Andre Raszynski

Experimental critical care in rats: gender differences in anesthesia, ventilation, and gas exchange.

OBJECTIVE To compare normative ventilatory and gas-exchange data and anesthetic requirements in male and female rats subjected to critical care conditions. DESIGN Prospective study. SETTING Critical care research laboratory in a hospital. SUBJECTS Twenty-two age-matched young male and female rats (Sprague-Dawley, Long Evans strain). INTERVENTIONS Anesthesia was induced with 65 and 45 mg/kg pentobarbital in male and female rats, respectively. The rats were then tracheostomized and cannulated in one femoral vein and artery. Anesthesia was maintained using 8-15 mg/kg/hr pentobarbital (iv) and controlled by continuous hemodynamic monitoring. MEASUREMENTS AND MAIN RESULTS Normoxic baselines for breathing frequency, tidal volume, minute volume, inspiratory-to-expiratory ratio, inspiratory drive (tidal volume/inspiratory time), respiratory system compliance, peak airway pressure, and gas-exchange profiles were established. Ventilatory and gas-exchange responses to oxygen and CO2 were then determined by exposure to 10 mins of hyperoxia (100% oxygen), two levels of mild and severe hypercapnic hyperoxia (inspired Pco2 of 30 and 60 torr; 4 and 8 kPa), and two levels of mild and severe normocapnic hypoxia (inspired PO2 of 81 and 48 torr; 10.7 and 6.3 kPa). The average anesthetic requirement (during a 5- to 6-hr experiment) was 30% less in the female rats than in the male rats (p < .05). Female rats showed significantly lower breathing frequency, minute volume (mL/min/kg), and inspiratory drive (mL/kg/sec) during hyperoxia, mild and severe hypercapnia, and mild hypoxia. Pulmonary peak airway pressure was significantly lower in the female rats, consistent with a significantly higher weight-indexed compliance during all exposures. The female rats also had significantly higher inspiratory-to-expiratory ratio and higher PaCO2 with lower pH during normoxia, hyperoxia, and mild hypercapnia. These gender differences had no effect on PaO2, which was similar in all exposures. CONCLUSIONS There are significant gender differences in ventilation, gas exchange, and anesthetic requirements in rats subjected to critical care conditions. The gas-exchange values observed in these spontaneously breathing rats may represent the optimal levels attainable during pentobarbital anesthesia with normal lungs. They may serve as standards for ventilator settings in the rat models used for critical care studies.

Validation of a Modified Pediatric Early Warning System Score A Retrospective Case–Control Study

The Pediatric Early Warning System (PEWS) score may be useful for detection of deterioration in clinical condition. In this retrospective study, the cases were patients transferred to the pediatric intensive care unit (PICU), and controls were those not transferred to the PICU. The maximum PEWS score in both groups were analyzed using Mann–Whitney U test and receiver operating characteristic curve (ROC). The study population included 100 cases and 250 controls. There was no difference in the age of cases and controls (6.3 vs 6.3 years). The length of hospital stay (18.09 ± 32 vs 3.93 ± 2.9 days; P < .001) and the maximum PEWS score (2.95 ± 1.5 vs 1.4 ± 0.8) were significantly higher for the cases (P < .0001). The PEWS score area under the ROC was 0.81 (95% confidence interval = 0.75-0.86). The sensitivity and specificity for a score 2.5 were 62% and 89%, respectively. The use of the modified PEWS score can help identify patients on wards who are at risk for deterioration.

Effect of hypothermia on ventilation in anesthetized, spontaneously breathing rats: theoretical implications for mechanical ventilation

Objective: To test if hypothermia, induced by a sustained pentobarbital anesthesia, in rats can reduce ventilatory demands without compromising pulmonary gas-exchange efficiency. Design: Prospective study. Setting: Research laboratory in a hospital. Subjects: One group of 11 female Sprague Dawley rats. Interventions: The rats were anesthetized with 45 mg/kg pentobarbital, tracheostomized and intubated; their femoral veins and arteries were cannulated. After surgery, anesthesia and fluid balance were maintained (10 mg/kg per h pentobarbital, and 5 ml/kg per h saline, i. v.). Rectal temperature, mean arterial blood pressure (MAP), and heart rate (HR) were continuously monitored. The respiratory variables and gas-exchange profiles were determined at 38 °C (normothermia), and during stepwise hypothermia at 37, 35, 33, 31 and 29 °C. The arterial pressure of carbon dioxide (PaCO2), pH and arterial pressure of oxygen (PaO2) during hypothermia were corrected at body temperature. Measurements and results: Graded systemic hypothermia, with maintained anesthesia, produced a strong correlation between reduction in the respiratory frequency and rectal temperature (r2 = 0.55; p < 0.0001; n = 66). The minute volume was significantly reduced, starting at 35 °C, without significant changes in the tidal volume (repeated measures of analyses of variance followed by Dunnett multiple comparisons test). No significant changes occurred in the PaCO2, pH, PaO2, hemoglobin oxygen saturation, the calculated arterial oxygen content and estimated alveolar-arterial oxygen difference during mild hypothermia (37–33 °C). The PaO2, however, was significantly reduced below 31 °C. The MAP remained stable at different levels of hypothermia, whereas HR was significantly reduced below 33 °C. Conclusions: Mild hypothermia in rats, induced by a sustained pentobarbital anesthesia, reduces ventilation without compromising arterial oxygenation or acid-base balance, as measured at body temperature. Theoretically, our observations in spontaneously breathing rats imply that a combination of mild hypothermia with anesthesia could be safely utilized to maintain adequate ventilation, using relatively low minute ventilation. We speculate that such a maneuver, if applied during mechanical ventilation, may prevent secondary pulmonary damage by allowing the use of lower ventilator volume-pressure settings.

Estimation of Nitrogen Balance Based on a Six-Hour Urine Collection in Infants

The accuracy of a 6-hr vs a 24-hr urine collection for the determination of urinary urea nitrogen was studied in 15 infants. Patients age ranged from 2 weeks to 3 yr, encompassing a wide variety of diagnoses. All patients had normal renal function at the time of the study. Participants had indwelling foley catheters throughout the study. Urine specimens were collected over a continuous 24-hr period. Aliquots obtained from urine collected over 0 to 6 hr and the total urine collection were analyzed utilizing the urease enzymatic method in the Astra. Statistical analysis was performed comparing the actual 24-hr determination to the estimation based on the 6-hr collection, utilizing linear regression. The analysis of data produced a highly significant correlation (r = 0.904, p less than 0.0001). When a 24-hr urine collection is not possible, a 6-hr collection is a useful alternative for the calculation of nitrogen balance in infants.

Therapeutic hypercapnia enhances the inflammatory response to endotoxin in the lung of spontaneously breathing rats

Objective: To test the hypothesis that therapeutic hypercapnia enhances the proinflammatory responses to endotoxemia in the lung and spleen of rats. Design: Prospective randomized study. Settings: Hospital research institute. Subjects: Forty-eight adult male rats. Interventions: Rats were randomly assigned for a 24-hr period to four breathing groups (n = 11/group), including air (controls), normoxic air with 5% CO2 (therapeutic hypercapnia), air and endotoxemia (5 mg/kg endotoxin), and therapeutic hypercapnia with endotoxemia. After euthanasia, the lung and spleen were removed for pro- and anti-inflammatory cytokine analyses and pulmonary histology evaluation. Four additional rats were used to examine changes in gas exchange and acid-base balance during exposure to therapeutic hypercapnia with and without endotoxemia before and at 4, 12, and 24 hrs into the study, using a permanently catheterized femoral artery. Measurements and Main Results: The ratios of proinflammatory cytokines (interleukin-1&bgr; [IL-1&bgr;] and IL-6) and an anti-inflammatory cytokine (IL-10) in the lungs and spleen were used as indices of inflammatory status. The wet-weight to dry-weight ratios, histologic changes in lung interstitial inflammation, and alveolar structures were used as indices of endotoxin-induced acute lung injury. IL-1&bgr; and IL-6 expression was significantly high in the lung of therapeutic hypercapnia-treated endotoxemic rats compared to the lung of rats subjected to only endotoxemia (p < .05 and p < .001, respectively). In the spleen, therapeutic hypercapnia-treated endotoxemic rats had low expression of IL-1&bgr; and IL-6 compared to rats subjected to only endotoxemia (p > .05 and p < .001). Therapeutic hypercapnia following endotoxemic challenge was associated with a proinflammatory response in the lung and an anti-inflammatory response in spleen, as assessed by the ratios of IL-1&bgr; and IL-6 to IL-10. The wet-weight to dry-weight ratio and the interstitial space were significantly increased only in therapeutic hypercapnia-treated endotoxemic rats (p < .05). The alveolar-septal thickness was significantly increased by 21% in endotoxemic rats (p < .001) and by 33% in therapeutic hypercapnia-treated endotoxemic rats (p < .001). Conclusions: A 24-hr exposure to therapeutic hypercapnia in endotoxin-stimulated, spontaneously breathing rats is associated with a proinflammatory immune response in the lung and anti-inflammatory response in the spleen as well as an increase in certain histologic indices of endotoxin-induced lung injury.

The effects of CO2 on cytokine concentrations in endotoxin-stimulated human whole blood.

Objectives:Hypercapnia is known to modulate inflammation in lungs. However, the effect of hypocapnia and hypercapnia on blood cytokine production during sepsis is not well understood. We hypothesized that CO2 modulates ex vivo inflammatory cytokine production during endotoxin stimulation. To test this hypothesis, we measured the production of pro- and anti-inflammatory cytokines in endotoxin-stimulated human whole blood cultures under hypercapnic, normocapnic, and hypocapnic conditions. Design:Prospective randomized study. Setting:Basic research laboratory. Subjects:Ten male and 10 female volunteers. Interventions:Venous blood samples, taken from volunteers were cultured at 37°C, under hypocapnic (2% CO2), normocapnic (5% CO2), and hypercapnic (7% CO2) conditions, with and without endotoxin stimulation. After 24 hrs of incubation, each cultures supernatant was analyzed for tumor necrosis factor-α, interleukin-1β, interleukin-6, interleukin-10, and interferon-γ concentrations by enzyme-linked immunosorbent assay. Data were analyzed using nonparametric repeated measures of analysis of variance followed by Dunns multiple comparisons test. Analysis of variance with Bonferroni correction was used to compare gender differences in cytokine concentrations. The Pearson test was used to estimate correlation between hydrogen ion and individual cytokine concentrations. Measurements and Main Results:Concentrations of the proinflammatory cytokines tumor necrosis factor-α, interleukin-1β and of the anti-inflammatory cytokine interleukin-10 under hypercapnic condition were significantly decreased (p < 0.05, 0.01, and 0.001, respectively) for both genders when compared with either normocapnic or hypocapnic conditions. Concentrations of tumor necrosis factor-α and interleukin-1β were significantly higher in men. In women, concentrations of interleukin-6 were significantly decreased under hypercapnic condition when compared with hypocapnic condition. An inverse relationship was found between hydrogen ion concentration and concentrations of tumor necrosis factor-α and interleukin-10. Conclusions:Our results are consistent with the hypothesis that CO2 can affect the production of pro- and anti-inflammatory cytokines after ex vivo stimulation with endotoxin.

Effect of extracorporeal membrane oxygenation on tobramycin pharmacokinetics in sheep.

Background and MethodsCritically ill infants undergoing extracorporeal membrane oxygenation (ECMO) therapy often receive multiple pharmacologic agents. Although the disposition of many drugs has been assessed in patients undergoing cardiopulmonary bypass and in patients receiving mechanical ventilation, only limited data exist for selected medications in patients undergoing ECMO. To evaluate the potential influence of ECMO on aminoglycoside pharmacokinetics, we studied the disposition of tobramycin in ten sheep before and during ECMO therapy. Each sheep received a single iv dose of tobramycin during a control period before ECMO and on a study day during ECMO. Identically timed serial blood samples over 4 hrs were obtained after each tobramycin dose. Paired serum tobramycin concentrations were obtained pre- and postmembrane oxygenator during ECMO in six sheep. ResultsAlterations in specific pharmocokinetic variables for tobramycin were observed as a result of ECMO. Estimates of elimination halflife and volume of distribution for tobramycin were significantly increased during ECMO as compared with control (pre-ECMO) values (1.8 ±PT 0.3 vs. 2.7 ±PT 0.8 [SD] hrs [p < .01] and 0.3 ±PT 0.1 vs. 0.5 ±PT 0.2 L/kg [p < .005], respectively). Tobramycin body clearance was unaffected by the procedure (1.8 ±PT 0.8 vs. 1.7 ±PT 0.4 mL/min/kg). Paired serum tobramycin concentrations obtained pre- and postmembrane oxygenator demonstrated no drug removal. ConclusionsThese data suggest that ECMO circuitry does not sequester tobramycin and that the prolonged elimination half-life observed during ECMO therapy is not due to a change in drug clearance but is due to an ECMO-induced increase in tobramycin volume of distribution. To achieve and maintain preselected target tobramycin serum concentrations during ECMO, the usual dosage interval should remain unchanged, but the dose should be increased to compensate for the alteration in the drugs volume of distribution. The clinical applicability of these findings needs to be confirmed in carefully controlled clinical studies involving infants receiving ECMO therapy.

Drug use density in critically ill children and newborns: analysis of various methodologies.

Objective: To compare in the pediatric, cardiac, and neonatal intensive care units, three methods of assessing vancomycin and linezolid drug use density by number of: defined daily doses (DDDs), prescribed daily doses, and days of drug use per 100 patient days. Design: Retrospective study. Setting: A tertiary care children’s hospital. Patients: We reviewed the charts of patients admitted to the cardiac intensive care unit and neonatal intensive care unit in 2005 who were treated with vancomycin, and those admitted to the pediatric intensive care unit who were treated with vancomycin or linezolid during 2004 and 2005. Interventions: None. Measurements and Main Results: The number of patients, treatment days, total amount of vancomycin/linezolid, total intensive care unit admissions, and patient days were recorded. We used the World Health Organization definition of DDD for vancomycin and linezolid (2000 and 1200 mg, respectively). The prescribed daily dose for each intensive care unit was calculated for each year by dividing the total amount of the medication administered by the total number of treatment days. The drug use densities were then calculated as the total DDDs, prescribed daily doses, and days of drug use per 100 patient days. The vancomycin use densities were significantly different among the three intensive care units when compared by each method. They were significantly lower in all three units when expressed as DDDs per 100 patient days. The vancomycin drug use density in the pediatric intensive care unit was significantly decreased during 2005 compared with 2004 by all three methods. Conclusions: In critically ill children, drug use density of vancomycin is significantly less when evaluated by the DDD method compared with the prescribed daily dose method, a more appropriate method in children. However, the simplest and most accurate method of assessing drug use density is the number of days of drug use method, which allows comparison of drug use density between different pediatric facilities or clinical units.

Tracheobronchial injury during intratracheal pulmonary ventilation in rabbits

ObjectiveWe compared tracheobronchial injury following short-term intratracheal pulmonary ventilation (ITPV) and conventional mechanical ventilation (CMV) in a healthy rabbit model. ITPV, a form of tracheal gas insufflation, has been shown to decrease deadspace ventilation and increase CO2 removal and therefore may reduce ventilator-induced lung injury. SettingMedical center laboratory. SubjectsTwenty-five rabbits. InterventionsRabbits were randomly assigned to either ITPV or CMV (n = 15 and 10, respectively). Both groups were mechanically ventilated for 8 hrs at the same ventilator settings (Fio2, 0.4; rate, 30 breaths/min; flow, 4 L·min−1; positive end-expiratory pressure, 4 cm H2O; tidal volume, 40 mL). Peak, mean, and end-expiratory carinal pressures, ITPV flow rate, and hemodynamic variables were continuously monitored. Tissue samples for histologic analysis were obtained postmortem from the trachea contiguous to the tip of the endotracheal tube, the distal trachea, the carina, and the main bronchus. The histologic sections were scored, in a single-blind fashion, for ciliary damage, ulceration, hemorrhage, overall inflammation, intraepithelial inflammatory infiltrate, and edema. Measurements and Main ResultsITPV was associated with significantly lower Paco2 and deadspace ventilation ratio than CMV. The combined tracheobronchial injury scores for all samples were significantly higher in the ITPV group compared with the CMV group (p < .005; Mann-Whitney U test). The ITPV injury scores, compared with CMV injury scores, were significantly higher at the carina and main bronchus (p < .01; Kruskal-Wallis test followed by Dunn’s multiple comparison test). The area adjacent to the endotracheal tube showed the same degree of damage in both groups. Analysis of the injury scores in individual damage categories demonstrated the greatest difference in the ulceration category (p < .001). ConclusionsIn our study, ITPV, compared with CMV at the same minute ventilation, was associated with a significantly greater difference in tracheobronchial damage at the carina and main bronchus. We postulate that this difference may have been caused by the turbulence of the gas flow generated by the small-caliber ITPV catheter used in our neonatal-size animal model.

Fewer interventions in the immediate post-extubation management of pediatric intensive care unit patients: Safety and cost containment

PURPOSE The purpose of this article was to compare the safety and patient charges of two postextubation treatment regimens. MATERIALS AND METHODS Twenty-two pediatric patients, between the ages of 7 months and 13 years, who were mechanically ventilated for less than 5 days were studied in a prospective randomized nonblinded study at a multidisciplinary pediatric intensive care unit. Immediately after extubation all patients received supplemental oxygen, administered via mask or nasal cannulae, at a flow rate or concentration sufficient to maintain the pulse oximetric arterial oxygen saturations > 95%; arterial blood gas analyses were performed at 30 minutes after extubation. The subjects were randomly assigned to one of two protocols. Protocol A (our standard management) consisted of (1) three nebulized albuterol treatments administered 1 hour apart, and (2) a chest radiograph obtained within 60 minutes of extubation. Protocol B included one nebulized albuterol treatment administered immediately after extubation. We measured the heart rate, respiratory rate, and arterial blood pressure immediately after and at 60, 120, and 180 minutes following extubation. The following data were also recorded: arterial blood gas analysis results and continuous pulse oximetric arterial oxygen saturation levels. Any significant complications, such as stridor, respiratory distress, or requirement for reintubation, were noted if they occurred within 24 hours of extubation. Patient charge costs were calculated after obtaining the prevailing hospital and physician charges at the time of the study. RESULTS Eleven patients completed each arm of the study (total = 22). There were no statistically significant differences between the two groups with respect to arterial pH, serum bicarbonate, pulse oximetric arterial oxygen saturation, arterial blood pressure, respiratory rate, or heart rate (P > .05). Patients treated with Protocol A had a statistically, but not clinically, significant higher mean PaO2 and PaCO2 (P = .02 and P = .05, respectively) than those in Protocol B. Associated charges per patient for Protocol A were