Recurring BALB/c mouse lung inflammatory responses to episodic allergen exposure.

This study detailed the sequence of recurring inflammatory events associated with episodic allergen exposures of mice resulting in airway hyperreactivity, sustained inflammation, goblet-cell hyperplasia, and fibrogenesis that characterize a lung with chronic asthma. Ovalbumin (OVA)-sensitized female BALB/c mice were exposed to saline-control or OVA aerosols for 1 h per day for episodes of 3 d/wk for up to 8 wk. Lung inflammation was assessed by inflammatory cell recoveries using bronchoalveolar lavages (BAL) and tissue collagenase dispersions. Cell accumulations were observed within airway submucosal and associated perivascular spaces using immunohistochemical and tinctorial staining methods. Airway responsiveness to methacholine aerosols were elevated after 2 wk and further enhanced to a sustained level after wk 4 and 8. Although by wk 8 diminished OVA-induced accumulations of eosinophils, neutrophils, and monocyte-macrophages were observed, suggesting diminished responsiveness, the BAL recovery of lymphocytes remained elevated. Airway but not perivascular lesions persisted with a proliferating cell population, epithelial goblet-cell hyperplasia, and evidence of enhanced collagen deposition. Examination of lung inflammatory cell content before the onset of the first, second, and fourth OVA exposure episodes demonstrated enhancements in residual BAL lymphocyte and BAL and tissue eosinophil recoveries with each exposure episode. Although tissue monocyte-macrophage numbers returned to baseline prior to each exposure episode, the greatest level of accumulation was observed after wk 4. These results provide the basis for establishing the inflammatory and exposure criteria by which episodic environmental exposures to allergen might result in the development of a remodeled lung in asthma.

Enantiomer-selective pharmacokinetics and metabolism of ketorolac in children.

OBJECTIVE: To compare the pharmacokinetics and metabolism of R(+)- and S(-)- ketorolac in children. METHODS: Children from 3 to 18 years old received 0.6 mg/kg racemic ketorolac intravenously. Serial blood samples were obtained for 12 hours, and urine was collected for 12 to 24 hours. Racemic ketorolac was measured in plasma, and racemic ketorolac, para-hydroxyketorolac, and ketorolac glucuronide were measured in urine by HPLC. S(-)- and R(+)-ketorolac were measured in plasma; S(-)- and R(+)-ketorolac and ketorolac glucuronide were measured in urine by chiral HPLC separation. Plasma pharmacokinetic parameters for racemic drug and both enantiomers were determined for each patient. RESULTS: Clearance of racemic ketorolac in children was approximately 2 times the clearance reported in adults. Clearance of the S(-) enantiomer was 4 times that of the R(+) enantiomer. Terminal half-life of S(-)-ketorolac was 40% that of the R(+) enantiomer, and the apparent volume of distribution of the S(-) enantiomer was greater than that of the R(+) form. Recovery of S(-)-ketorolac glucuronide was 2.3 times that of the R(+) enantiomer. CONCLUSION: The higher clearance in children suggests that the weight-adjusted dose of ketorolac may have to be greater for children to achieve plasma concentrations comparable to those of adults. Because of the greater clearance and shorter half-life of S(-)-ketorolac, pharmacokinetic predictions based on racemic assays may overestimate the duration of pharmacologic effect. Enantiomeric pharmacokinetic differences are best explained by stereoselective plasma protein binding. Selective glucuronidation of the S(-) enantiomer suggests that stereoselective metabolism may also be a contributing factor.

Syndrome of inappropriate antidiuretic hormone secretion in children following spinal fusion.

OBJECTIVES: a) To determine if antidiuretic hormone (ADH) is elevated in patients undergoing spinal fusion, especially in those who have clinical evidence of syndrome of inappropriate antidiuretic hormone (SIADH); b) to evaluate the relationship between ADH secretion and the secretion of atrial natriuretic peptide (ANP). SETTING: Tertiary care pediatric intensive care unit (ICU) in a university hospital. DESIGN: A prospective cross-sectional, observational study with factorial design. PATIENTS: Thirty patients > or = 10 yrs of age undergoing spinal fusion admitted to the ICU for postoperative care. INTERVENTIONS: Patients underwent anterior, posterior, or both anterior/posterior spinal fusion. Blood was collected for serial measurements of ADH, ANP and serum electrolyte levels. Heart rate, blood pressure and central venous pressure were measured. MEASUREMENTS AND MAIN RESULTS: Thirty children were studied. Nineteen had idiopathic scoliosis, nine had neuromuscular scoliosis, one had Marfan's disease, and one had congenital scoliosis. Ten (33%) children met clinical criteria of SIADH. There was no difference in duration of surgery, blood loss, volume of iv fluid administration pre- and intraoperatively, or type of scoliosis between those who developed SIADH and those who did not. Hemodynamic variables were similar in both groups. ADH levels increased in both groups immediately postoperatively and at 6 hrs after surgery, but were much more elevated in those patients with SIADH. Patients with SIADH also had significantly higher ADH levels preoperatively. In relation to serum osmolality, ADH was considerably higher in those with SIADH compared with those who did not. Although ANP values tended to be higher in the group with SIADH, this did not reach statistical significance. CONCLUSION: SIADH occurs in a subset of children who undergo spinal fusion. The diagnosis of SIADH can be made easily using clinical parameters which are well-defined. In the face of SIADH, continued volume expansion may be harmful, and should therefore be avoided.

A randomized comparison of ketorolac tromethamine and morphine for postoperative analgesia in critically ill children.

OBJECTIVES: To evaluate the efficacy of a single dose of ketorolac compared with morphine for the relief of pain in children, and to determine the safety of ketorolac. SETTING: Tertiary pediatric intensive care unit in a university-affiliated hospital. DESIGN: Prospective, randomized, double-blind, parallel, single-dose, positive control study. PATIENTS: Children admitted to the intensive care unit with postoperative pain. INTERVENTIONS: Patients received a single dose of either morphine or ketorolac as the first postoperative analgesic when the pain score indicated significant pain. Blood pressure, heart rate, and urine output were recorded, as well as blood urea nitrogen, creatinine, bleeding time, hematuria or proteinuria, and aspartate aminotransferase. Side effects such as nausea and vomiting were noted. Morphine was used for rescue treatment if the patient continued to have significant pain > or =30 mins after study drug administration. MEASUREMENTS AND MAIN RESULTS: Of the 102 children studied, 48 received morphine and 54 received ketorolac. The percentage of patients reporting pain relief in the first and second hours after drug administration was not different between groups. Likewise, the proportion of patients who met the criteria for pain relief during the entire evaluation period was not different between groups. There was a trend toward fewer patients who received ketorolac requiring remedication in the first 4 hrs compared with those who received morphine, but this trend did not reach statistical significance. More patients in the morphine group failed to achieve pain relief at any time after the dose compared with those who received ketorolac. There were no differences between the two groups in physiologic or laboratory variables. Vomiting was more common in patients who received ketorolac. CONCLUSION: Ketorolac is comparable to morphine in relief of postoperative pain in children. A single dose of ketorolac does not result in abnormal postoperative bleeding or alter renal function. However, ketorolac may cause nausea and vomiting in some patients.

Idiopathic pulmonary hemorrhage in infancy. Clinical features and management with high frequency ventilation.

STUDY OBJECTIVES: To describe the clinical characteristics of infants with severe acute pulmonary hemorrhage and the effects of mechanical ventilation on gas exchange. SETTING: Tertiary care pediatric ICU in a university hospital. PATIENTS AND DESIGN: Case records of patients with severe acute pulmonary hemorrhage from January 1992 to July 1995 were reviewed. Acute pulmonary hemorrhage was defined as hemoptysis and/or epistaxis or blood obtained from endotracheal tube which could not be attributed to cardiac or vascular malformation, infectious process, or known trauma. INTERVENTIONS: Patients were initially managed with conventional ventilation. High frequency ventilation (HFV) was utilized when hypoxemia (PaO2/PAO2 < 0.2) and/or respiratory acidosis (PaCO2 > or = 60 mm Hg with pH < 7.25) persisted. MEASUREMENTS AND RESULTS: Six African-American male infants from Detroit, with a median age 2.3 months, presented with severe acute pulmonary hemorrhage. Chest radiographs showed diffuse bilateral infiltrates or opacification with a normal sized heart. All infants were managed with HFV, four by oscillation and two by jet. The indications for HFV were persistent hypoxemia (2), respiratory acidosis (1), and a combination of both (3). There was an improvement in pH and PaCO2, and a decreased need for oxygen 6 and 24 h after initiating HFV. PaO2/PAO2 and oxygenation index showed a tendency toward improvement. All infants survived, and there were no complications. No cause for pulmonary hemorrhage was found in any of the infants. CONCLUSIONS: Idiopathic acute pulmonary hemorrhage is a potentially life-threatening disorder encountered among inner-city infants. HFV is highly effective and safe in rapidly reversing the severe oxygenation and ventilation deficits in this setting.

Predicting outcome in children with severe acute respiratory failure treated with high-frequency ventilation.

OBJECTIVES: a) To demonstrate the effect of high-frequency ventilation on gas exchange in children with severe acute respiratory failure unresponsive to conventional ventilation; b) to identify patients at high risk of death early after institution of high-frequency ventilation. SETTING: Tertiary care pediatric intensive care unit in a university hospital. DESIGN: A cross-sectional, observational study with factorial design. PATIENTS: Thirty-one patients with severe acute respiratory failure defined as a Pao2/F1o2 of < 150 torr (< 20 kPa) with a positive end-expiratory pressure of > or = 8 cm H2O and/or Paco2 of > 60 torr (> 8 kPa) with an arterial pH < 7.25. INTERVENTIONS: Patients received either high-frequency oscillation or jet ventilation if respiratory failure was unresponsive to conventional ventilation and if the underlying disease process was deemed reversible. MEASUREMENTS AND MAIN RESULTS: Thirty-one children were managed with high-frequency ventilation, 11 children with jet and 20 children with oscillator. Arterial blood gases and level of ventilatory support were recorded before and at 6, 24, 48, 72, and 96 hrs after institution of high-frequency ventilation. There was an improvement in an arterial pH, Paco2, Pao2, and Pao2/FID2 6 hrs after institution of high-frequency ventilation (p < .01). This improvement, along with decreased need for oxygen, was sustained through the subsequent course. Twenty-three (74%) of 31 children treated with high-frequency ventilation survived. Survivors showed an increase in an arterial pH, Pao2, Pao2/FIO2, and a decrease in Paco2 within 6 hrs, whereas nonsurvivors did not. Oxygenation index was the best predictor of outcome. A combination of an initial oxygenation index of > 20 and failure to decrease the oxygenation index by > 20% by 6 hrs after initiation of high-frequency ventilation predicted death with 88% (7/8) sensitivity and 83% (19/23) specificity, with an odds ratio of 33 (p = .0036, 95% confidence interval 3-365). CONCLUSIONS: In patients with potentially reversible underlying diseases resulting in severe acute respiratory failure that is unresponsive to conventional ventilation, high-frequency ventilation improves gas exchange in a rapid and sustained fashion. The magnitude of impaired oxygenation and its improvement after high-frequency ventilation can predict outcome within 6 hrs.

Aerosolized ribavirin in mechanically ventilated children with respiratory syncytial virus lower respiratory tract disease: a prospective, double-blind, randomized trial.

OBJECTIVE: To study the effect of ribavirin aerosol therapy on the immediate clinical course of mechanically ventilated children with respiratory syncytial virus lower respiratory tract disease. DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: Pediatric intensive care unit (ICU) of a university teaching hospital. PATIENTS: Forty-one children requiring mechanical ventilation for respiratory syncytial virus lower respiratory tract disease. INTERVENTIONS: Patients were stratified by the presence or absence of and underlying disease and then randomized to receive aerosolized ribavirin (20 mg/mL) or saline for 18 hrs/day for 5 days or until endotracheal extubation, whichever came first. MEASUREMENTS AND MAIN RESULTS: Dependent variables included the time course of the illness and the change in FIO2, ventilatory rate, PaO2/FIO2 ratio, and ventilatory-efficiency index of patients while they received aerosol therapy. Ribavirin- and placebo-treated patient groups were not significantly different in the number of ventilator days (6.4 +/- 6.9 vs. 8.2 +/- 10.1; p = .5), oxygen days (10.8 +/- 7.7 vs. 12.2 +/- 11.8; p = .9), ICU days (7.9 +/- 7.0 vs. 10.3 +/- 11.0; p = .7), or hospital days (12.9 +/- 9.7 vs. 16.2 +/- 14.0; p = .6) after the initiation of aerosol therapy. The change in FIO2, ventilatory rate, PaO2/FIO2 ratio, or ventilatory-efficiency index did not differ between the two groups. No ventilator malfunction was observed. There were six deaths caused by intractable hypoxemia in patients with underlying cardiopulmonary disease. Four of these deaths were in the placebo group and two in the ribavirin group (p = .5). CONCLUSIONS: Ribavirin aerosol therapy can be safely administered to mechanically ventilated children with severe respiratory syncytial virus lower respiratory tract disease. However, this therapy does not appear to affect immediate clinical outcome in such patients.

Transporting the neurologically compromised child.

The initial evaluation, stabilization, and subsequent transport of the neurologically compromised child should take into account the pathophysiologic response of the CNS to a variety of injurious factors. Little can be done to avoid neuronal damage from the primary event. Secondary insults resulting from hypoxemia, ischemia, intracranial hypertension, and fluid shifts can and must be prevented to ensure maximum neuronal salvage, however. Maintenance of an adequate airway, breathing, and circulation assume an immediate and ongoing priority. Neuroresuscitation should be directed toward reversing alterations in cerebral metabolism, autoregulation, brain water, and ICP associated with individual pathologic states.

Limitations of the Glasgow Coma Scale in predicting outcome in children with traumatic brain injury.

OBJECTIVE: To study the hypothesis that, in the absence of an ischemic-hypoxic state, children with severe traumatic brain injury and with unfavorable Glasgow Coma Scale scores may have good recovery. DESIGN: Retrospective, observational, cross-sectional study with factorial design. SETTING: Inpatient population in a university hospital. PATIENTS: Seventy-nine children with traumatic brain injury admitted to the intensive care unit. INTERVENTIONS: All patients received close monitoring and strict control of intracranial pressure (less than 20 mm Hg) and cerebral perfusion pressure (greater than 60 mm Hg). MEASUREMENTS AND RESULTS: Admission Glasgow Coma Scale score, survival, need for cardiopulmonary resuscitation, presence of shock, peak intracranial pressure, duration of coma, Glasgow Outcome Scale score, and the results of neuropsychologic tests were analyzed. Of 79 children, 70 (89%) survived. Although the mortality rate was higher among patients with Glasgow Coma Scale scores of 3 to 5, 14 (64%) of 22 of these children survived. Nonsurvivors had a significantly higher incidence of shock and need for cardiopulmonary resuscitation. Except for two patients who had prolonged hypoxemia, all children, including those with Glasgow Coma Scale scores of 3 to 5, had a satisfactory outcome (Glasgow Outcome Scale scores of 4 or 5). Neuropsychologic outcome was not significantly different in the survivors with Glasgow Coma Scale scores of 3 to 5 and those with Glasgow Coma Scale scores of 6 or more. CONCLUSIONS: A low Glasgow Coma Scale score does not always accurately predict the outcome of severe traumatic brain injury; in the absence of hypoxic-ischemic injury, children with traumatic brain injury and Glasgow Coma Scale scores of 3 to 5 can recover independent function.

Metabolism and pharmacokinetics of acetaminophen in a severely poisoned young child.

A 1-year-old child with severe acetaminophen (APAP) poisoning after ingestion of 10 gm APAP demonstrated central nervous system depression, shock, hypothermia, and metabolic acidosis. There was dramatic improvement during treatment with intravenously administered N-acetylcysteine (NAC) and hemodialysis, and the patient recovered without sequelae. A detailed study of APAP metabolism was carried out during the initial 72 hours after ingestion. APAP-sulfate and APAP-glucuronide accounted for 29% and 33%, respectively, of total drug in urine, whereas cysteine and NAC conjugates accounted for only 12%. The low incidence of severe toxicity in children after overdoses of APAP may be related to greater capacity to metabolize APAP via a nontoxic pathway.