Jerry J. Zimmerman

Helium-oxygen improves Clinical Asthma Scores in children with acute bronchiolitis

OBJECTIVE To determine the efficacy of a helium-oxygen mixture in children admitted to the pediatric intensive care unit with acute respiratory syncytial virus (RSV) bronchiolitis. DESIGN Randomized, double-blind, controlled, crossover study and nonrandomized, prospective study. SETTING A pediatric intensive care unit in a university hospital. PATIENTS Nonintubated children with signs of acute lower respiratory tract infection and a positive rapid immunoassay for RSV admitted to the pediatric intensive care unit. INTERVENTIONS Treatment with either helium-oxygen or air-oxygen was administered in random order for 20 mins. Nonrandomized patients received helium-oxygen as initial therapy. MEASUREMENTS AND MAIN RESULTS Clinical Asthma Score, respiratory rate, heart rate, and pulse oximetry oxygen saturation values were recorded at baseline (before randomization) and at the end of each 20-min treatment period (helium-oxygen or air-oxygen). Nonrandomized patients were studied 20 mins into helium-oxygen delivery. Eighteen patients were studied, 13 of whom were randomized. Five children with severe bronchiolitis (Clinical Asthma Score of > or =6) were initially given helium-oxygen and scored at 20 mins. Mean Clinical Asthma Score was 3.04 (range 1 to 7.5) in the 13 randomized patients and 4.25 (range 1 to 9) in the 18 patients overall. Clinical Asthma Score decreased in the 13 randomized patients (mean 0.46, p < .05) and in the 18 patients overall (mean 1.23, p < .01) during helium-oxygen delivery. In randomized patients with Clinical Asthma Scores of <6 (n = 12), a positive correlation (rs = .72) was observed between the Clinical Asthma Score at baseline and the change in Clinical Asthma Score during helium-oxygen administration (p = .009). Respiratory rate and heart rate decreased during helium-oxygen treatment but were not statistically significant. No complications occurred during helium-oxygen delivery. CONCLUSIONS Inhaled helium-oxygen improves the overall respiratory status of children with acute RSV lower respiratory tract infection. In patients with mild-to-moderate bronchiolitis (Clinical Asthma Scores of <6), the beneficial effects of helium-oxygen were most pronounced in children with the greatest degree of respiratory compromise.

Bronchoalveolar oxyradical inflammatory elements herald bronchopulmonary dysplasia.

OBJECTIVES To quantify oxyradical inflammatory markers in serial endotracheal tube aspirates obtained from premature neonates at risk for developing bronchopulmonary dysplasia, and to correlate these parameters with clinical manifestations of the disease. DESIGN Prospective cohort study. SETTING Tertiary neonatal intensive care unit. PATIENTS Twenty-eight intubated, premature infants, with 15 infants displaying simple respiratory distress syndrome and 13 infants eventually developing bronchopulmonary dysplasia. INTERVENTIONS Endotracheal tube aspirates were collected and clinical severity scores were calculated longitudinally from an inception cohort during the first week of life. Diagnosis of bronchopulmonary dysplasia by standard criteria was recorded at 30 days of life. Various biochemical analyses related to pulmonary oxyradical stress were determined on endotracheal tube aspirates and were normalized according to the magnitude of serum/aspirate urea ratios. The demographic, illness severity, and biochemical characteristics of infants with simple respiratory distress syndrome and those characteristics of infants developing bronchopulmonary dysplasia were evaluated by masked comparison. MEASUREMENTS AND MAIN RESULTS Populations of respiratory distress syndrome and bronchopulmonary dysplasia infants could be differentiated during the first week of life by means of the following parameters: gestational age; birth weight; Score of Neonatal Acute Physiology; Neonatal Therapeutic Intervention Scoring System; epithelial lining fluid leukocytes; elastase; myeloperoxidase; xanthine oxidase and catalase enzyme activities; and total sulfhydryls. CONCLUSIONS Infants with simple respiratory distress syndrome could be segregated from those infants who developed bronchopulmonary dysplasia by the magnitude of the epithelial lining fluid oxyradical inflammation markers. While infants developing bronchopulmonary dysplasia typically exhibited increased concentrations of these markers during the first week of life, those infants with simple respiratory distress syndrome displayed low, uniform, or decreasing values of these markers over this interval. Infants developing bronchopulmonary dysplasia demonstrate an early pulmonary inflammatory response, and one key aspect of this response involves various oxyradical-generating systems.

Longitudinal analysis of neutrophil superoxide anion generation in patients with septic shock

ObjectiveTo examine polymorphonuclear leukocyte respiratory burst function serially in patients with septic shock. DesignProspective, longitudinal, descriptive study. SettingAdult and pediatric (university hospital) intensive care units. PatientsEight critically ill patients, with septic shock and eight critically ill patients without evidence of infection or sepsis. Measurements and Main ResultsSeverity of patient illness was estimated serially using the Acute Physiology and Chronic Health Evaluation (APACHE II) scoring system. For each patient, neutrophil superoxide anion synthesis was assayed spectrophotometrically in multiple blood samples over a period of 7 to 12 days after clinical identification of septic shock. The initial sample was obtained <12 hrs after admission. Reaction velocities initially, at 2 to 3 mins, and at 4 to 5 mins (nmol superoxide anion/min/106 neutrophils), and extent of reaction at 5 mins (nmol superoxide anion/5 mins/108 neutrophils) were determined for each assay.On the day of admission, the mean APACHE II score and initial velocity for the septic shock group were 21.5 ± 10 and 4.6 ± 2 nmol superoxide anion/min/106 neutrophils, respectively. Over the next 7 to 12 days, as the patients recovered, there was a significant (paired t-test) decrease in APACHE II scores (p < .005) and increase in initial velocity (p < .0005). The increase in initial velocity correlated with the accompanying decrease in APACHE II scores (r2 = .46). Neutrophil superoxide anion generation in the critically ill group was not suppressed compared with the septic shock group and remained normal throughout the evaluation period. Conclusions: In vitroneutrophil respiratory burst function is significantly depressed during early septic shock. As patients improve clinically, as quantitated by decreasing APACHE II scores, neutrophil respiratory burst function recovers, approaching normal values. (Crit Care Med 1993; 21:666–672)

Current perspectives on septic shock.

Although septic shock may be initiated by invading microbes, it is the metabolic and immunologic host responses that determine the true pathophysiology of this common critical care illness. Currently, septic shock therapeutics emphasize empiric and symptomatic treatment. Biochemical elucidation of the septic process will ultimately result in specific interventions for this ominous intensive care syndrome.

Prolonged mechanical ventilation of infants after open heart surgery

Records of 140 infants younger than 2 yr of age who had undergone open heart surgery were studied to evaluate the duration of postoperative mechanical ventilation (MV), to determine the relationship between prolonged MV and mortality, and to identify variables predisposing the patient to prolonged MV. MV was required beyond the first postoperative day in 56 infants, and was prolonged for at least 7 days in 19 infants. Mortality was approximately the same (16% to 17%) whether or not MV was required for more than 7 days. Preoperative and intraoperative variables associated with longer MV included younger age, longer cardiopulmonary bypass time, longer aortic cross-clamp time, and preoperative MV. Multiple predisposing factors increased the probability of prolonged MV. Postoperative variables including premature extubation and a second surgical procedure also were associated with prolonged MV. The consequences of prolonged MV may be minimized by early nutritional support, aggressive surveillance for treatable complications, and avoidance of premature extubation.

Detection of enhanced neutrophil adhesion to parainfluenza-infected airway epithelial cells using a modified myeloperoxidase assay in a microtiter format

Despite growing evidence that respiratory virus infections precipitate episodes of airway obstruction and airway hyper-responsiveness in young children and in asthma, little information is available on the mechanisms by which virus infections alter the airway physiology. Airway inflammatory changes (including influx of inflammatory cells such as neutrophils) have been described during episodes of airway hyper-responsiveness in both animal models and human subjects. Neutrophil damage to several cell types has been shown to require adhesion as a primary step. In order to examine the potential interactions between virus-infected airway epithelial cells and neutrophils, we have studied the ability of neutrophils to adhere to virus-infected airway epithelial cell cultures. Neutrophil adherence was determined indirectly, using myeloperoxidase as a marker for adherent neutrophils in an assay system described here. Airway epithelial cell cultures (both primary human tracheal epithelial cells, and two permanent cell lines, A549 and BEAS-2B) were grown in 96-well tissue culture plates and infected with human parainfluenza virus type 2. Infected airway epithelial cell cultures supported significantly enhanced levels of neutrophil adherence (up to 50-75% of neutrophils added to the wells) compared to uninfected control cultures. Moreover, this adherence occurred in a virus dose-dependent fashion, with increasing levels of adherence noted at increasing viral multiplicities of infection. The assay system described allows the detection of small numbers of adherent neutrophils (as few as 1000 neutrophils) in a 96-well format.

Opioid Analgesia in Mechanically Ventilated Children: Results from the multicenter MOTIF study

Objective: To examine the clinical factors associated with increased opioid dose among mechanically ventilated children in the pediatric intensive care unit. Design: Prospective, observational study with 100% accrual of eligible patients. Setting: Seven pediatric intensive care units from tertiary-care children’s hospitals in the Collaborative Pediatric Critical Care Research Network. Patients: Four hundred nineteen children treated with morphine or fentanyl infusions. Interventions: None. Measurements and Main Results: Data on opioid use, concomitant therapy, demographic and explanatory variables were collected. Significant variability occurred in clinical practices, with up to 100-fold differences in baseline opioid doses, average daily or total doses, or peak infusion rates. Opioid exposure for 7 or 14 days required doubling of the daily opioid dose in 16% patients (95% confidence interval 12%–19%) and 20% patients (95% confidence interval 16%–24%), respectively. Among patients receiving opioids for longer than 3 days (n = 225), this occurred in 28% (95% confidence interval 22%–33%) and 35% (95% confidence interval 29%–41%) by 7 or 14 days, respectively. Doubling of the opioid dose was more likely to occur following opioid infusions for 7 days or longer (odds ratio 7.9, 95% confidence interval 4.3–14.3; p < 0.001) or co-therapy with midazolam (odds ratio 5.6, 95% confidence interval 2.4–12.9; p < 0.001), and it was less likely to occur if morphine was used as the primary opioid (vs. fentanyl) (odds ratio 0.48, 95% confidence interval 0.25–0.92; p = 0.03), for patients receiving higher initial doses (odds ratio 0.96, 95% confidence interval 0.95–0.98; p < 0.001), or if patients had prior pediatric intensive care unit admissions (odds ratio 0.37, 95% confidence interval 0.15–0.89; p = 0.03). Conclusions: Mechanically ventilated children require increasing opioid doses, often associated with prolonged opioid exposure or the need for additional sedation. Efforts to reduce prolonged opioid exposure and clinical practice variation may prevent the complications of opioid therapy.

Advances and issues in bronchopulmonary dysplasia

Introduction Bronchopulmonary dysplasia (BPD) can truly be considered a disease of medical progress. It was first fully described in the literature and named by Northway et el.’ in 1967. Dr. Northway, a radiologist at Stanford University, recognized a distinctive radiographic pattern of chronic lung disease in infants surviving in the neonatal intensive care unit there directed by Dr. Philip Sunshine. More specifically, these patients were premature infants with respiratory distress syndrome (hyaline membrane disease) who were being managed with intermittent positivepressure ventilation using mechanical ventilators that delivered relatively high pressure and oxygen tension to the respiratory tract. Concurrently, one of the other pioneer neonatal intensive care units at Vanderbilt University observed the same phenomenon as Dr. Mildred Stallman’s team managed to increase the survival of premature infants with respiratory failure by using miniaturized mechanical ventilation instruments. Earlier in the decade, the death of Patrick Kennedy (son of President and Mrs. John Kennedy) focused the nation’s attention on the respiratory complications of premature birth. This tragic death and the combination of new knowledge and technology in newborn care led to the establishment of neonatal intensive care units and the emergence of new diseases such as BPD. It is ironic that a quarter of a century later, BPD remains an enigma to neonatologists and pediatric pulmonologists and intensivists. It is for this reason that several specialized centers of research supported by the National Institutes of Health have concentrated their efforts on enhancing and understanding the basic science and clinical aspects of lung injury, cellular repair processes, and treatment of BPD. Fortunately, during the past few years, there have been significant advances in our understanding of BPD. Although a number of issues remain, more progress is expected in the future as lung injury processes become explained. This review will summarize research developments of the past few years on the bases of published articles in refereed journals. More detailed information can be obtained in the scientific reports per se.

History and current application of intravenous therapy in children.

More than 36,000,000 individuals in the United States were hospitalized in 1985,1 and, on the average, 25% of hospitalized patients have insertion of an intravenous catheter (IVC).2 Considering those 9,000,000 IVC placements in 1985, it may be surprising to learn that “modern” intravenous (IV) therapy has a lifetime that is barely 40 years old. For the pediatrician, IV access holds particular importance, since its acquisition is often the rate-limiting step in initiation of a therapeutic plan, particularly in the setting of cardiopulmonary resuscitation. This article is a review of the nearly 500-year history of IV therapy and an overview of the IV techniques and products currently available for use in pediatric patients.

In vitro modulation of human neutrophil superoxide anion generation by various calcium channel antagonists used in ischemia-reperfusion resuscitation.

Generation of toxic oxygen species by activated polymorphonuclear leukocytes (PMNs) may represent an important mechanism of ischemia-reperfusion injury. Concentration-response data concerning inhibition of superoxide anion (O2-) generation by NADPH oxidoreductase (NADPH OR) from isolated human PMN were generated for five calcium channel antagonists commonly utilized in ischemia-reperfusion investigational therapeutics. Regression analysis derived IC50 values for verapamil, nimodipine, nicardipine and lidoflazine were 45, 20, 12 and 7 microM respectively. Inhibition of the extent of reaction at 5 min paralleled inhibition of initial velocity. No inhibition by flunarizine was noted at concentrations less than or equal to 25 microM (where it did not alter reaction mixture composition). Only nicardipine demonstrated a significant concentration-response effect relative to prolonging lag time preceding O2- synthesis. Inhibition appeared at least partially reversible for all five agents. Neither PMN activation/desensitization, free-radical scavenging, nor PMN cytotoxicity appeared to be involved in the inhibition of PMN O2- synthesis by these agents. Ca2+ antagonist inhibition of PMN NADPH OR appears to involve more than simple inhibition of Ca2+ flux across the PMN plasma membrane. Direct inhibition of the intracellular events involved in the activation and/or activity of NADPH OR may be operative.