-treated infants are seen in the table.
well-established resuscitative procedures such as providing a clear
In 1959 O’Dell12 demonstrated that sulfisoxazole competed with
airway for the onset of respiration’’. There is no way to know how
bilirubin for albumin binding, thereby increasing the unbound
many infants were harmed by this device.
bilirubin concentration in the blood, which was quickly depositedin the brain. The national impact of sulfisoxazole use in jaundicedinfants was never reported but was undoubtedly great]
Sulfisoxazole was removed from use in newborn infants. There was
Charles and Larsen10 present an interesting review of the history of
another important byproduct of this work. Stern13 emphasized
puerperal sepsis (pelvic infection following delivery) and neonatal
publically that all drugs used in newborns should be tested for their
infections. As the authors point out, the industrial revolution led
effect on bilirubin binding. He suggested to Professor Rolf
the migration of large numbers of people into cities and childbirth
Brodersen at the University of Aarhus, Denmark that he devised a
moved into the hospital. Puerperal sepsis became epidemic. In the
practical method of testing drugs for this displacing effect.
mid-1800s, an early advocate of puerperal sepsis’ contagiousness
Brodersen14 dedicated many of his later years to this question and
was Oliver Wendell Holmes, at that time dean of the Harvard
screened many drugs for their effect. This work led to the
Medical School. A few years later, Semmelweiss, in Vienna, showed
realization that ceftriaxone had a displacing effect similar to
that hand washing before pelvic examination reduced the mortality
sulfisoxazole and prevented its use in jaundiced newborn infants.15
in the obstetric ward. In 1879, Pasteur demonstrated bacteria in the
Unfortunately, the FDA requires no screening of new drugs for their
blood and lochia of puerperal sepsis victims. The organism was
effect on bilirubin binding and few laboratories are currently
Group A Streptococcus. The use of careful antiseptic practices was
the only recourse against infection until the introduction of
From 1982 until his death in 1998, Professor Brodersen was my
sulfonamides in the 1930s and then penicillin in the 1940s. The
mentor and I have saved the many letters we exchanged regarding
use of antibiotics may have changed the pattern of infection withgram negative organisms and penicillin resistant Staphylococcusaureus becoming more prevalent. By the end of the 1950s hospital
nurseries around the world were experiencing cross-infections with
virulent S. aureus. More recently Group B Streptococcus has beenthe primary infectious agent among mothers and babies. As a
result of this experience with infections, there have been numerous
trials of antibiotic prophylaxis in newborn infants. The infantsusually chosen for such prophylaxis were those at increased risk
Journal of Perinatology 2003; 23:154–161
experiments in progress. Although, outwardly, a very formal man
distention, slate-colored or pallid cyanosis (the ‘‘gray baby’’
and a rigorous scientist, he was always friendly and frequently
syndrome), cold moist skin, and weak pulse; they died shortly
humorous in his responses to my ideas. For example, when I asked
him what animal to use in studying in vivo bilirubin displacement
The use of prophylactic chloramphenicol in newborn infants
(animal models had been suggested by some skeptics of his work)
had already spread across the country. Once the possible danger of
he wrote, ‘‘If you nevertheless, against all sense, find that you have
the drug was recognized, many investigators looked into mortality
to satisfy the skeptics, I would recommend the pig. It is in several
figures. In 1959 Kent and Wideman20 at the University of Alabama
respects related to man (at least to some men) and has the
hospital found the death rate among infants with premature
advantage that we do not yet know that binding to porcine
rupture of the membranes rose from 29/1000 to 144/1000 after
albumin is different from that to the human protein’’. ‘‘You
antibacterial prophylaxis using chloramphenicol was begun. Of
wanted an inexpensive animal model. I believe that pigs are
160 infants so treated, 17 died exhibiting the characteristics of the
expensive but you can eat them afterwards thus eliminating your
‘‘gray sickness.’’ In 1958 Burns et al questioned the high mortality
in infants with prolonged rupture of the membranes who werebeing treated with antibiotics at the Los Angeles County Hospital. They began a prospective, controlled trial of no antibiotics versusseveral combinations of antibiotics including chloramphenicol.
The mortality in babies weighing 2001 to 2500 g was 2.5% with no
Dr. Silverman1 (p. 81) recounts the suggestion made by
antibiotic treatment and 45% with chloramphenicol treatment.21
Dr. Alexander in 1956 that a trial be performed using
A study by Buetow, using vital statistics for the city of Baltimore
chloramphenicol, erythromycin, and sulfadiazine as infection
showed that there was a significant rise in infant mortality in 1957
prophylaxis in infants weighing less than 2000 g at birth.
(Figure 2). This rise resulted in an excess of 118 neonatal deaths,
Instead of a trial, the widespread use of this combination
best explained by the use of prophylactic chloramphenicol.22
This excess mortality continued into 1958 until the dose of
Chloromycetin was discovered by Dr. Burkholder of Yale in
chloramphenicol was reduced to 20 mg/kg/day. The
1947. This antibiotic was found in cultures of a new actinomycete
aforementioned reports suggested that a large number of infant
isolated from the soil of a field near Caracas, Venezuela and later
deaths across the country were related to the drug. The tragic
named Streptomyces venezuelae. Unlike penicillin and
practice of using chloramphenicol ended in about 1960 as these
streptomycin, chloromycetin had a broad range of activity againstGram positive and Gram negative organisms. Clinical trials showedthat it was the first drug effective against rickettsial infections andtyphoid fever. The drug was synthesized and namedchloramphenicol in the research laboratories of Parke, Davis andCompany. The drug was marketed in 1949 and was the first broad-spectrum antibiotic available. In 1952 the National ResearchCouncil, recognizing the hazard of aplastic anemia caused by thedrug, recommended cautionary labeling of the drug and its generaluse decreased after the labeling was changed.16 There were nostudies or reports at that time of toxicity in newborn infants. Lietman17 wrote an excellent review of the history of this drug’s usein neonates.
The first suggestion of a problem in newborn infants appears to
be by Lambdin. In a letter to the editor in Pediatrics in 1960,18 hestates that the recognition of the problem with chloramphenicol‘‘was brought to the attention of Parke, Davis and Company, andto others by our observation in the early months of 1958’’. Theproblem was publicized by a letter from the company dated 21January 1959, addressed to all physicians in the US and Canada.
Sutherland published the first description of three cases of
cardiovascular collapse in newborn infants receiving large doses ofchloramphenicol.19 The infants were treated because of prolongedrupture of the membranes and concern about infection. A few days
Figure 2. Neonatal Death Rats per 1000 Live Births in Baltimore City,
after the treatment began, the infants developed abdominal
1935–59. Reproduced with permission: Buetow22 (p. 218).
Journal of Perinatology 2003; 23:154–161
reports became common knowledge in medical circles. Not only
rabbits receiving novobiocin. In the summary they state that this is
was the use of chloramphenicol as a prophylactic antibiotic
‘‘another instance of an epidemic among the newborn from an
curtailed, the dosage recommendations were changed from 100–
incompletely understood metabolic effect of a drug’’. In 1962,
150 mg/kg/day to 50 mg/kg/day in term infants and 25 mg/kg/day
Hargreaves and Holton26 showed that the drug directly inhibited
in preterm infants. Parke, Davis and Company developed an assay
the bilirubin conjugating enzyme in rat liver preparations.
for the drug in serum and worked collaboratively with many
Fortunately, none of the infants in the Cincinnati epidemic
medical centers to determine the cause of the toxicity.23
developed kernicterus during their hospitalization and only 12
Chloramphenicol’s toxicity was related to its accumulation
babies required exchange transfusion. It was fortunate that this
resulting from impaired glucuronidation by the liver of newborns
effect was recognized before the drug was used widely in newborn
and impaired renal excretion of the drug. The exact biochemical
mechanism of the toxicity was never fully explained. An importantby-product of this episode was the recommendation that drug levelsbe determined during antibiotic treatment.
In 1965, I arrived at the Ohio State University Hospital and tookover the care of babies in the newborn nursery. At that time, the
babies were bathed on admission and afterwards every other day
In 1955 two pharmaceutical research laboratories isolated an
with 3% hexachlorophene (HCP) soap and then rinsed off with
antibiotic from Streptomyces, a fungal organism. Interest in this
water. To monitor the colonization rate with S. aureus, each
finding was high because of the new antibiotic’s effect on S.
infant had an umbilical stump culture done at the time of the
aureus which was becoming resistant to other antibiotics.
discharge physical examination. The usual colonization rate was
Historically, this period was the time that resistant strains of S.
about 10%. If the rate went up significantly, we looked for a cause,
aureus were causing nosocomial hospital infections around the
generally an environmental change (such as crowding with high
world. The generic name, novobiocin, was given to the drug.
census) or a procedural change (such as inadequate hand
Animal studies showed little toxicity but it was noted in dogs that
‘‘A yellow color has been noted in the serum of dogs given
In 1969, we noted the first case of a blistering skin lesion in a
Novobiocin but this is probably due to some metabolite of the
full term infant. This blistering was obviously the ‘‘scalded skin’’
antibiotic; it produces an indirect reaction for bilirubin and is not
syndrome usually caused by a specific phage type of S. aureus.
related to liver damage.’’ The same yellow pigment was noted in
Over the next 6 weeks 33 more cases occurred.27 Cohort care of the
infants (admitting to one nursery and discharging all infants from
In 1959, there was a staphylococcal infection epidemic in a
that nursery and then cleaning before resuming admissions to that
term newborn nursery at the Cincinnati General Hospital. To abort
nursery) was unsuccessful. Ultimately, the epidemic was stopped by
the outbreak, novobiocin was given to all infants admitted to the
colonization of the umbilical stump and nares in the delivery room
nursery since the organism was resistant to penicillin and
with a benign strain of Staphylococcus. This approach had been
erythromycin. An increase in the number of infants with
successful in several other hospitals.28 Since I had to explain the
hyperbilirubinemia was quickly noted by Dr. Sutherland, who had
procedure to each of the mothers, I became known at the hospital
earlier been one of the first to recognize chloramphenicol toxicity.
as the ‘‘friendly Staph doctor.’’
The icterus increased not only in incidence but also rose to higher
As we looked back over our colonization data, we were able to
levels more quickly. During the period of novobiocin
pinpoint the week in which the colonization rate had begun
administration, 60 babies or 9% of admissions had marked
increasing. The apparent precipitating event was the change from
jaundiced, whereas before and after the administration of
3% liquid HCP bathing to 0.75% bar HCP bathing. After the
novobiocin, 3 to 4% of admissions were so jaundiced. As Sutherland
epidemic was controlled, we changed back to using 3% liquid HCP
and Keller25 explains in the article there was much controversy
bathing and water rinsing. Then the liquid HCP was applied as a
previously published about the nature of this yellow pigment in the
lotion to the body and allowed to dry without rinsing. At that time I
serum of those receiving novobiocin. Actually, in the package insert
of the drug, the manufacturer included a description of the
HCP [2,20-Methylene-bis (3,4,6-trichlorophenol)] was patented
procedure they recommended for removing the yellow color from
in 1941 in the US. The chemical was widely used as an
the serum so that the color would not interfere with other
antibacterial in soaps, cosmetics, and antiseptic solutions
throughout the world. In 1952 Farquharson et al.29 showed that
With multiple chemical methods, Sutherland and Keller showed
HCP bathing of newborn infants markedly reduced the rate of
that the pigment was indeed bilirubin. They also showed that the
impetigo in the nursery. Gluck and Wood30 reaffirmed that finding
clearance of intravenously administered bilirubin was delayed in
in 1961 and presented their bathing method as appropriate for
Journal of Perinatology 2003; 23:154–161
decreasing staphylococcal colonization. This method was quicklyadopted in hospitals around the world and was in place at ourhospital when I arrived.
Kimbrough,31 working for the FDA, reviewed the toxicity of HCP
in 1971. Reports of HCP toxicity were first limited to accidental oralingestions. The signs of poisoning were primarily gastrointestinal,but some neurological signs occurred. In 1959 Herter described aninfant treated with HCP as a lotion for 4 days resulting in skinexcoriations followed by twitching and convulsions. In 1968,Larson reported HCP transcutaneous absorption and neurologicaltoxicity in burn patients. This syndrome had been previously called‘‘burn encephalopathy’’.32 In his review, Kimbrough also detailsthe animal studies done up to 1971. In rat studies Kimbrough andGaines showed HCP toxicity caused hind limb paralysis and spongydegeneration of the white matter. The final recommendation ofKimbrough33 was that ‘‘the unnecessary use of concentrated HCPpreparations should be curtailed’’.
Two other studies in 1971 raised concern. Hart33 reported cystic
changes in the white matter of monkeys washed daily with HCPand Curley et al.34 showed that infants bathed daily with HCPabsorbed the chemical into the blood. On December 8, 1971 theFDA mailed a warning to all US physicians. The letter concluded byrecommending (jointly with the Committee on Fetus and Newborn
Figure 3. Spongiform Myelinopathy of the Braistem. Photograph
of the American Academy of Pediatrics) not to use HCP for total
body bathing of infants. In a review by Plueckhahn,35 the authorcites a report by the French Ministry of Health that HCP, over 6%,had been accidentally included in certain batches of a baby talcum
increase and there were some reports verifying a resurgence.
powder and was implicated as the cause of death in 40 infants aged
However, other reports questioned whether HCP appeared effective
only because the pattern of infections around the world was
The crucial information was reported in 1973 in the Morbidity
beginning change again for unknown reasons. Most nurseries
and Mortality Weekly Report.36 A pathological specimens review
reverted to using triple dye for cord stump treatment and the
from the University of Washington revealed that vacuolation of the
brain’s reticular formation was present in 63% of autopsied infantswho had been exposed 3 or more times to 3% HCP by bathing andunder 1% in those less exposed. Of 21 cases, 18 were infants
weighing less than 1400 g at birth. The details of this study were
In 1963, President Kennedy’s son, Patrick Bouvier, died of
reported by Shumann et al.37 in 1975. In 1973, Powell et al.38
respiratory distress syndrome (RDS), then known as hyaline
(including Gluck who had instituted the bathing method) reported
membrane disease. The publicity attending his illness raised the
seven cases of spongiform myelinopathy of the brainstem in infants
popular interest in neonatology, which had not yet received that
under 1400 g exposed to HCP. Figure 3 shows the typical lesions. In
name. As Dr. Silverman1 (p. 87) details, publicity is often
1976, Gowdy and Ulsamer39 reported a study of 76 brains from
dangerous in medical affairs. A paper given in October 1964 at the
infants bathed with HCP and 69 control specimens. They found no
annual meeting of the College of American Pathologists described
statistically significant increase in vacuolization of infants bathed
the beneficial effect of Epsom salts enemas on RDS. This startling
with HCP. However, they did find detectable levels of HCP in 5
idea was reported on p. 1 of the New York Times and subsequently
brains showing vacuolization. In 1980, Anderson et al.40 reported
in Time magazine, Medical Tribune and the Lancet. I remember
additional cases of spongiform myelinopathy with HCP detectable
hearing these reports and dismissing them as absurd. However, the
in the brain in premature infants. In none of these reports was
news spread rapidly and use of the enemas was frequent.
there a clinical condition that could be related to the pathological
Van Gelder42 wrote a letter published in Pediatrics asking for a
findings. Lockhart41 presents a fascinating history of the
report of other physicians’ experience with what he considered a
involvement of the FDA in this saga.
‘‘potentially hazardous’’ treatment. Dr. Stowens, the originator of
When HCP was no longer available for bathing babies there was
the treatment, responded saying, ‘‘I am happy to be able report
great concern that the rate of staphylococcal infections would
that since the appearance of the stories numerous other physicians
Journal of Perinatology 2003; 23:154–161
in all parts of the country who have not shared Dr. Van Gelder’s
were relatively large and irritating. Vomiting sometimes occurred
querulousness or inability to analyze and reach independent
when the tube was removed, and the infants could not receive
conclusions have reported to me of their successes with this form of
frequent, small volume feedings. In 1951 Royce et al.47 described
successful the using of an indwelling polyethylene nasogastric tube
In 1965 Dr. Stowens reported his pathological studies in hyaline
for feeding small (for that time) premature infants.
membrane disease and his hypothesis that ‘‘the basis of the
In 1963, Tomsovic et al reported the use of gastrostomy tubes in
respiratory difficulty in premature infants might be related to
small infants; they cited poor tolerance for intermittent gavage or
inability of the infants to achieve the proper level of total body
retention nasogastric feedings of infants below 1500 g. In their
water necessary for extrauterine existence.’’ The treatment
series the infants were not fed for 3 days and then a gastrostomy
originated from Dr. Stowens erroneous analysis of the pathology of
was performed. In all, 11 infants were operated on and none died
RDS. He described the method and results of using the enemas in
as a result of the surgery.48 Similar results were reported by Berg
28 infants.43 He stated that all infants improved but no objective
et al.49 in 1964. Jones and Reid50 recommended this approach for
measures were presented. In an addendum to the article he noted
small infants with severe respiratory distress. None of these reported
that he had sent details of the method of treatment to many
physicians. ‘‘Reports from 24 physicians have yielded data on 121
In 1969 Vengusamy et al.51 reported a controlled study of
infants.’’ ‘‘Of the 121 infants, 94 recovered.’’ It is startling to
mortality associated with gastrostomy in infants weighing less than
realize that these statements were acceptable for publication. Even
1250 g at birth. A total of 54 infant pairs were matched and
more startling is his final statement, ‘‘One infant manifested a
sequentially analyzed. In all, 34 pair had similar outcomes. In the
precipitous drop in respiratory and cardiac rates after enema and
20 pairs with dissimilar outcomes, 13 control infants and seven
was treated with intravenous calcium gluconate. It was believed
gastrostomy infants survived. At that point, the statistical criteria
that this infant developed magnesium toxicity, but magnesium
were met and the study terminated. The morbidity in gastrostomy
determinations were not performed.’’ Dr. Stowens was the first to
infants was also increased with 18 instances of wound infection.
Fortunately, this study as well as improvements in gavage feeding
I know of no other articles in the medical literature describing
brought the episode of gastrostomy feeding for premature infants to
the results of this treatment but, 1 year later, Andrews et al.44
showed the devastating effect of this treatment in newborn lambs. There is no way of knowing how many babies died as a result ofthis treatment but as late as 1973 a report of the fatal use of thistreatment was recorded.45 One problem during that time period,
before the extensive use of ventilators, was that babies with RDS
In 1967 20 infants, all born in a small St. Louis maternity hospital
would frequently become exhausted from the breathing effort, stop
for unwed mothers, developed a sickness characterized by profuse
breathing, and die. The same picture would result from
sweating, fever, tachycardia, tachypnea, hepatomegaly and acidosis.
This epidemic occurred over a period of almost 5 months. Nineinfants were severely affected and two died. The course was rapidonce signs of illness developed; one infant died 3 hours after theonset of fever and sweating.52 Six children had an exchange
transfusion and promptly improved. The disease was named the
Feeding premature infants has always because a problem since
they may have poor sucking and swallowing coordination and
The first four cases developed between April 17 and 19. The
strength. In 1900 Pierre Budin described current artificial feeding
nursery, closed on April 24, was thoroughly cleaned and
methods. ‘‘When infants are feeble, they sometimes refuse to suck.
disinfected, and reopened on May 3. A second cluster of cases
Milk is then made to trickle into their mouths, directly from the
followed between May 10 and 15.53 The only apparent
nipple, by exerting pressure upon it, or they are fed from a small
epidemiologic difference between the sick and well infants was that
spoon, till they become strong enough to take the breast; but, if
the sick infants had been in the hospital longer when their illness
they allow the milk to dribble out of their mouths, if they do not
began. This fact suggested toxic material exposure. An incompletely
swallow, or if they reject what is given to them, gavage, feeding by
identified phenolic substance was found in the serum and urine of
the stomach tube, must be considered’’.46
affected infants. It was thought that a phenolic disinfectant used at
Budin cites Marchant of Charenton in 1851 as the first to use
the hospital was the cause; however a case beginning after that
intermittent gavage feeding in premature infants. In 1884 Professor
disinfectant was removed suggested it was not the cause. A search
Tarnier introduced this method to the Maternite´ Hospital in Paris
for all phenolic compounds in use revealed a hand soap and
for many premature infants. The method of intermittent gavage
shampoo containing hexachlorophene, an instrument and general
feeding was never completely satisfactory because the rubber tubes
disinfectant containing phenols, and an antimicrobial laundry
Journal of Perinatology 2003; 23:154–161
neutralizer containing pentachlorophenate (PCP). None of the first
staffing records showed that the affected infants had significantly
four compounds matched the exposure or time pattern of epidemic.
more care by the nurses using the phenolic compound.
PCP was used in a final laundry rinse before drying and all the
Additionally, it was found that the exhaust air registry in the
nursery washables were rinsed in it. The PCP solution had been
nursery was blocked and that the clothes used for cleaning may
used for some time in the laundry but in excessive amounts since
have been laundered with the nursery linen. Once the disinfectant
only shortly before the onset of the epidemic.54
was removed from use, the epidemic ceased.55
PCP was positively identified in the serum and in autopsy
The phenolic compounds probably caused jaundice by a toxic
tissues. The chemical was absorbable through skin and excreted in
effect on the liver, inhibiting the enzymes responsible for
the urine where, for infants in diapers, it might reabsorbed. The
conjugating and excreting bilirubin. These cases demonstrate the
exact mechanism of toxicity is unknown but is likely because of
unique susceptibility of newborn infants. As the investigators
uncoupling of cellular oxidation and phosphorylation leading to
mention,56 newborn infants absorb materials easily through their
an increased metabolic rate, fever, sweating and dehydration.
epidermis. Also, their respiratory rate is higher than adults so
Owing to the possibility of this compound’s further misuse, the
newborn infants may inhale larger amounts of environmental
manufacturer withdrew it from use in September 1967.
contaminants. And finally, the newborn’s liver conjugates chemicalsubstances more slowly than an adult.
In 1972, doctors at a New Jersey hospital performed five exchange
I am grateful for the helpful comments and suggestions of Dr. WA Silverman
transfusions for hyperbilirubinemia in a period of 36 hours. The
and Dr. Jeffrey P. Baker, and for the extensive grammatical review by AlexF. Robertson IV.
newborn infants were otherwise normal. Not knowing the cause forthis cluster of cases and concerned that an extrinsic factor was atwork, the hospital staff changed the brand of infant formula and
disposable diapers, stopped giving vitamin K injections, and moved
Silverman WA. Retrolental Fibroplasia: a modern parable. New York: Grune
the babies out of the nursery. No unusual feeding or bathing
practice or laundering of linen was identified. Staff members
Dunn PM. Dr. James Blundell (1790–1878) & neonatal resuscitation. Arch
reported that, in preparation for one of their colleagues delivery,
they cleaned the bassinet reserved for that baby several times with
Baskett TF, Nagele F. Bernhard Schultze and the swinging neonate.
their routine disinfectant detergent (Vestal LpH, Vestal Laboratories,
St. Louis MO). That baby needed three exchange transfusions for
Kreiselman J. An improved apparatus for treating asphyxia of the newborn
jaundice. This led to an investigation of the disinfectant which
infant. Am J Obstet Gyn 1940;39:888 –90.
contained several phenolic compounds. Further reconstruction of
Bloxsom A. Resuscitation of the newborn infant. Use of the positive pressure
the events showed that there had been an epidemic of diarrhea in
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Regional technology policy Summary of advisory report 23 The three questions that the Minister of Economic Affairs submitted to the Advisory Council for Science and Technology Policy (AWT) can be summarised as follows: 1. To what extent do the regions differ in terms of 'innovation intensity' and are these differences amenable to influence by policy? 2. What can the regions do
Volume 17 Issue 1 Winter 2005 Talking Tobacco: A conversation about the past and future of smoking cessation research at Group Health By Katie Saunders Cigarette smoking continues to be a blight on between behavior and health, (2) make healthier the nation’s health. Despite substantial reduc-lifestyle choices, and (3) sustain these choices tions in U.S. smoking rates si