Targeted enzyme therapy of experimental glomerulonephritis in rats.

We sought to determine whether systemic administration of proteases ameliorates membranous nephritis induced in rats by immunization and challenge with cationic bovine gamma globulin, and whether targeting of protease to glomerular capillaries increases efficacy. Proteases substituted with biotin were targeted via the cationic protein avidin A, which by virtue of its charge has affinity for the glomerular basement membrane. Despite identical pretreatment proteinuria, rats given untargeted protease (biotin-conjugated without avidin, or unconjugated plus avidin) had significantly less proteinuria than saline-treated controls and nephrotic rats given avidin plus biotin-conjugated (targeted) protease had even less proteinuria and reduced glomerular rat IgG and C3. Among more severely nephrotic rats, targeted protease was again more effective than untargeted protease at reducing proteinuria, and also decreased the size of electron-dense glomerular deposits, hypercholesterolemia, and creatininemia. Inactivated targeted proteases had no effect on proteinuria, hypercholesterolemia, or azotemia. Finally, active targeted protease did not affect proteinuria in the nonimmune mediated nephrosis induced by puromycin aminonucleoside. We conclude that systemic protease can specifically diminish glomerular immune deposits, proteinuria, hyperlipidemia, and creatininemia associated with experimental immune complex glomerulonephritis but not toxic nephrosis, and that targeted protease is more effective than untargeted protease.

Diuretic therapy of heart failure in infants and children.

Diuretics are the mainstay of traditional therapy for congestive heart failure. The syndrome of heart failure is now understood to involve complex interactions of neurohumoral substances released in response to poor cardiac function. Developmental changes during infancy and childhood will affect both the activation of systemic neurohumoral responses and the pharmacokinetic and pharmacodynamic actions of diuretics. Few human studies directly evaluate the efficacy of diuretic therapy in heart failure in adults. The pharmacodevelopmental aspects of diuretic therapy in infants and children are also incompletely studied. This review will describe the kidney's role in the pathogenesis of sodium and water retention in heart failure and the developmental changes in the kidney related to fluid retention. Known principles of diuretic therapy in congestive heart failure will be described. All these factors can then be used by the reader to evaluate the role of diuretic therapy in the complex syndrome of heart failure in infants and children.

Paralyzation and sedation of the ventilated trauma patient.

Sedation and analgesia will be required in the mechanically ventilated pediatric trauma patient. Adequate provision of both has a number of beneficial physiologic and psychologic effects. There are a number of categories of sedatives available for use. To provide optimal management and avoid adverse sequellae, an understanding of the pharmacology of these agents should guide their use in this group of patients, who are likely to have variable pharmacokinetic responses and therapeutic goals. Neuromuscular blockade is warranted in only a select population of mechanically ventilated ICU patients. Given newer ventilator technology and modes, it is certainly possible to achieve patient-ventilator synchrony with the use of sedation alone. Neuromuscular blockade is associated with a number of possible adverse effects, including prolonged weakness or paresis, and prohibits ongoing clinical assessment. When the use of this therapy is deemed necessary, it is again essential to understand the pharmacodynamics and pharmacokinetics of the available agents to avoid potential complications.

Renal replacement therapies in pediatric multiorgan dysfunction syndrome.

Both peritoneal dialysis (PD) and continuous hemodiafiltration (CHDF) techniques are used in children who develop acute renal failure as part of multiorgan dysfunction syndrome (MODS). An important goal of renal support in MODS is treatment and prevention of fluid overload. This report describes an experience with PD and CHDF in children with MODS and presents an analysis of fluid balance for each modality. Medical records of patients with MODs treated with PD/CHDF were reviewed. Fluid balance was studied only in patients with documented fluid overload treated with PD/CHDF for more than 24 h. Successful fluid control was defined as more fluid output than input over the course of PD/CHDF. CHDF was used in 37 patients, median age 47 months (range 0.2-284 months), for a mean of 110 h (range 4-733 h). PD was initiated in 25 patients, median age 4 months (range 0.1-156 months), for a mean of 145 h (range 7-992 h). Successful fluid control was achieved in 17 of 26 (65%) CHDF patients and in 5 of 14 (36%) PD patients (P < 0.01, chi-squared). In conclusion, CHDF is more effective than PD in treating and preventing fluid overload in children with MODS.

A probabilistic statement of the structure activity relationship for environmental risk analysis.

In this paper, we define a mode of biological response of an organism to a chemical in terms of a general mathematical model of the response surface. The model describes the combined effects of dose-level exposure and time-duration exposure using 570 96-hr toxicity tests with fathead minnows. The response surface along the dose and time axes for each chemical in these tests were completely defined by two scale factors, one for dose and one for time, and two form factors, one for dose and one for time. The scale factors for dose and time are proportional with the inverse of LC50 and Lt50, respectively. The form factors measure the relative response strategies with respect to dose and time exposures. Only the scale factor for the dose is correlated with the logarithm of the octanol water partition coefficient (log P) and molecular weight (Mw). Additional and independent observations beyond log P and Mw are needed to correlate various modes of chemical action with the form factors. It is shown that narcosis-producing chemicals can be distinguished from other classes of chemicals by the dominance of the response strategy with respect to the dose over time exposures.

The pediatric sedation unit: a mechanism for pediatric sedation.

OBJECTIVES: We have created a pediatric sedation unit (PSU) in response to the need for uniform, safe, and appropriately monitored sedation and/or analgesia for children undergoing invasive and noninvasive studies or procedures in a large tertiary care medical center. The operational characteristics of the PSU are described in this report, as is our clinical experience in the first 8 months of operation. METHODS: A retrospective review of quality assurance data was performed. These data included patient demographics and chronic medical diagnoses, procedure, or study performed; sedative or analgesic medication given; complications (defined prospectively); and sedation and monitoring time. Patient-specific medical records related to the procedure and sedation were reviewed if a complication was noted in the quality assurance data. RESULTS: Briefly, the PSU was staffed with an intensivist and pediatric intensive care unit nurses. Patients were admitted to the PSU and assessed medically for risk factors during sedation. Continuous heart rate, respiratory rate, and pulse oximetry monitoring were used, and blood pressure was determined every 5 minutes. After sedation and stabilization, with monitoring continued, the patient was transported to the site to undergo the procedure or study. The pediatric intensive care unit nurse remained with the patient at all times. All necessary emergency equipment was transported with the patient. After the procedure or study was completed, the patient was returned to the PSU for recovery to predetermined parameters. We were able to analyze 458 episodes of sedation for this review. Procedures and studies included radiologic examinations, cardiac catheterization, orthopedic manipulations, solid organ and bone marrow biopsy, gastrointestinal endoscopy, bronchoscopy, evoked potential measurements, and others. Patients were 2 weeks to 32 years of age. The average time from initiation of sedation to last dose of medication administered was 84 minutes. The average time from initiation of sedation to full recovery was 120 minutes. Sedative and analgesia medications use was not standardized; however, the majority of children needing sedation received propofol or midazolam. For patients requiring analgesia, ketamine or fentanyl was added. In 79 of 458 (12%) sedation episodes, complications were documented. Mild hypotension (4.4%), pulse oximetry <93% (2.6%), apnea (1.5%), and transient airway obstruction (1.3%) were the most common complications noted. Cancellation of 11 (2.4%) procedures was attributable to complications. No long-term morbidity or mortality was seen. CONCLUSIONS: Many children require sedation or analgesia during procedures or studies. Safe sedation is best ensured by appropriate presedation risk assessment and with monitoring by a care provider trained in resuscitative measures who is not involved in performing the procedure itself. Uniformity of care in a large institution is a standard met by the creation of a centralized service, with active input from the department of anesthesiology. We present the PSU as a model for achieving these goals.

Optimal sedation of mechanically ventilated pediatric critical care patients.

OBJECTIVE: To derive a target range of optimal sedation for the COMFORT Scale and to prospectively test that target range against intensivist assessment of adequacy of sedation. DESIGN: Serial prospective agreement cohort studies. SETTING: Twelve-bed pediatric intensive care unit in an urban academic teaching hospital. PATIENTS: Eighty-five mechanically ventilated children (aged 0 to 102 months). INTERVENTIONS: Three serial prospective studies comparing simultaneous, independent ratings conducted by trained observers using an objective scale and intensive care physicians using global assessment. The initial study was designed to derive the target range. The second study was conducted to verify that target range in a second population. The third study was added to evaluate relative variability in methods used in the second study. MEASUREMENTS AND MAIN RESULTS: Adequacy of sedation using visual analog scale and descriptive ratings or the COMFORT Scale (a previously validated behaviorally anchored scale to rate eight behavioral or physiologic dimensions of distress). The first study comprised 100 observations. Groups of patients described by the intensivist as inadequately sedated, optimally sedated, and excessively sedated had different mean COMFORT scores (30.5 +/- 0.7 vs. 22.9 +/- 5.8 vs. 14.3 +/- 0.7, respectively, p < .05). The target range of optimal sedation was defined as COMFORT scores of 17 to 26. The second study verified the target range prospectively in a second group of 96 observations. The COMFORT score was strongly associated with the sedation adequacy rating by the intensivist (p < .001; r2 = .662). COMFORT scores accurately predicted the patient assignment to adequacy of sedation categories by the intensivist in 66.1% of observations. Discrepancy between physicians occurred in 38.5% of 16 paired physician ratings in the second study. In the third study, 120 observations comparing paired COMFORT scores to paired physician ratings of the same subjects demonstrated significantly less variability in COMFORT assessment of adequacy of sedation. COMFORT scores were similarly unbiased (1.1% vs. 0.22%) but more precise (8.0% vs. 16.7%) than intensivist ratings (p < .025). CONCLUSION: Adequacy of sedation is measured more consistently by observers using the COMFORT Scale than by intensivist global assessment.