. . . . . . . . . . . . . .
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/ 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 oxygen-air lock. J Pediatr 1950;37:311–9.
Kendig JW, Maples PG, Maisels MJ. The Bloxsom air lock: a historical the nursery several months before, and in response to this epidemic perspective. Pediatrics 2001;108:e116.
the concentration of the disinfectant used for cleaning was Apgar V, Kreiselman J. Studies on resuscitation. An experimental evaluation increased. The day before the cluster of cases occurred the nursery of the Bloxsom air-lock. Am J Obstet Gynecol 1953;65:45–52.
was vigorously cleaned. The cleaning solution was immediately Bloxsom A, Angelique SM. Neonatal infant mortality. Before and after the changed to hexachlorophene and no more cases occurred.
use of the air lock for the treatment of newborn infants in a large maternity After 3 years, a pediatrician in a Wyoming community reported hospital. Am J Obstet Gynecol 1954;67:647–50.
an unusual incidence of unexplained hyperbilirubinemia in their Reichelderfer TE, Nitowsky HM. A controlled study of the use of the Bloxsom nursery. Also, there had been three exchange transfusions within a air lock. Pediatrics 1956;18:918–27.
1-month period. This episode was not as dramatic as the New Charles D, Larsen B. Streptococcal puerperal sepsis and obstetric infections: Jersey epidemic but careful analysis of the nursery records showed A historical perspective. Reviews of Infectious Disease 1986;8:411–22.
that the incidence of hyperbilirubinemia was unusually high in Silverman WA, Andersen DH, Blanc WA, Crozier DN. A difference in April and May of that year. Again, there was no known change in mortality rate and incidence of kernicterus among premature infantsallotted to two prophylactic antibacterial regimens. Pediatrics 1956;18: procedure or medication that might give an explanation. However, because of the previous experience in New Jersey and the fact that O’Dell GB. Studies in kernicterus: I. The protein binding of bilirubin. J Clin the hospital used the same disinfectant, the investigators concentrated on cleaning methods. In this hospital, individual Stern L. Drug interaction: II. Drugs, the newborn infant, and the binding of nurses cleaned with either hexachlorophene or the phenolic bilirubin to albumin. Pediatrics 1972;49:916–8.
solution. And several nurses used inappropriately high Brodersen R, Robertson A. Chemistry of bilirubin and its interaction with concentrations of the phenolic solution for cleaning. Review of the albumin. In: Levine RL, Maisels MJ, editors. eds. Hyperbilirubinemia in the Journal of Perinatology 2003; 23:154–161 Newborn. Report of the 85th Ross Conference Of Pediatric Research.
Anonymous. Neuropathology in newborn infants bathed with hexachlor- Columbus: Ross Laboratories; 1983. p. 91–8.
Brodersen R, Robertson A. Ceftriaxone binding to human serum albumin: Shuman RM, Leech RW, Alvord EC. Neurotoxicity of hexachlorophene in competition with bilirubin. Molecular Pharmacology 1989;36:478 –83.
humans II. A clinicopathological study of 46 premature infants. Arch Neurol Woodward TE, Weisman CL. Chloromycetin (Chloramphenicol). In: Antibiotics Monographs. No. 6. New York: Medical Encyclopedia, Inc;1958.
Powell H, Swarner O, Gluck L, Lampert P. Hexachlorophene myelinopathy Lietman PS. Chloramphenicol and the neonate F 1979 view. Clinics in in premature infants. J Pediatr 1973;82:976–81.
Gowdy JM, Ulsamer AG. Hexachlorophene lesions in newborn infants. Am J Lambdin MA. On the ‘‘gray syndrome’’ and chloramphenicol toxicity.
Anderson JM, Cockburn F, Forfar J, Harkness RA, Kelly RW, Kilshaw B.
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Awt - adviesraad voor het wetenschaps- en technologiebeleid

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

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