Neuromonitoring Modalities in Pediatric Cardiac Anesthesia: A Review of the Literature.

Recent decades have witnessed incredible developments in the care of children with congenital heart disease (CHD), such that survival into adulthood is the expected outcome. Improved survival has shifted the focus from improvements in mortality to improvements in morbidity, with long-term neurologic sequelae among the most important. Children with CHD who undergo corrective procedures in infancy and early childhood have a high rate of neurodevelopmental disability later in childhood. Impaired neurocognition is a result of many factors, including prenatal brain injury; preoperative hemodynamic derangements; exposure to anesthetic drugs; and the abnormal physiological states associated with cardiopulmonary bypass, low-flow perfusion, and deep hypothermic circulatory arrest. The intraoperative period presents a challenge to the anesthesiologist because this is a vulnerable period for the neurologic system. Transcranial Doppler ultrasound, electroencephalography, near-infrared spectroscopy, and processed electroencephalography are the neuromonitoring modalities that may be used intraoperatively. Even though each modality has merits, no single modality is able to reliably guide changes to management that improve neurologic outcomes. The best strategy is likely a multimodal neurologic monitoring strategy, although the combination of monitoring may depend on local resources and patient risk factors. This review provides a brief overview of the current knowledge regarding neurodevelopmental outcomes in children with CHD and summarizes the evidence for the use of the following 4 neuromonitoring modalities: transcranial Doppler, cerebral near-infrared spectroscopy, standard electroencephalography, and processed electroencephalography.

The effect of intraoperative methadone during pediatric cardiac surgery on postoperative opioid requirements.

BACKGROUND: Pain control in pediatric patients undergoing cardiac surgery presents a unique challenge. Postoperatively, many of these patients require long-term opioid infusions and sedation leading to need for prolonged weaning from opioids and longer hospital stays. We hypothesized that intravenous methadone as the sole opioid in children having cardiac surgery with cardiopulmonary bypass would improve perioperative pain control and decrease overall perioperative use of opioid analgesics and sedatives. METHODS: We instituted a practice change involving pediatric patients aged <18 years who underwent cardiac surgery with cardiopulmonary bypass over a 14-month period, comparing the patient population who had surgery prior to the institution of intraoperative methadone usage to patients who had surgery in the months following. We then separated patients into two groups: neonatal (aged < 30 days) and non-neonatal (aged > 30 days to 18 years). Our primary outcome was intraoperative and postoperative opioid requirements measured in morphine equivalents intraoperatively, during the first 24 hours postoperatively, and up to postoperative day 7. Secondary outcomes included extubation rates in the OR, pain and sedation scores, sedation requirements, and time to start of oxycodone. RESULTS: Patients in both groups had similar demographics. In neonatal patients, the postintervention group required significantly lower doses of intraoperative opioids. There was no statistically significant difference in postoperative opioid use. In non-neonatal patients, the postintervention group required significantly less intraoperative opioids. Postoperatively, those in the postintervention group required significantly less opioids in the first 24 hours. CONCLUSION: The use of intraoperative methadone appears to be a reasonable alternative to the use of fentanyl with potential other benefits both intra- and postoperatively of decreased total dose of opioids and other sedatives. Future studies will assess for any improvement in total postoperative opioid requirements during the total hospital stay, and potential use of methadone by the ICU team.

Routine postprocedure ultrasound increases rate of detection of femoral arterial thrombosis in infants after cardiac catheterization.

OBJECTIVES: To examine the effect of implementing postcatheterization ultrasound (US) on femoral arterial thrombosis detection rates and factors associated with thrombosis in infants. BACKGROUND: Although femoral arterial thrombosis is an uncommon complication of cardiac catheterization, it can cause limb threatening complications. Previous studies assessing the utility of postprocedure US to detect thrombosis in infants have utilized US as an adjunct to standard clinical detection methods, are small scale, or include small cohorts of infants within older populations. METHODS: We reviewed institutional records of patients 0-12 months undergoing catheterization from 2007 to 2016. Demographics and procedural data were compared between the thrombosis and non-thrombosis group. Pre- and post-US groups were compared for detected thrombosis rate. Using univariate and multivariable analyses, we identified factors associated with thrombosis. RESULTS: In total, 270 patients underwent 509 catheterizations, with 40 (7.9%) documented thromboses. The rate of thrombus detection in patients younger than 6 months increased from 8.3% to 23.4% (P = 0.006) after implementing routine US. On multivariable analysis, lower weight (P < 0.001), larger arterial sheath size (P < 0.001), and longer procedure duration (P = 0.003) were independently associated with higher odds of thrombosis. CONCLUSIONS: Higher rates of femoral arterial thrombosis detection were observed since implementing an US screening program. Further studies are needed to evaluate age-related changes in hemostasis in this population and how advanced screening methods and anticoagulation protocols may help improve short-term and long-term sequelae of femoral arterial thrombosis.

A Study of Practice Behavior for Endotracheal Intubation Site for Children With Congenital Heart Disease Undergoing Surgery: Impact of Endotracheal Intubation Site on Perioperative Outcomes-An Analysis of the Society of Thoracic Surgeons Congenital Cardiac Anesthesia Society Database.

BACKGROUND: In adults undergoing cardiopulmonary bypass surgery, oral intubation is typically preferred over nasal intubation due to reduced risk of sinusitis and infection. In children, nasal intubation is more common and sometimes preferred due to perceived benefits of less postoperative sedation and a lower risk for accidental extubation. This study sought to describe the practice of nasal intubation in the pediatric population undergoing cardiopulmonary bypass surgery and assess the risks/benefits of a nasal route against an oral one. METHODS: Patients <18 years of age in the Society of Thoracic Surgeons Congenital Heart Surgery Database between January 2010 and December 2015 were included. Patients with a preoperative endotracheal tube, tracheostomy, or known airway anomalies were excluded. Multivariable modeling was used to assess the association between route of tracheal intubation and a composite measure of infection risk (wound infection, mediastinitis, septicemia, pneumonia, and endocarditis). Covariates were included to adjust for important patient characteristics (eg, weight, age, comorbidities), case complexity, and center effects. Secondary outcomes included length of intubation, hospital length of stay, and airway complications including accidental extubations. We also performed a subanalysis in children <12 months of age in high-volume centers (>100 cases/y) examining how infection risk may change with age at the time of surgery. RESULTS: Nasal intubation was used in 41% of operations in neonates, 38% in infants, 15% in school-aged children, and 2% in adolescents. Nasal intubation appeared protective for accidental extubation only in neonates (P = .02). Multivariable analysis in infants and neonates showed that the nasal route of intubation was not associated with the infection composite (relative risk [RR], 0.84; 95% CI, 0.59-1.18) or a shorter length of stay (RR, 0.992; 95% CI, 0.947-1.039), but was associated with a shorter intubation length (RR, 0.929; 95% CI, 0.869-0.992). Restricting to high-volume centers showed a significant interaction between age and intubation route with a risk change for infection occurring between approximately 6-12 months of age (P = .003). CONCLUSIONS: While older children undergoing nasal intubation trend similar to the adult population with an increased risk of infection, nasal intubation in neonates and infants does not appear to carry a similar risk. Nasal intubation in neonates and infants may also be associated with a shorter intubation length but not a shorter length of stay. Prospective studies are required to better understand these complex associations.

Pediatric Transfusion Algorithms: Coming to a Cardiac Operating Room Near You.

Pediatric cardiac surgical patients are at particular risk for post-cardiopulmonary bypass hemorrhage. Moreover, both the incidence and volume of blood transfusions have been associated with increased morbidity in pediatric cardiac patients. Transfusion of red blood cells, platelets, and coagulation factors is necessary to combat the hemodilution associated with cardiopulmonary bypass and to treat postoperative bleeding. We are challenged to apply new pharmacologic, extracorporeal, and laboratory testing advances in an evidence-based, systemic fashion to allow for appropriate transfusion. Transfusion algorithms may aid in this process, but current evidence for efficacy of transfusion algorithms in this population is limited to single-center studies. Development of a transfusion algorithm for the pediatric cardiac population requires individualization at both the institutional level, considering local resources, equipment, and case mix, and the patient level, considering age, cardiac diagnosis, and planned procedure, at minimum. A growing body of literature suggests that application of appropriate intraoperative testing (platelet count, fibrinogen concentration, thromboelastometry) along with recognition of risk factors for bleeding, adequate bypass anticoagulation, and judicious use of factor concentrates allows for thoughtful transfusion and potentially improved outcomes in pediatric cardiac patients. This review examines the evolution of transfusion algorithms in pediatric cardiac surgery and examines the considerations involved in building an algorithm for this challenging, heterogenous population.

Double-Blind, Randomized, Placebo-Controlled Trial Comparing the Effects of Antithrombin Versus Placebo on the Coagulation System in Infants with Low Antithrombin Undergoing Congenital Cardiac Surgery.

OBJECTIVES: To determine whether precardiopulmonary bypass (CPB) normalization of antithrombin levels in infants to 100% improves heparin sensitivity and anticoagulation during CPB and has beneficial effects into the postoperative period. DESIGN: Randomized, double-blinded, placebo-controlled prospective study. SETTING: Multicenter study performed in 2 academic hospitals. PARTICIPANTS: The study comprised 40 infants younger than 7 months with preoperative antithrombin levels <70% undergoing CPB surgery. INTERVENTIONS: Antithrombin levels were increased with exogenous antithrombin to 100% functional level intraoperatively before surgical incision. MEASUREMENTS AND MAIN RESULTS: Demographics, clinical variables, and blood samples were collected up to postoperative day 4. Higher first post-heparin activated clotting times (sec) were observed in the antithrombin group despite similar initial heparin dosing. There was an increase in heparin sensitivity in the antithrombin group. There was significantly lower 24-hour chest tube output (mL/kg) in the antithrombin group and lower overall blood product unit exposures in the antithrombin group as a whole. Functional antithrombin levels (%) were significantly higher in the treatment group versus placebo group until postoperative day 2. D-dimer was significantly lower in the antithrombin group than in the placebo group on postoperative day 4. CONCLUSION: Supplementation of antithrombin in infants with low antithrombin levels improves heparin sensitivity and anticoagulation during CPB without increased rates of bleeding or adverse events. Beneficial effects may be seen into the postoperative period, reflected by significantly less postoperative bleeding and exposure to blood products and reduced generation of D-dimers.

Correlation between minute carbon dioxide elimination and pulmonary blood flow in single-ventricle patients after stage 1 palliation and 2-ventricle patients with intracardiac shunts: A pilot study.

BACKGROUND: Assessment of pulmonary blood flow and cardiac output is critical in the postoperative management of patients with single-ventricle physiology or 2-ventricle physiology with intracardiac shunting. Currently, such hemodynamic data are only obtainable by invasive procedures, such as cardiac catheterization or the use of a pulmonary artery catheter. Ready availability of such information, especially if attainable noninvasively, could be a valuable addition to postoperative management. AIMS: The aim of this study was to assess the correlation between volume of CO2 elimination obtained by volumetric capnography and pulmonary blood flow in pediatric patients with single-ventricle physiology after stage 1 palliation as well as in patients with other cardiac lesions associated with intracardiac shunting. METHODS: This prospective cohort study included children with congenital or acquired heart disease who underwent cardiac catheterization as part of clinical care. Cardiac output, pulmonary blood flow, and volume of CO2 elimination were simultaneously collected. Spearman's rank correlation coefficients were used to assess correlation between measurements after controlling for minute ventilation. RESULTS: Thirty-five patients were enrolled and divided into 3 groups. Group 1 (n = 8) included single-ventricle patients after stage 1 palliation. Group 2 (n = 10) patients had structural heart disease with 2 ventricles and intracardiac shunting. Group 3 (n = 17) had structurally normal hearts. Among Group 1 patients, the correlation coefficients (R2 ) between volume of CO2 elimination and pulmonary blood flow and volume of CO2 elimination and cardiac output were 0.60 (P = .02) 95% CI [0.01-0.79] and 0.29 (P = .74) 95% CI [-0.91 - 0.86], respectively. In patients with 2 ventricles associated with intracardiac shunts (Group 2), the correlation coefficients between volume of CO2 elimination and pulmonary blood flow and volume of CO2 elimination and cardiac output were 0.86 (P = .001) 95% CI [0.53 - 0.97] and 0.73 (P = .001) 95% CI [0.29 - 0.95], respectively. Among Group 3 patients, the correlation coefficient between volume of CO2 elimination and pulmonary blood flow was 0.66 (P = .038) 95% CI [0.29 - 0.87]. CONCLUSION: Volume of CO2 elimination may be a surrogate marker of pulmonary blood flow in single-ventricle patients and patients with biventricular physiology with intracardiac shunting. Also, among patients with normal cardiac anatomy, volume of CO2 elimination may be a marker of cardiac output.

Percutaneous endoscopic gastrostomy vs surgical gastrostomy in infants with congenital heart disease.

BACKGROUND: Infants with congenital heart disease often require feeding tube placement to supplement oral intake. Gastrostomy tubes may be placed by either surgical or percutaneous endoscopic methods, but there is currently no data comparing outcomes of these procedures in this population. AIMS: The aim of our retrospective study was to investigate the perioperative outcomes between the 2 groups to determine if there are clinically significant differences. METHODS: We reviewed the charts of all infants with congenital heart disease at a single academic institution having isolated surgical or percutaneous endoscopic gastrostomy tube placement from January 2011 to December 2015. Anesthetic time, defined by cumulative minimum alveolar concentration hours of exposure to volatile anesthetic, was the primary outcome. Operative time, intraoperative complications, and postoperative intensive care admissions were secondary outcomes. RESULTS: One hundred and one infants with congenital heart disease were included in this study. Anesthetic exposure was shorter in the endoscopic group than the surgical group (0.20 MAC-hours vs 0.56 MAC-hours, 95% confidence interval 0.23, 0.49, P < .001). Average operative times were also shorter in the endoscopic gastrostomy vs the surgical group (8 ± 0.7 minutes vs 35 ± 1.3 minutes, 95% confidence interval 23.7, 31.0, P < .001). Adjusting for prematurity and preoperative risk category, the surgical group was associated with a 3.45 fold increase in the likelihood of a higher level of care postoperatively (95% confidence interval 1.20, 9.90, P = .02). CONCLUSION: In infants with congenital heart disease, percutaneous endoscopic gastrostomy placement is associated with reduced anesthetic exposure and fewer postoperative intensive care unit admissions compared to surgical gastrostomy.

Natural history of nonimmune-mediated thrombocytopenia and acute kidney injury in pediatric open-heart surgery.

OBJECTIVE: Thrombocytopenia and acute kidney injury (AKI) are common following pediatric cardiac surgery with cardiopulmonary bypass (CPB). However, the relationship between postoperative nadir platelet counts and AKI has not been investigated in the pediatric population. Our objective was to investigate this relationship and examine independent predictors of AKI. DESIGN: After IRB approval, we performed a retrospective review of the institution's medical records and database. SETTING: This study was performed at a single institution over a 5-year period. PATIENTS: We included patients <21 years of age undergoing cardiac surgery with CPB. INTERVENTIONS: Demographics, laboratory, and surgical characteristics were captured, and clinical event rates were recorded. MEASUREMENTS: Descriptive statistics were used to evaluate platelet and creatinine distributions. T-tests and chi-squared tests were used to compare characteristics among Acute Kidney Injury Network groups. Multivariable logistic and ordinal logistic regression models were used to determine the association of our predictor of interest, postoperative nadir platelet count and AKI. RESULTS: Eight hundred and fourteen patients (23% infants and 23% neonates) were included in the analysis. Postoperative platelet counts decreased 48% from baseline reaching a mean nadir value of 150 × 109 ·l-1 on postoperative day 3. AKI occurred in 37% of patients including 13%, 17%, and 6% with Acute Kidney Injury Network stages 1, 2, and 3, respectively. The magnitude of nadir platelet counts correlated with the severity of AKI. Independent predictors of severity of AKI include nadir platelet counts, CPB time, Aristotle score, patient weight, intra-operative packed red blood cell transfusion, and having a heart transplant procedure. CONCLUSIONS: In pediatric open-heart surgery, thrombocytopenia and AKI occur commonly following CPB. Our findings show a strong association between nadir platelet counts and the severity of AKI.

In Vitro Evaluation of the Fresenius Kabi CATSmart Autotransfusion System.

Use of autotransfusion systems to collect, wash, and concentrate shed blood during surgical procedures is a widely used method for reducing postoperative anemia and the need for blood transfusions. The aim of this study was to evaluate the CATSmart Continuous Autotransfusion System wash program performance with small (200 or 700 mL) and large volumes (1,000 mL) of shed blood and to determine non-inferiority of the CATSmart to the C.A.T.S plus system. Human whole blood was collected in citrate phosphate dextrose, diluted, and divided into two aliquots to be processed as a pair using the C.A.T.S plus and CATSmart systems with their corresponding wash programs: low-volume, high quality/smart, or emergency wash. Final packed red cell product was analyzed for red blood cell (RBC), white blood cell, and platelet counts; hemoglobin; hemolysis; RBC recovery rates; and elimination of albumin, total protein, and potassium. The mean hematocrit (HCT) after processing with CATSmart and C.A.T.S plus systems were 59.63% and 57.71%, respectively. The calculated overall RBC recovery rates on the CATSmart and C.A.T.S plus systems were 85.41% and 84.99%, respectively. Elimination of albumin (97.5%, 98.0%), total proteins (97.1%, 97.5%), and potassium (92.1%, 91.9%) were also calculated for the CATSmart and C.A.T.S plus systems. The CATSmart and C.A.T.S plus systems both provided a high-quality product in terms of HCT, protein elimination, and hemolysis rates across the range of tested shed blood volumes and all wash programs. The study was able to confirm the CATSmart is non-inferior to the C.A.T.S plus system.

Platelet Counts, Acute Kidney Injury, and Mortality after Coronary Artery Bypass Grafting Surgery.

BACKGROUND: Cardiac surgery requiring cardiopulmonary bypass is associated with platelet activation. Because platelets are increasingly recognized as important effectors of ischemia and end-organ inflammatory injury, the authors explored whether postoperative nadir platelet counts are associated with acute kidney injury (AKI) and mortality after coronary artery bypass grafting (CABG) surgery. METHODS: The authors evaluated 4,217 adult patients who underwent CABG surgery. Postoperative nadir platelet counts were defined as the lowest in-hospital values and were used as a continuous predictor of postoperative AKI and mortality. Nadir values in the lowest 10th percentile were also used as a categorical predictor. Multivariable logistic regression and Cox proportional hazard models examined the association between postoperative platelet counts, postoperative AKI, and mortality. RESULTS: The median postoperative nadir platelet count was 121 × 10/l. The incidence of postoperative AKI was 54%, including 9.5% (215 patients) and 3.4% (76 patients) who experienced stages II and III AKI, respectively. For every 30 × 10/l decrease in platelet counts, the risk for postoperative AKI increased by 14% (adjusted odds ratio, 1.14; 95% CI, 1.09 to 1.20; P < 0.0001). Patients with platelet counts in the lowest 10th percentile were three times more likely to progress to a higher severity of postoperative AKI (adjusted proportional odds ratio, 3.04; 95% CI, 2.26 to 4.07; P < 0.0001) and had associated increased risk for mortality immediately after surgery (adjusted hazard ratio, 5.46; 95% CI, 3.79 to 7.89; P < 0.0001). CONCLUSION: The authors found a significant association between postoperative nadir platelet counts and AKI and short-term mortality after CABG surgery.

Reduction in blood transfusion in a cohort of infants having cardiac surgery with cardiopulmonary bypass after instituting a goal-directed transfusion policy.

BACKGROUND: Current trends in pediatric cardiac surgery and anesthesiology include goal-directed allogeneic blood transfusion, but few studies address the transfusion of platelets and cryoprecipitate. We report a quality improvement initiative to reduce the transfusion of platelets and cryoprecipitate in infants having cardiac surgery with cardiopulmonary bypass (CPB). METHODS: Data from 50 consecutive patients weighing four to ten kilograms having cardiac surgery with CPB were prospectively collected after the institution of a policy to obtain each patient's platelet and fibrinogen levels during the rewarming phase of CPB. Data from 48 consecutive patients weighing four to ten kilograms having cardiac surgery with CPB prior to the implementation of the policy change were retrospectively collected. Demographics, laboratory values and blood product transfusion data were compared between the groups, using the Chi-square/Fisher's exact test or the T-Test/Wilcoxon Rank-Sum test, as appropriate. RESULTS: The results showed more total blood product exposures in the control group during the time from bypass through the first twenty-four post-operative hours (median of 2 units versus 1 unit in study group, p=0.012). During the time period from CPB separation through the first post-operative day, 67% of patients in the control group received cryoprecipitate compared to 32% in the study group (p=0.0006). There was no difference in platelet exposures between the groups. CONCLUSION: Checking laboratory results during the rewarming phase of CPB reduced cryoprecipitate transfusion by 50%. This reproducible strategy avoids empiric and potentially unnecessary transfusion in this vulnerable population.

A change in anticoagulation monitoring improves safety, reduces transfusion, and reduces costs in infants on cardiopulmonary bypass.

BACKGROUND: An immature coagulation system coupled with the hypothermia and hemodilution associated with cardiopulmonary bypass (CPB) in infants makes the activated clotting time (ACT) an ineffective monitor for anticoagulation in this population. The Medtronic HMS Plus Hemostasis Management System (HMS; Medtronic, Inc., Minneapolis, MN, USA) is shown to decrease thrombin generation and blood product requirements. AIM: We conducted a quality improvement initiative to test our hypothesis that the use of HMS results in reduced incidence of subtherapeutic ACT values, blood product usage, and operating room time for infants undergoing cardiac surgery. METHODS: Fifty consecutive patients weighing <10 kg having cardiac surgery requiring CPB had anticoagulation managed by the HMS. Data were compared to that of 50 consecutive patients weighing <10 kg having cardiac surgery who had their anticoagulation monitored by the ACT alone. Comparisons between categorical variables were performed with chi-square tests. Comparisons between continuous variables were performed with the Wilcoxon rank-sum test. Statistical significance was defined as two-tailed P value < 0.05. RESULTS: The HMS group had a 61% decrease in incidence of ACT values <480 s and elimination of ACT values < 400 s at any time on bypass. The HMS group received fewer blood products and spent fewer minutes in the operating room after protamine administration, translating to fewer donor exposures and a savings of $403 in transfusion costs and $440 in operating room time costs. CONCLUSION: Our findings highlight the benefits of individualized heparinization for pediatric patients undergoing CPB with a monitored heparinization system.

The effect of cisatracurium and rocuronium on lung function in anesthetized children.

BACKGROUND: Neuromuscular blocking drugs have been implicated in intraoperative bronchoconstrictive episodes. We examined the effects of clinically relevant doses of cisatracurium and rocuronium on the lung mechanics of pediatric subjects. We hypothesized that cisatracurium and rocuronium would have bronchoconstrictive effects. METHODS: We studied ASA physical status I and II pediatric subjects having elective dental or urological procedures, requiring general anesthesia with endotracheal intubations with either cisatracurium or rocuronium. Pulmonary function tests were performed before and after neuromuscular blocking drug dosing and again after albuterol administration. Using forced deflation and passive deflation techniques, forced vital capacity (FVC) and maximum expiratory flow rate at 10% (MEF10) of FVC were obtained. Fractional changes from the baseline were used to compare subjects. Changes in MEF10 of >30% were considered clinically significant. A Shapiro-Wilk test, paired t test, and Wilcoxon rank sum test were used to analyze the data. RESULTS: Twenty-five subjects (median age = 5.25 years; range = 9 months-9.9 years) were studied; 12 subjects received cisatracurium and 13 subjects received rocuronium. Data are shown as mean proportional change ± SD or, in the case of not normally distributed, median proportional change (first, third quartile) with P values. In the cisatracurium group, there were no differences between baseline and postneuromuscular blocker administration in the fractional change from the baselines of FVC (1.00 ± 0.04, P = 0.5), but there was a significant decrease in MEF10 (0.80 ± 0.18, P = 0.002). In the rocuronium group, there were small yet significant decreases of FVC (0.99 [first quartile 0.97, third quartile 1], P = 0.02) and significant decreases in MEF10 (0.78 ± 0.26, P = 0.008). After administration of albuterol in the cisatracurium group, FVC increased slightly but significantly from baseline values (1.02 ± 0.02, P = 0.005). MEF10 increased significantly beyond baseline values (1.24 ± 0.43, P =0.04). In the rocuronium group, there were also significant differences between baseline and postalbuterol administration from the baseline value of FVC (1.02 ± 0.02, P = 0.004) and MEF10 (1.23 ± 0.29, P = 0.01). CONCLUSIONS: At clinically relevant doses, both cisatracurium and rocuronium caused changes in lung function, indicating constriction of smaller airways. In general, these changes were mild and not clinically detectable. However, in the rocuronium group, 3 of 13 patients showed more noticeable decreases in MEF10 (≤50%), demonstrating the potential for significant broncho-bronchiolar constriction in susceptible patients.