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Lung development is orchestrated by highly integrated morphogenic programs of interrelated patterns of gene and protein expression. Injury to the developing lung in the canalicular and saccular phases of lung development alters subsequent alveolar and vascular development resulting in simplified alveolar structures, dysmorphic capillary configuration, variable interstitial cellularity and fibroproliferation that are characteristic of the 'new' bronchopulmonary dysplasia (BPD). Fetal and neonatal infection, abnormal stretch of the developing airways and alveoli, altered expression of surfactant proteins (or genetically altered proteins), polymorphisms of genes encoding for vascular endothelial growth factors, and reactive oxygen species result in imparied gas exchange in the developing lung. However, the 'new' BPD represents only one form of neonatal chronic lung disease and the consistent use of both the physiologic definition and severity scale would provide greater accuracy in determining the impact of the disease currently defined by its treatment. Our present labelling of the clinical state of oxygen supplementation and/or ventilatory support at 36 weeks' postmenstrual age and the histopathologic severity of alveolar arrest and vascular 'simplification' may not always be predictive of the degree of altered lung development and thus longer-term pulmonary function evaluations are needed to determine the impact of this disorder in specific infants. The proposed role of novel molecular therapies, and the combined effects of currently established therapies, as well as exogenous surfactant and inhaled nitric oxide or repetitive surfactant dosing, on the severity and incidence of new BPD hold considerable promise for reducing the long-term pulmonary morbidity among infants delivered prematurely.

OBJECTIVE This review examines perspectives of human infection with avian influenza A H5N1 (AI H5N1), specifically focusing on the presentation, diagnosis, and management of those critically ill with AI H5N1. DATA SOURCE PubMed (1966-2006), PubMed "related articles," publications and Web sites of the World Health Organization and the Centers for Disease Control and Prevention, personal files, abstract proceedings, and reference lists. STUDY SELECTION We reviewed English-language publications pertaining to clinical presentation, diagnosis, and management of AI H5N1 and infection control expressly relating to the intensive care setting. DATA SYNTHESIS The majority of reported patients with AI H5N1 are critically ill and require intensive care management. These patients progress rapidly to severe acute respiratory distress syndrome. Multiorgan failure occurs in a large proportion. Because of the nonspecific clinical, laboratory, and radiologic features, it is critical to seek a history of exposure to poultry or wild birds in suspected cases. Reverse transcription polymerase chain reaction performed on nasopharyngeal aspirate is the most reliable method for the laboratory diagnosis of AI H5N1. Treatment includes starting neuraminidase inhibitor oseltamivir as early as possible in addition to the standard supportive management. Aerosol generating procedures should be minimized to avoid nosocomial transmission. Strict infection control procedures are paramount to staff safety, although human-to-human transmission is rare as of this time. CONCLUSIONS Many patients with AI H5N1 are critically ill either at presentation or shortly thereafter. Intensivists and intensive care units are therefore at the front line for this new cause of severe lung injury. Practitioners must be familiar with the nonspecific presentation of AI H5N1 and its diagnostic and therapeutic options. Although treating the infected patient with AI H5N1 is a priority, safeguarding healthcare workers and other patients must be considered of equal priority.

Highly pathogenic Influenza A H5N1 was first identified in Guangdong Province in 1996, followed by human cases in Hong Kong in 1997 1,2. The number of confirmed human cases now exceeds 300 and the associated Case Fatality Rate exceeds 60% 3. The genetic diversity of the serotype continues to increase. Four distinct clades or sub-clades have been linked to human cases 4-7. The gradual genetic changes identified in the sub-clades have been attributed to copy errors by viral encoded polymerases that lack an editing function, thereby resulting in antigenic drift 8. We report here the concurrent acquisition of the same polymorphism by multiple, genetically distinct, clade 2.2 sub-clades in Egypt, Russia, Kuwait, and Ghana. These changes are not easily explained by the current theory of “random mutation” through copy error, and are more easily explained by recombination with a common source. The recombination role is further supported by the high fidelity replication in swine influenza 9 and aggregation of single nucleotide polymorphisms in H5N1 clade 2.2 hemagglutinin 10.

Highly pathogenic Influenza A H5N1 was first identified in Guangdong Province in 1996, followed by human cases in Hong Kong in 1997. The number of confirmed human cases now exceeds 300, and the associated Case Fatality Rate exceeds 60%. The genetic diversity of the serotype continues to increase. Four distinct clades or sub-clades have been linked to human cases. The gradual genetic changes identified in the sub-clades have been attributed to copy errors by viral encoded polymerases that lack an editing function, thereby resulting in antigenic drift. We report here the concurrent acquisition of the same polymorphism by multiple, genetically distinct, clade 2.2 sub-clades in Egypt, Russia, and Ghana. These changes are not easily explained by the current theory of “random mutation” through copy error, and are more easily explained by recombination with a common source. This conclusion is supported by additional polymorphisms shared by clade 2.2 isolates in Egypt and Germany.

The high-risk low-birth-weight newborn not uncommonly develops intracranial hemorrhage and intraventricular hemorrhage (ICH/IVH) from the immature state of the germinal matrix. Posthemorrhagic hydrocephalus may develop. Infants with small hemorrhages (grades I, II of Papile), with or without hydrocephalus have been shown to develop normally in 80%-90% of cases. There is limited information in the literature about the management and outcome of infants with more severe hemorrhages (grades III, IV of Papile), due to the dismal outlook as to their outcome in most centers. The current status and concerns as to the management of these infants is reviewed, and the aspects of neurosurgical and neonatal follow-up and outcome are described. A significant number of these infants have severe handicaps, which are primarily motor. However, a group of infants is noted who have normal intellectual performance despite varying degrees of motor handicaps: 18% have normal intellectual and motor development. In the current series predictors of poorest outcome are the presence of grade IV hemorrhage and/or seizures. The vast majority of the grades III and IV hemorrhages develop hydrocephalus that is a complex management issue for the neurosurgeon.

We studied the effect of nebulized FPL 55712, a competitive leukotriene antagonist, on gas exchange in four anesthetized and mechanically ventilated basenji-greyhound dogs previously sensitized to Ascaris antigen. After control measurements, each dog received nebulized FPL 55712 followed by nebulized antigen, and the multiple inert gas elimination technique was used to recover VA/Q distributions at 15, 30, 45, and 60 minutes. The protocol was repeated in two additional experiments in the same animals using either saline + antigen or FPL 55712 alone. Measurements after treatment with FPL 55712 alone did not differ from control values. Both Ascaris antigen and FPL 55712 plus antigen decreased dynamic compliance below control values, but there was no difference in dynamic compliance between the two treatments. Mean systemic arterial pressure was not changed by any treatment. FPL 55712 plus antigen, unlike antigen alone, decreased cardiac output (1.7 v 3.5 L/min, P < .05) and caused an extremely broad and bimodal distribution of perfusion with increased bloodflow (31.0 v 1.6%, P < .05) to lung units with VA/Q ratios

We combined high-frequency oscillatory ventilation and intermittent mandatory ventilation, using a system composed of an Emerson airway vibrator, a Babybird 1 ventilator, and rate/pressure monitors. The Emerson device, a modified air compressor with rate controller, oscillated a small volume of gas at the airway. This device was coupled to the bird unit through a circuit of our design. Humidified fresh gas and pressure-relief valves were provided by the bird ventilator, and mean airway pressure was adjusted by its expiratory-limb venturi device or by the end-expiratory pressure control. The volume of gas delivered by the oscillator to various sites was measured with a plethysmograph tuned to high frequencies. At frequencies of 20 to 30 Hz, a 27-ml volume from the oscillator decreased to between 7 and 14 ml at the proximal airway, and to between 0.1 and 2.3 ml at the distal tip of the endotracheal tube. The magnitude of this decrease depended on the size of the endotracheal tube, the circuit resistance of the ventilator, oscillation frequency, and the position of the oscillator's expansion-chamber valve. We have used this system for over 3 yr to ventilate sick neonates safely and effectively.

Combined high-frequency oscillatory ventilation (HFOV) and intermittent mandatory ventilation (IMV) was used in 12 neonates with inadequate gas exchange with conventional IMV. Diagnoses included diaphragmatic hernia with hypoplastic lungs, pneumonia, persistent fetal circulation, and severe respiratory distress syndrome. In most patients there was severe air leak. Within 10 hours of beginning HFOV-IMV the mean arterial PCO2 fell from 60 +/- 5 (means +/- SEM) to 38 +/- 2 mm Hg (P less than 0.01) and the mean IMV rate was reduced from 96 +/- 8 to 17 +/- 4 breaths per minute (P less than 0.001). The mean arterial-alveolar oxygen tension ratio rose from 0.05 +/- 0.01 to 0.09 +/- 0.01 (P less than 0.005). Mean airway pressure in the trachea was reduced from 16 +/- 2 to 10 +/- 3 cm H2O (P less than 0.05). Four patients died, three of whom had diaphragmatic hernias with hypoplastic lungs. Five of the eight survivors had mild bronchopulmonary dysplasia requiring supplemental oxygen. These studies demonstrate that in some neonates with respiratory failure who fail to respond to conventional IMV, combined HFOV-IMV can be successful.

Fifty preterm infants (mean birth weight, 1266±303 g; mean gestational age, 30±2 weeks) who required a ventriculoperitoneal (VP) shunt for posthemorrhagic hydrocephalus (92% with Grade III or IV hemorrhage) were followed for neurodevelopmental problems. VP shunts were placed at a median age of 29 days (range, 18 to 87 days) after serial lumbar punctures failed to control progressive and symptomatic ventriculomegaly. A total of 34 infants (68%) required one shunt revision or more (median, 4 revisions) for infection or obstruction. Shunt infection occurred in 25 infants (50%) after initial placement or revision for a gross operative infection rate of 18.8%. Seven infants died, 2 from shunt infections. The infants were evaluated with audiological, ophthalmological, and neurodevelopmental examinations. Of the survivors, 11 (28%) have severe visual loss, 10 (24%) have hearing loss, and 4 (11%) have impairment of both senses. Of the infants, 21 (49%) have significant paralysis or muscle weakness, 19 (38%) have seizure disorders, and 7 (16%) are microcephalic. Developmental and motor scores were obtained using the Bayley or Knobloch-Gesell scales at 2, 6,12,18 and 24 months of age. Both developmental and motor scores were normal in 7 of the surviving infants (18%). Sixteen infants (41%) have one abnormal score and in 16 infants (41%) both developmental and motor scores were abnormal, indicating profound developmental delay. Twenty-six of the survivors (60%) have multiple handicaps. There was no association between developmental or motor scores and the number of shunt infections or revisions. Grade IV hemorrhage or the occurrence of repeated seizures was a predictor of poor neurodevelopmental outcome.

We developed a method to measure accurately pressures at the airway opening (Pao) and in the trachea (Ptr) in neonates during high frequency oscillatory ventilation (HFOV) from 15-30 Hz. All component parts of the pressure-measuring system were tested as a unit against a reference transducer in a closed chamber in which sinusoidal pressure waves could be generated. The resulting waveforms were displayed on an oscilloscope and measured. Ptr was measured through the intramural lumen of a Hi-Lo jet tracheal tube (National Catheter Co., Argyle, NY) opening 1 cm above the distal tip. Pressure readings from uncorrected waveforms indicated a discrepancy between measured and actual pressures, as high as 100% at frequencies of 100 Hz. When the resonance of the system was damped with a CorrecTORR (Norton Health Care Products, Akron, OH), the ratio of test to reference transducer output was flat +/- 5% from 0-160 Hz for the Pao system and flat +/- 4% from 0-100 Hz for the Ptr system. Ptr system accuracy was verified in an excised rabbit lung and the systems were used clinically in neonatal HFOV. We conclude that Pao and Ptr can be measured accurately during HFOV by this method.

Chest radiographs of 18 newborns treated with endotracheal instillation of human surfactant for respiratory distress syndrome (RDS) were compared with those of 18 similar but untreated infants. In the treated infants, severity of RDS significantly improved after surfactant administration. Most treated infants (16/18) exhibited a left-to-right shunt, presumably through a patent ductus arteriosus; similar findings were noted in untreated infants (17/18). Complications of respiratory assistance in the treated infants included transient pulmonary interstitial emphysema (n = 1), pneumothorax (n = 1), and mild (n = 4) to moderate (n = 2) bronchopulmonary dysplasia; the incidences of these complications did not exceed those in untreated infants. In three treated infants, a transient interstitial lung disease developed 3-4 days after surfactant administration.

We performed a randomized, prospective clinical trial comparing intratracheal administration of human surfactant with conventional treatment with intermittent mandatory mechanical ventilation alone for treatment of severe respiratory distress syndrome in preterm infants of less than 30 weeks gestation. Twenty-two infants (mean gestational age 27.0 weeks, mean birth weight 987 gm) were given surfactant, and 23 infants (mean gestational age 27.2 week, mean birth weight 1055 gm) received intermittent mandatory ventilation. Infants given surfactant required less FiO2 during the first week, had lower mean airway pressure during the first 48 hours, and had improved ventilatory index and a/A PO2 ratio. Death or the occurrence of bronchopulmonary dysplasia was significantly less among infants given surfactant (P = 0.019). Pneumothorax, pulmonary interstitial emphysema, and need for FiO2 greater than or equal to 0.3 for greater than 30 days was significantly less in the surfactant group. This trial confirms the efficacy of treatment with human surfactant in preterm infants with severe respiratory distress syndrome.

The optimum time for VP shunt placement in infants with posthemorrhagic hydrocephalus is controversial. We studied 28 preterm infants born between 1979-1983 (Mean birthweight 1338±329gm; mean gestational age 30±2wk) in whom serial lumbar punctures failed to control progressive and symptomatic ventriculomegaly after grade III (62%) or grade IV (38%) intraventricular hemorrhage. VP shunts were placed at a median age of 28 days (range 11-78 days). Seventeen infants (61%) required 1 or more shunt revisions and 10(36%) had shunt infections. Three infants died, 1 from a shunt infection. The infants were evaluated with audiologic, ophthalmologic and neurologic examinations. Eight infants (29%) have profound visual loss, 5 of whom have cortical blindness, and 7 (25%) have hearing impairment. Five infants have profound neurological sequelae and 7 have seizure disorders. A developmental quotient(DQ) and motor index (MI) were obtained between 4-12 months adjusted age using the Bayley and/or Knobloch-Geselfl scales. The number of infants having various developmental scores is shown below: Although nearly 20% of these infants have normal DQM HCEEP)

To the Editor.— In their study of the effect of prophylactic phenobarbital on intraventricular hemorrhage, Bedard and coworkers1 utilize a powerful and efficient statistical method known as sequential analysis. In addition to performing the analysis correctly, it is important to describe this method clearly and accurately since it may be unfamilar to nonstatisticians. We believe there are errors in the illustration of the sequential plan (their figure, p 436) that may confuse others who wish to use this experimental design or who are trying to interpret their results.