Implementation of the Cardiac Inpatient Neurodevelopmental Care Optimization (CINCO) programme: an interdisciplinary, generalisable approach to inpatient neurodevelopmental care.

BACKGROUND: Children with CHD are at risk for neurodevelopmental delays, and length of hospitalisation is a predictor of poorer long-term outcomes. Multiple aspects of hospitalisation impact neurodevelopment, including sleep interruptions, limited holding, and reduced developmental stimulation. We aimed to address modifiable factors by creating and implementing an interdisciplinary inpatient neurodevelopmental care programme in our Heart Institute. METHODS: In this quality improvement study, we developed an empirically supported approach to neurodevelopmental care across the continuum of hospitalisation for patients with CHD using three plan-do-study-act cycles. With input from multi-level stakeholders including parents/caregivers, we co-designed interventions that comprised the Cardiac Inpatient Neurodevelopmental Care Optimization (CINCO) programme. These included medical/nursing orders for developmental care practices, developmental kits for patients, bedside developmental plans, caregiver education and support, developmental care rounds, and a specialised volunteer programme. We obtained data from the electronic health record for patients aged 0-2 years admitted for at least 7 days to track implementation. RESULTS: There were 619 admissions in 18 months. Utilisation of CINCO interventions increased over time, particularly for the medical/nursing orders and caregiver handouts. The volunteer programme launch was delayed but grew rapidly and within six months, provided over 500 hours of developmental interaction with patients. CONCLUSIONS: We created and implemented a low-cost programme that systematised and expanded upon existing neurodevelopmental care practices in the cardiac inpatient units. Feasibility was demonstrated through increasing implementation rates over time. Key takeaways include the importance of multi-level stakeholder buy-in and embedding processes in existing clinical workflows.

Developmental care pathway for hospitalised infants with CHD: on behalf of the Cardiac Newborn Neuroprotective Network, a Special Interest Group of the Cardiac Neurodevelopmental Outcome Collaborative.

Infants and children born with CHD are at significant risk for neurodevelopmental delays and abnormalities. Individualised developmental care is widely recognised as best practice to support early neurodevelopment for medically fragile infants born premature or requiring surgical intervention after birth. However, wide variability in clinical practice is consistently demonstrated in units caring for infants with CHD. The Cardiac Newborn Neuroprotective Network, a Special Interest Group of the Cardiac Neurodevelopmental Outcome Collaborative, formed a working group of experts to create an evidence-based developmental care pathway to guide clinical practice in hospital settings caring for infants with CHD. The clinical pathway, "Developmental Care Pathway for Hospitalized Infants with Congenital Heart Disease," includes recommendations for standardised developmental assessment, parent mental health screening, and the implementation of a daily developmental care bundle, which incorporates individualised assessments and interventions tailored to meet the needs of this unique infant population and their families. Hospitals caring for infants with CHD are encouraged to adopt this developmental care pathway and track metrics and outcomes using a quality improvement framework.

Pediatric ECMO: unfavorable outcomes are associated with inflammation and endothelial activation.

BACKGROUND: Inflammatory and endothelial activation responses during extracorporeal membrane oxygenation (ECMO) support in children are poorly understood. In this study, we aimed to determine if circulating inflammatory, endothelial activation, and fibrinolytic markers are associated with mortality and with neurologic outcomes in children on ECMO. METHODS: We conducted a secondary analysis of a two-center prospective observational study of 99 neonatal and pediatric ECMO patients. Inflammatory (interferon gamma [IFNγ], interleukin-6 [IL-6], IL-1ß, tumor necrosis factor alpha [TNFα]), endothelial activation (E-selectin, P-selectin, intercellular adhesion molecule-3 [ICAM-3], thrombomodulin [TM]), and fibrinolytic markers (tissue plasminogen activator [tPA], plasminogen activator inhibitor-1 [PAI-1]) were measured in plasma on days 1, 2, 3, 5, 7, and every third day thereafter during the ECMO course. RESULTS: All ECMO day 1 inflammatory biomarkers were significantly elevated in children with abnormal vs. normal neuroimaging. ECMO day 1 and peak levels of IL-6 and PAI-1 were significantly elevated in children who died compared to those who survived to hospital discharge. Tested biomarkers showed no significant association with long-term neurobehavioral outcomes measured using the Vineland Adaptive Behavioral Scales, Second Edition. CONCLUSIONS: High levels of circulating inflammatory, endothelial activation, and fibrinolytic markers are associated with mortality and abnormal neuroimaging in children on ECMO. IMPACT: The inflammatory, endothelial activation, and fibrinolytic profile of children on ECMO differs by primary indication for extracorporeal support. Proinflammatory biomarkers on ECMO day 1 are associated with abnormal neurologic imaging in children on ECMO in univariable but not multivariable models. In multivariable models, a pronounced proinflammatory and prothrombotic biomarker profile on ECMO day 1 and longitudinally was significantly associated with mortality. Further studies are needed to identify inflammatory, endothelial, and fibrinolytic profiles associated with increased risk for neurologic injury and mortality through potential mediation of bleeding and thrombosis.

Single breath nitrogen test as predictor of lung function decline and COPD over an 8-year follow-up.

BACKGROUND: The single breath nitrogen (SBN2) test was proposed for early detection of "small airways disease" in the seventies. Few longitudinal studies have subsequently evaluated the relationships between SBN2 test measurements and lung function decline or COPD incidence. AIM: This study evaluates whether SBN2 test abnormalities may be significant predictors of lung function decline and COPD incidence over an 8-year follow-up. STUDY DESIGN AND METHODS: In this longitudinal study, 907 adults (20+ years old; 56% males) from the prospective Po River Delta epidemiological study underwent SBN2 test at baseline and spirometry testing at both baseline and follow-up 8-year apart. Multinomial and multiple regression models were used to assess associations of SBN2 indexes and rates of FEV1 decline or risk of COPD incidence over time, after adjusting for sex, height and baseline age, FEV1 and smoking status. COPD was defined according to either GOLD or ATS-ERS criteria. RESULTS: Among SBN2 indexes, only the slope of alveolar plateau (N2-slope) was significantly associated with rates of FEV1 decline (7.93 mL/year for a one-unit change in N2-slope, p<0.0001), and with an increased risk of developing COPD as defined by GOLD (RR 1.81, 95%CI 1.29-2.52, mild; RR 2.78, 95%CI 1.70-4.53, moderate or severe obstruction) and ATS-ERS criteria (RR 1.62, 95%CI 1.14-2.29, mild; RR 3.40, 95%CI 1.72-6.73, moderate or severe obstruction). CONCLUSION: In this population-based study, N2-slope from SBN2 test is a significant predictor of lung function decline and COPD incidence over an 8-year follow-up, confirming the role of the "small airways disease" in the natural history of COPD.

Cyclohexanone Exposure in Children on Extracorporeal Membrane Oxygenation Support.

The aim of this study was to determine if plasma cyclohexanone and metabolites are associated with clinical outcomes of children on extracorporeal membrane oxygenation (ECMO) support. We performed a secondary analysis of a prospective observational study of children on ECMO support at two academic centers between July 2010 and June 2015. We measured plasma cyclohexanone and metabolites on the first and last days of ECMO support. Unfavorable outcome was defined as in-hospital death or discharge Pediatric Cerebral Performance Category score > 2 or decline ≥ 1 from baseline. Among 90 children included, 49 (54%) had unfavorable outcome at discharge. Cyclohexanediol, a cyclohexanone metabolite, was detected in all samples and at both time points; concentrations on the first ECMO day were significantly higher in those with unfavorable versus favorable outcome at hospital discharge (median, 5.7 ng/µl; interquartile range [IQR], 3.3-10.6 ng/µl vs. median, 4.2 ng/µl; IQR, 1.7-7.3 ng/µl; p = 0.04). Twofold higher cyclohexanediol concentrations on the first ECMO day were associated with increased risk of unfavorable outcome at hospital discharge (multivariable-adjusted hazard ratio [HR], 1.24 [95% CI, 1.05-1.48]). Higher cyclohexanediol concentrations on the first ECMO day were not significantly associated with new abnormal neuroimaging or 1-year Vineland Adaptive Behavior Scales-II score < 85 or death among survivors.

Neurologic Outcomes in a Two-Center Cohort of Neonatal and Pediatric Patients Supported on Extracorporeal Membrane Oxygenation.

Contemporary studies of long-term outcomes in children supported on extracorporeal membrane oxygenation (ECMO) in the United States are limited. We enrolled 99 ECMO patients between July 2010 and June 2015 in a two-center prospective observational study that included neurologic and neuropsychologic evaluation at 6 and 12 months, using standardized outcome measures. Pre-ECMO, 20 (20%) had a pre-existing neurologic diagnosis, 40 (40%) had cardiac arrest, and 10 of 47 (21%) children with neuroimaging had acute abnormal findings. Of 50 children eligible for follow-up at 6 or 12 months, 40 (80%) returned for at least one visit. At the follow-up visit of longest interval from ECMO, the median Vineland Adaptive Behavior Scales-II (VABS-II) score was 91 (interquartile range [IQR], 81-98), the median Pediatric Stroke Outcome Measure (PSOM) score was 1 (IQR, 0-2), and the median Mullen Scales of Early Learning composite score was 85 (IQR, 72-96). Presence of new neuroimaging abnormalities during ECMO or within 6 weeks post-ECMO was associated with VABS-II score <85 or death within 12 months after ECMO. The Pediatric Cerebral Performance Category at hospital discharge showed a strong relationship with unfavorable VABS-II and PSOM scores at 6 or 12 months after ECMO. In this study, we report a higher prevalence of pre-ECMO neurologic conditions than previously described. In survivors to hospital discharge, median scores for adaptive behavior and cognitive, neurologic, and quality of life assessments were all below the general population means, but most deficits would be considered minor within each of the domains tested.

Chronic bronchitis before age 50 years predicts incident airflow limitation and mortality risk.

BACKGROUND: Previous studies on the relationship of chronic bronchitis to incident airflow limitation and all-cause mortality have provided conflicting results, with positive findings reported mainly by studies that included populations of young adults. This study sought to determine whether having chronic cough and sputum production in the absence of airflow limitation is associated with onset of airflow limitation, all-cause mortality and serum levels of C-reactive protein (CRP) and interleukin-8 (IL-8), and whether subjects' age influences these relationships. METHODS: 1412 participants in the long-term Tucson Epidemiological Study of Airway Obstructive Disease who at enrolment (1972-1973) were 21-80 years old and had FEV(1)/FVC (forced expiratory volume in 1 s/forced vital capacity) > or = 70% and no asthma were identified. Chronic bronchitis was defined as cough and phlegm production on most days for > or = 3 months in two or more consecutive years. Incidence of airflow limitation was defined as the first follow-up survey with FEV(1)/FVC <70%. Serum IL-8 and CRP levels were measured in cryopreserved samples from the enrolment survey. RESULTS: After adjusting for covariates, chronic bronchitis at enrolment significantly increased the risk for incident airflow limitation and all-cause mortality among subjects <50 years old (HR 2.2, 95% CI 1.3 to 3.8; and HR 2.2, 95% CI 1.3 to 3.8; respectively), but not among subjects > or = 50 years old (HR 0.9, 95% CI 0.6 to 1.4; and HR 1.0, 95% CI 0.7 to 1.3). Chronic bronchitis was associated with increased IL-8 and CRP serum levels only among subjects <50 years old. CONCLUSIONS: Among adults <50 years old, chronic bronchitis unaccompanied by airflow limitation may represent an early marker of susceptibility to the effects of cigarette smoking on systemic inflammation and long-term risk for chronic obstructive pulmonary disease and all-cause mortality.

Neurologic Outcomes Following Care in the Pediatric Intensive Care Unit.

PURPOSE OF REVIEW: With increasing survival of children requiring admission to pediatric intensive care units (PICU), neurodevelopmental outcomes of these patients are an area of increased attention. Our goal was to systematically review recently published literature on neurologic outcomes of PICU patients. RECENT FINDINGS: Decline in neurofunctional status occurs in 3%-20% of children requiring PICU care. This proportion varies based on primary diagnosis and severity of illness, with children admitted for primary neurologic diagnosis, children who suffer cardiac arrest or who require invasive interventions during the PICU admission, having worse outcomes. Recent research focuses on early identification and treatment of modifiable risk factors for unfavorable outcomes, and on long-term follow-up that moves beyond global cognitive outcomes and is increasingly including tests assessing multidimensional aspects of neurodevelopment. SUMMARY: The pediatric critical care research community has shifted focus from survival to survival with favorable neurologic outcomes of children admitted to the PICU.

Association of physical activity and human sleep disorders.

BACKGROUND: It is generally believed that exercise exerts a beneficial effect on the quality of sleep. However, most studies regarding exercise and sleep have been concerned with the influence of exercise on sleep architecture and efficiency, and not on its effects in the prevention and treatment of sleep disorders. Moreover, epidemiological evidence of the benefits of exercise on sleep are limited. OBJECTIVE: To investigate the influence of moderate exercise or physical activity on self-reported sleep disorders among a randomly selected population of adults. SUBJECTS AND METHODS: Study subjects were participants in the Tucson Epidemiological Study of Obstructive Airways Disease who in the 12th survey completed health questionnaires that included several questions on physical exercise and sleep disorders. Sleep disorders were classified as disorders in maintaining sleep, excessive daily sleepiness, nightmares, and any sleep disorder. Six questions regarding exercise and physical activity were asked. Analyses were performed using multivariate logistic regression models with selected measures of sleep disorders as dependent variables and measures of exercise and physical activity as the independent or predictor variables. RESULTS: There were 319 men and 403 women included in the analyses. The results showed that more women than men reported participating in a regular exercise program and having sleep symptoms of disorders in maintaining sleep and nightmares and that more men than women did regular vigorous activity and walking at a brisk pace for more than 6 blocks per day. Both men and women had significantly reduced risk of disorders in maintaining sleep associated with regular activity at least once a week, participating regularly in an exercise program, and walking at a normal pace for more than 6 blocks per day. Reduced risk of any sleep disorder was associated with regular activity at least once a week, and for men, walking at a brisk pace for more than 6 blocks. Among women increases in age also reduced the risk of nightmares. CONCLUSIONS: These data provide additional evidence that a program of regular exercise may be a useful therapeutic modality in the treatment of patients with sleep disorders.

Antigen enhances neuronally induced contraction of intrapulmonary bronchi from IgE-producing rabbits.

The effect of in vitro antigen exposure on contraction induced by electrical field stimulation (EFS) was examined in bronchial rings isolated from rabbits producing specific IgE antibodies. After exposure to antigen, tissues showed an enhanced isometric contractile response to EFS especially at low frequencies, leading to a significant change in the mean slope factor (p less than 0.05) derived from modeling the log frequency response curve using a 4-parameter logistic function. Also, the mean log EF20 +/- SEM decreased from 1.03 +/- 0.05 to 0.88 +/- 0.07 Hz (p less than 0.02). This antigen-induced effect was blocked by pretreatment with 3 microM chlorpheniramine and not observed in unsensitized tissues. Antigen challenge of tissues passively sensitized with IgE (but not IgG) antibodies led to a similar EFS-enhancing effect, significantly reducing the mean slope factor (p less than 0.025). Substituting EFS with exogenous acetylcholine resulted in no antigen-induced enhancement of contraction. The data suggest that antigen-IgE interaction leads to local histamine release sufficient to enhance the function of excitatory airway neurons.

Comparison of preschool vision screening methods in a population with a high prevalence of astigmatism.

PURPOSE: To compare the effectiveness of four methods of screening 3- to 5-year-old children for astigmatism high enough to require spectacle correction. METHODS: Lea Symbols Visual Acuity Screening (LSVAS), MTI Photoscreening (MTIPS), Nidek KM-500 Keratometry Screening (KERS), and Retinomax K-Plus Noncycloplegic Autorefraction Screening (NCARS) were attempted on 379 preschool children who are members of a Native American tribe having a high prevalence of astigmatism that is primarily corneal in origin. The need for spectacle correction was determined by cycloplegic refraction. Receiver Operating Characteristic (ROC) curves were fit, confidence intervals were determined, and area under the curves was compared. RESULTS: Astigmatism > or = 1.00 D was present in the right eye of 47.5% and in the left eye of 48.0% of children. Spectacles were prescribed for children < 48 months of age who had cylinder > or = 2.00 D and children > or = 48 months who had cylinder > or = 1.50 D, with the result that 33% of subjects required spectacles. Area under the ROC curve was 0.98 for NCARS, 0.92 for KERS, 0.78 for MTIPS, and 0.70 for LSVAS, and each of these values differed significantly from the other three (all P < 0.007). Testability was significantly higher for NCARS (99.5%) and KERS (99.7%) than for MTIPS (93.5%) and LSVAS (92.0%). CONCLUSIONS: In a population that included many children with astigmatism, objective, fully automated screening methods (NCARS and KERS) were superior to both visual acuity screening and photoscreening with subjective interpretation in identifying children who had astigmatism requiring spectacle correction.

Ambulatory monitoring of peak expiratory flow. Reproducibility and quality control.

Eighty-five children and 230 adults from a population study performed ambulatory peak flow readings three times a day for 1 to 2 weeks following a home visit. Three peak expiratory flow (PEF) readings were reported for each of 5,809 test sessions. Within each test session, the third maneuver most frequently (40% of the time) gave the highest PEF reading. This did not vary throughout the day. In subgroups of children and women with a history of asthma or asthma symptoms (hereinafter referred to as "asthma"), the first maneuver during the evening test sessions more frequently gave the highest readings. However, maneuver-induced bronchospasm occurred during less than 5% of the test sessions in both subjects with asthma and in other subjects. The within test session PEF reproducibility was good: overall, the highest and second highest reading matched within one division (10 L/min) 73% of the time and within 30 L/min (9% of the reading) 95% of the time. The best reproducibility was noted after the first two days of testing, during evening and bedtime test sessions (vs morning), and in girls and men. In the group with at least 2 weeks of testing, the coefficient of repeatability (CR) for the week-to-week PEF lability index was 10% for healthy adults and 17% for healthy children. As expected, repeatability was not as good for adults with asthma (CR = 17%) and children with asthma (CR = 28%).

Spirometry and maximal respiratory pressure references from healthy Minnesota 65- to 85-year-old women and men.

OBJECTIVE: To obtain spirometry and maximal respiratory pressure (MRP) reference values for elderly persons. DESIGN: Survey. SETTING: General community. PARTICIPANTS: Four hundred seventy-one healthy ambulatory white women and men age 65+ years. METHODS: A stringent spirometry quality assurance program exceeded American Thoracic Society recommendations. A "healthy" subgroup of 176 women and 112 men between the ages of 65- and 85 years were identified by excluding those with conditions that negatively influenced FEV1 in a multiple regression analysis. Reference equations and normal ranges for FEV1, FVC, FEF25-75%, peak flow, and maximal inspiratory and expiratory pressures (MRPs) were determined from the healthy group with good quality maneuvers. RESULTS: Less than 10% of the subjects were unable to perform three acceptable spirometry maneuvers and ten MRP maneuvers. When the age and height corrected FEV1s from this group were compared with other spirometry reference studies, mean values from the women were nearly identical to those from Morris, while these men had substantially lower FEV1 values (by 0.3- to 0.5L) than elderly men in Crapo's study. Mean peak flow was over 20% higher when compared with previous studies, suggesting greater initial expiratory effort by our subjects. The maximal inspiratory pressure (MIP) values were about 20% higher than those reported by the Cardiovascular Health Study, perhaps because five MIP maneuvers were always performed. CONCLUSION: Spirometry and MRP reference values used for elderly patients should come from population studies using similar techniques and with large numbers of subjects over age 65 years.

Rates of decline in lung function among subjects who restart cigarette smoking.

Several studies have demonstrated that smokers who are able to break the habit generally experience reductions in respiratory symptoms and improvement in pulmonary function; however, far less attention has been given to smokers who are unsuccessful in their attempts at quitting. Recent reports have suggested that these subjects (restarters) may have steeper rates of decline in pulmonary function than subjects never attempting to quit smoking. In this study, we compared rates of decline in FEV1 between restarters and subjects who remained current, ex-smokers, or never-smokers throughout the observation period. The results showed that, in both sexes, subjects who attempt to quit the habit and then restart have significantly steeper rates of decline in their FEV1 than subjects who continue smoking uninterrupted. Female restarters also have significantly steeper rates of decline in FEV1 than ex-smokers. These effects were independent of the amount smoked and respiratory diseases.

An 8-year follow-up of carbon monoxide diffusing capacity in a general population sample of northern italy.

STUDY OBJECTIVE: Diffusing capacity of the lung for carbon monoxide (DLCO) is frequently assessed as part of a thorough pulmonary function assessment in patients with pulmonary or cardiopulmonary diseases. However, little information regarding the longitudinal trends of DLCO is available. In this study, we examined the temporal trends in DLCO to determine the effects of smoking and changes in smoking habits. DESIGN: A longitudinal study was recently conducted in the Po River Delta area of northern Italy, in which DLCO measurements were taken approximately 8 years apart in the same subjects; this offered the unique opportunity to assess the temporal changes in DLCO. The longitudinal DLCO data were analyzed independently in two age groups (20 to 40 years, and > or = 40 years) using a repeated-measures analysis. RESULTS: Included were 928 subjects > 20 years old who had DLCO assessments both at baseline and follow-up. Male subjects had higher mean levels of DLCO than female subjects in the older age group (> or = 40 years). Continuous smokers had significantly lower DLCO levels than "never-smokers," but their changes in DLCO during follow-up were the same. This suggests that the lung damage due to smoking had occurred prior to DLCO testing. We also found that the annual decline in DLCO accelerated with age in adults > or = 40 years old. CONCLUSIONS: We conclude that in adults > or = 40 years of age from the general population, DLCO accelerates downwards regardless of gender, smoking, and initial FEV(1) level.

Predictors of oxygen desaturation during submaximal exercise in 8,000 patients.

STUDY OBJECTIVES: To determine predictors of oxygen desaturation during submaximal exercise in patients with various lung diseases. DESIGN AND SETTING: This retrospective case series used pulmonary function laboratory results from all patients referred to a major tertiary-care center. PATIENTS AND MEASUREMENTS: All patients > or = 35 years old who underwent spirometry, diffusing capacity of the lung for carbon monoxide (DLCO), lung volumes, and pulse oximetry during 3-min submaximal step-test exercise during 1996 were included (4,545 men and 3,472 women). Logistic regression models, correcting for gender, age, and weight, determined the odds ratios (ORs) for oxygen desaturation of > or = 4% during exercise for each category of lung function abnormality (compared to those with entirely normal lung function). RESULTS: Approximately 74% of the patients had airways obstruction, while only 5.6% had restriction of lung volumes. One third of those with obstruction had a low DLCO, compared to 56% with restriction, while 2.7% had a low DLCO without obstruction or restriction. The risk of oxygen desaturation during submaximal exercise was very high (OR, 34) in patients with restriction and low DLCO (as in interstitial lung disease) and in patients with obstruction and low DLCO (as in COPD; OR, 18), intermediate (OR, 9) in patients with only a low DLCO, and lowest in those with a normal DLCO (OR, 4 if restricted; OR, 2 if obstructed). A cut point of DLCO < 62% predicted resulted in 75% sensitivity and specificity for exercise desaturation. No untoward cardiac events occurred in any patients during or following the submaximal exercise tests. CONCLUSIONS: The risk of oxygen desaturation during submaximal exercise is very high in patients with a low DLCO. Submaximal exercise tests are safe, even in elderly patients with heart and lung diseases.

Respiratory effects of non-tobacco cigarettes: a longitudinal study in general population.

Data from four consecutive surveys of Tucson longitudinal study of airways obstructive disease were used to examine the relation of respiratory symptoms and pulmonary function to non-tobacco cigarette smoking. The surveys were conducted over a six-year period and provided data on 1802 subjects 15-60 years of age, with a total of 5659 individual questionnaires. Estimated odds ratio (OR) of current non-tobacco smoking for chronic cough was 1.73, for chronic phlegm: 1.53, and for wheeze: 2.01 (p less than 0.05). These estimates were adjusted for age, tobacco smoking and occurrence of the symptom in preceding survey. The increased risk of the symptoms was related to the habit continued for several years, and there was no immediate remission of the symptoms after quitting smoking. A significant (p less than 0.05) reduction in pulmonary function (FEV1, Vmax50 and their ratios with FVC) was found a year or more after current non-tobacco smoking was reported. Although the average consumption of non-tobacco cigarettes, believed to be marijuana smoking, was less than one per day, significant effects were still detectable in both pulmonary function and respiratory symptoms.

On the maximum likelihood estimation of respiratory response slopes.

Several approaches have been suggested for estimating a respiratory response slope when both x and y variables are observed with error. Recently, a maximum likelihood estimate under the assumption of a bivariate normal distribution has been proposed. A method of moments solution yields a slope estimate of y/x as long as the underlying process mean is nonzero. This paper extends the maximum likelihood approach to the case where the process mean is zero. In this case, certain additional error assumptions must be made to yield a unique estimate. These concepts are applied to the problem of estimating an effective lung volume for steady-state breath-to-breath gas exchange data during exercise.

Kinetics of VO2 with impulse and step exercise in humans.

The constancy of the time course (i.e., dynamic linearity) of the O2 uptake (VO2) response to exercise was examined by testing the law of superposition on data from impulse and step work rate forcings. Two impulses (10 s at a 235-W increase above a 25-W base line, I-235; and 5 s at a 475-W increase above a 25-W base line, I-475), four steps (ST) (25-65 W, ST1; 65-105 W, ST2; 25-105 W, ST3; and 25-145 W, ST4), and the corresponding off-transient responses were performed six to eight times by each of five subjects. The integrated area (G) of the VO2 response for I-235 was similar to that of ST1 and ST2 (P greater than 0.05); the I-475 G was significantly greater (P less than 0.05). The time constant of VO2 during the step function on-transient response for the second exponential component was significantly faster for ST1 and significantly slower for I-235 and I-475 than for ST2, ST3, and ST4 (P less than 0.05). However, I-235 and I-475 time constants for VO2 were not different from the ST off-transient values. Attempts to superimpose the integral of the impulse on the ST data showed that the early rapid increase in VO2 in the ST was underpredicted by the impulse and that the impulse response lagged behind the ST at all points before steady state. It can be concluded that VO2 kinetics failed the test of superposition and are therefore described by a nonlinear dynamic system.

Extracorporeal bicarbonate space after bicarbonate or a bicarbonate-carbonate mixture in acidotic dogs.

The effects of sodium bicarbonate and a bicarbonate-carbonate mixture on expired CO2 and the volume of distribution of bicarbonate were studied in eight anesthetized, paralyzed, and ventilated dogs made acidotic with HCl (5 mmol/kg) infused over 90 min. Both sodium bicarbonate and Carbicarb resulted in systemic alkalinization and comparable increases in the serum bicarbonate at 50 min (7.07 +/- 0.91 vs. 7.99 +/- 0.77, respectively; P = NS). Sodium bicarbonate infusion resulted in an increase in CO2 excretion that accounted for a fractional CO2 excretion of 0.20 +/- 0.09, whereas infusion of a bicarbonate-carbonate mixture resulted in a fractional CO2 excretion of -0.06 +/- 0.09 (P less than 0.01). The uncorrected volume of distribution of bicarbonate after sodium bicarbonate infusion was higher than that seen with the bicarbonate-carbonate mixture (0.60 +/- 0.07 vs. 0.34 +/- 0.03 l/kg; P less than 0.01). However, when the volume of bicarbonate distribution was corrected for expired CO2, there was no difference between treatment with sodium bicarbonate and the bicarbonate-carbonate mixture (0.44 +/- 0.07 vs. 0.38 +/- 0.04 l/kg; P = NS). These data demonstrate that, in this animal model of acidosis, sodium bicarbonate treatment of systemic acidosis is accompanied by a generation of a considerable amount of CO2, whereas treatment with a bicarbonate-carbonate mixture is not. This suggests that in states of impaired ventilation, a bicarbonate-carbonate mixture may offer more efficient systemic alkalinization and may be associated with less CO2 generation than sodium bicarbonate.