Mubarak Chaudhry

Effect of bitter tastants on human bronchi

To the Editor: We read with interest the report of the effects of bitter tastants on airway smooth muscle by Deshpande et al.1 and the related News and Views article by Sanderson and Madison2. Deshpande et al.1 report a previously undescribed modulator of airway tone with a unique mode of relaxation in airway smooth muscle that may prove to be clinically significant. We attempted to reproduce the data presented using second-order human bronchi obtained from people with lung cancer after surgical resection. We set rings (n = 24 from nine subjects) at a passive tension of 2 g and contracted them with 1 mM methacholine or 1 mM acetylcholine. We did control relaxations using 10 μM isoprenaline (n = 9). In contrast to the report by Deshpande et al.1, isoprenaline induced rapid (7.9 ± 5.9 min) and potent relaxation of bronchi constricted with acetylcholine (145 ± 39% inhibition of maximum, n = 3) and methacholine (103 ± 49% inhibition of maximum, n = 6) (Fig. 1a). Their claim that bitter taste receptor agonists have three times the efficacy of b-agonists1 may result from the poor performance of isoprenaline in their report. Our own experience and that reported in the literature3,4 is that isoprenaline is a potent and highly efficacious bronchodilator of human airway smooth muscle. We repeated the experiments reported by Deshpande et al.1 using three of the bitter tastants as bronchodilators in bronchi constricted with 1 mM methacholine. Saccharin (n = 5) produced no response up to concentrations of 3 mM (Fig. 1b). Quinine (1 mM; n = 5) and 1–3 mM chloroquine (n = 5) induced relaxation of bronchi (Fig. 1b). At these concentrations, we found that the average time for relaxation to baseline was 23 ± 6 min for quinine and 34 ± 16 min for chloroquine (Fig. 1b). After a mean washout time of 37 ± 10 min, the contractile response to methacholine was reduced (15 ± 19% and 27 ± 15% of the rings that were pre-exposed to quinine and chloroquine, respectively (Fig. 1b)). Our inability to reverse the effects of bitter tastants in the human bronchial preparation used in our study stands in contrast to the report by Deshpande et al.1, in which chloroquine mediated-relaxation was fully reversible in mouse tracheal rings. We interpret these findings as showing that, at very high concentrations, bitter tastants may indeed relax smooth muscle; however, our inability to reverse the effect in washout suggests either irreversible inhibition of contraction or cell injury. Some of the differences between our results may be explained by the use of second-order bronchi in our studies as compared with the fourth-order bronchi in the study by Deshpande et al.1. Different pharmacological classes of agonists have differential effects depending on airway diameter5. In asthma, large airways are thought to be the main contributors to airflow obstruction, whereas in chronic obstructive pulmonary disease, smaller airway constriction has a greater role in the pathophysiology. The localization and function of bitter taste receptors within human airways needs clarification if we are to understand the possible roles of TAS2R agonists as bronchodilators.

Validation of the Intensive Care National Audit and Research Centre Scoring System in a UK Adult Cardiac Surgery Population

OBJECTIVE The Intensive Care National Audit and Research Centre (ICNARC) scoring system was conceived in 2007, utilizing 12 physiologic variables taken from the first 24 hours of adult admissions to the general intensive care unit (ICU) to predict in-hospital mortality. The authors aimed to evaluate the ICNARC score in predicting mortality in cardiac surgical patients compared to established cardiac risk models such as logistic EuroSCORE as well as to the Acute Physiology and Chronic Health Evaluation (APACHE) II. DESIGN Retrospective analysis of data collected prospectively. SETTING Single-center study in a cardiac intensive care in a regional cardiothoracic center. PARTICIPANTS Patients undergoing cardiac surgery between January 2010 and June 2012. METHODS A total of 1,646 patients were scored preoperatively using the logistic EuroSCORE and postoperatively using ICNARC and APACHE II. Data for comparison of scoring systems are presented as area under the receiver operating characteristic curve. MEASUREMENTS AND MAIN RESULTS The mean age at surgery was 67 years±10.1. The mortality from all cardiac surgery was 3.2%. The mean logistic EuroSCORE was 7.31±10.13, the mean ICNARC score was 13.42±5.055, while the mean APACHE II score was 6.32±7.731. The c-indices for logistic EuroSCORE, ICNARC, and APACHE II were 0.801, 0.847 and 0.648, respectively. CONCLUSION The authors have, for the first time, validated the ICNARC score as a useful predictor of postoperative mortality in adult cardiac surgical patients. This could have implications for postoperative management, focusing the utilization of resources as well as a method to measure and compare performance in the cardiothoracic ICU.

Hyperoxic Vasoconstriction of Human Pulmonary Arteries: A Novel Insight into Acute Ventricular Septal Defects

Objectives. Acute rises in pulmonary artery pressures following postinfarction ventricular septal defects present a challenge. We hypothesised that the abnormally high oxygen content exposure to the pulmonary arteries may be a factor. We investigated the contractile responses of human pulmonary arteries to changes in oxygen tension. Methods. Isometric tension was measured in large and medium sized pulmonary artery rings obtained from lung resections for patients with bronchial carcinoma (n = 30). Fresh rings were mounted in organ baths bubbled under basal conditions with hyperoxic or normoxic gas mixes and the gas tensions varied during the experiment. We studied whether voltage-gated calcium channels and nitric oxide signalling had any role in responses to oxygen changes. Results. Hypoxia caused a net mean relaxation of 18.1% ± 15.5 (P < 0.005) from hyperoxia. Subsequent hyperoxia caused a contraction of 19.2% ± 13.5 (P < 0.005). Arteries maintained in normoxia responded to hyperoxia with a mean constriction of 14.8% ± 3.9 (P < 0.005). Nifedipine inhibited the vasoconstrictive response (P < 0.05) whilst L-NAME had no effect on any hypoxic vasodilatory response. Conclusions. We demonstrate that hyperoxia leads to vasoconstriction in human pulmonary arteries. The mechanism appears to be dependent on voltage-gated calcium channels. Hyperoxic vasoconstriction may contribute to acute rises in pulmonary artery pressures.

The differential effects of systemic vasoconstrictors on human pulmonary artery tension

OBJECTIVES Acute pulmonary hypertension following cardiac surgery can have a significant effect on postoperative morbidity and mortality. However, limited data are available on the efficacy and potency of clinically used systemic vasopressors on the pulmonary vasculature. The aim of this study was to use human pulmonary artery to characterize the pharmacological effects of clinically used vasopressors on the human pulmonary vasculature. METHODS Fifty-seven pulmonary artery rings of internal diameter 2-4 mm and 2 mm long, mounted in a multiwire myograph system, were used to measure changes in isometric tension. We constructed concentration response curves by cumulative addition to the myograph chambers of KCl, noradrenaline (NA), adrenaline (AD), vasopressin, endothelin-1 (ET-1) and prostaglandin F2a (PGF2a). RESULTS AD, NA, ET-1, PGF2a and KCl caused dose-dependent vasoconstriction in the pulmonary artery samples (EC50 246 nM [95% confidence interval, CI, 153-394 nM], 150 nM [95% CI 51-447 nM], 1.46 nM [95% CI 0.69-3.1 nM], 6.35 µM [95% CI 3.58-11.2 µM] and 17.24 mM [95% CI 12.43-24.07 mM], respectively), whereas vasopressin had no significant effect. The order of efficacy was KCl = PGF2a > AD > NA > ET-1 and the order of potency was ET-1 T-AD = NA > PGF2a > KCl. CONCLUSIONS This study demonstrated the efficacy and potency of clinically used vasopressors and endogenous vasopressors on human pulmonary vascular tone. PGF2a and KCl equally caused maximal amounts of constriction, whereas ET-1 had less effect and vasopressin had no effect. These effects may need to be taken into account in the clinical setting because they might result in the development of pulmonary hypertension.

Short- and long-term outcomes of pneumonectomy in a tertiary center.

Background Surgery is the most important therapeutic modality for lung cancer. Surgical outcomes are normally reported as 30-day or 90-day mortality or 5-year survival; 10-year survival is rarely mentioned in national data or international studies. Methods Three hundred and six patients (79% male) underwent pneumonectomy, mainly for lung cancer, from January 1998 to February 2013. Their short- and long-term outcomes up to September 2014 were analyzed retrospectively. The mean age was 64 years (range 22–82 years) and 24% were aged ≥70 years. Thoracoscore was used to calculate the risk of hospital mortality. Results Operative mortality was 4.5% whereas predicted mortality was 8%. The operative mortality for cancer patients was 3.3%; the national mortality for lung cancer is 6.5%. Only 2 patients died in hospital after a pneumonectomy in the last 5 years. Half of the patients who died in hospital were ≥70 years old; 29% (4 patients) died after urgent operations for nonmalignant disease. Overall 5- and 10-year survival was 32% and 20%. Median and mean survival was 26 and 57 months, respectively. Long-term survival was better in females aged <70 years, in left pneumonectomy patients, and in those with squamous cell lung cancer. Conclusion Our mortality for pneumonectomy was 50% less than the national mortality rate and significantly lower than that predicted by the Thoracoscore for lung cancer. This confirms that pneumonectomy is still an effective modality for the treatment of lung cancer, with low operative mortality and good long-term survival, especially in younger patients.

The effect of deep hypothermia on the human pulmonary circulation.

OBJECTIVE Acute rises in pulmonary artery pressures following complex cardiac surgery are associated with high morbidity and mortality. We hypothesised that periods of deep hypothermia predispose to elevated pulmonary pressures upon rewarming. We investigated the effect of this hypothermic preconditioning on isolated human pulmonary arteries and isolated perfused lungs. METHODS Isometric tension was measured in human pulmonary artery rings (n=24). We assessed the constriction and dilation of these arteries at 37 °C and 17 °C. Isolated perfused human lung models consisted of lobes ventilated via a bronchial cannula and perfused with Krebs via a pulmonary artery cannula. Bronchial and pulmonary artery pressures were recorded. We investigated the effect of temperature using a heat exchanger. RESULTS Rewarming from 17 °C to 37 °C caused a 1.3 fold increase in resting tension (p<0.05). Arteries constricted 8.6 times greater to 30 nM KCl, constricted 17 times greater to 1 nM Endothelin-1 and dilated 30.3 times greater to 100 μM SNP at 37 °C than at 17 °C (p<0.005). No difference was observed in the responses of arteries originally maintained at 37 °C compared to those arteries maintained at 17 °C and rewarmed to 37 °C. Hypothermia blunted the increase in pulmonary artery pressures to stimulants such as potassium chloride as well as to H-R but did not precondition arteries to higher pulmonary artery pressures upon re-warming. CONCLUSIONS Deep hypothermia reduces the responsiveness of human pulmonary arteries but does not, however, precondition an exaggerated response to vasoactive agents upon re-warming.

Early and late prognostic significance of remote and reversible preoperative neurological events in patients undergoing coronary artery bypass grafting

OBJECTIVES Preoperative neurological event with functional impairment is high risk for operative morbidity and mortality after coronary artery bypass grafting (CABG). However, data regarding the influence of remote and reversible neurological events on early and late survival are lacking. METHODS The clinical profile and operative outcome of 5542 patients who underwent first-time CABG from 01 April 1999 through 30 June 2008 were analysed. Late survival data were 100% complete. The relationship between preoperative neurological event and survival (early and late) was investigated using multivariate logistic regression and survival analyses. RESULTS Mean age was 65.2+/-9.2 years, and 494 patients (8.9%) had remote reversible neurological events preoperatively. There were 129 (2.3%) operative and 595 (10.7%) late deaths after a mean follow-up of 4.9+/-2.7 years. Reversible neurological events had strong univariate (odds ratio (OR) 2.80, 95% confidence interval (CI) 1.82-4.33, p<0.0001) and multivariate associations (OR 2.14, 95% CI 1.34-3.41, p=0.001) with operative mortality. Although reversible neurological events exhibited a powerful univariate relationship with late deaths (hazard ratio (HR) 1.66, 95% CI 1.30-2.12, p<0.0001), this was not maintained after controlling for other factors in multivariable analysis (HR 1.24, 95% CI 0.97-1.59, p=0.08). Neurological complications, more frequent in patients with preoperative events, were implicated in 25% of operative deaths in patients with preoperative neurological events. The respective 5- and 10-year survival rates for patients with reversible neurological events (86% and 68%) were substantially lower than others (91% and 80%, p<0.0001). CONCLUSIONS Remote reversible neurological events increase the risk of fatal and non-fatal postoperative neurological complications. Rigorous measures to improve cerebral protection are warranted in these patients.

Characterization of optimal resting tension in human pulmonary arteries

AIM To determine the optimum resting tension (ORT) for in vitro human pulmonary artery (PA) ring preparations. METHODS Pulmonary arteries were dissected from disease free sections of the resected lung in the operating theatre and tissue samples were directly sent to the laboratory in Krebs-Henseleit solution (Krebs). The pulmonary arteries were then cut into 2 mm long rings. PA rings were mounted in 25 mL organ baths or 8 mL myograph chambers containing Krebs compound (37 °C, bubbled with 21% O2: 5% CO2) to measure changes in isometric tension. The resting tension was set at 1-gram force (gf) with vessels being left static to equilibrate for duration of one hour. Baseline contractile reactions to 40 mmol/L KCl were obtained from a resting tension of 1 gf. Contractile reactions to 40 mmol/L KCl were then obtained from stepwise increases in resting tension (1.2, 1.4, 1.6, 1.8 and 2.0 gf). RESULTS Twenty PA rings of internal diameter between 2-4 mm were prepared from 4 patients. In human PA rings incrementing the tension during rest stance by 0.6 gf, up to 1.6 gf significantly augmented the 40 mmol/L KCl stimulated tension. Further enhancement of active tension by 0.4 gf, up to 2.0 gf mitigate the 40 mmol/L KCl stimulated reaction. Both Myograph and the organ bath demonstrated identical conclusions, supporting that the radial optimal resting tension for human PA ring was 1.61 g. CONCLUSION The radial optimal resting tension in our experiment is 1.61 gf (15.78 mN) for human PA rings.

Single versus multiple lung biopsies for suspected interstitial lung disease

Background There is a belief that in patients with suspected interstitial lung disease, multiple biopsies from different lobes are more likely to result in a diagnosis. We compared the results of single biopsies with those of multiple biopsies in terms of positive yield of histological diagnoses and the patients’ postoperative outcomes. Methods Data of 115 patients who underwent video-assisted thoracoscopic lung biopsy, between 2009 and 2015, for suspected interstitial lung disease were analyzed retrospectively and grouped according to single or multiple lung biopsies. High-resolution computed tomography of the chest was reviewed prior to the procedure, and the most appropriate areas for sampling were chosen. Data analysis was carried out with the Mann-Whitney U test, using MedCalc version 16.1 statistical software. Results Of the 115 patients, 67 had a single biopsy and 48 had more than one biopsy. A histological diagnosis was arrived at in all cases. The duration of chest drainage (p = 0.033) and postoperative hospital stay (p = 0.012) were longer in the multiple-biopsies group. Conclusion A single lung biopsy is sufficient to arrive at a diagnosis of interstitial lung disease when the sampling site is guided by high-resolution computed tomography and a multidisciplinary approach. Multiple biopsies are less cost-effective, offer no added advantage in terms of diagnostic yield, and are associated with more morbidities and a longer hospital stay.

Antegrade rapid prime displacement in elective coronary artery surgery is associated with lower perioperative blood transfusions and a shorter hospital stay

OBJECTIVES Haemodilution during cardiopulmonary bypass is associated with increased perioperative blood transfusions and is thought to reduce intraoperative oxygen delivery to the brain. We sought to evaluate our method of rapid antegrade prime displacement in the context of the perioperative blood transfusion rate, intraoperative cerebral saturations and postoperative hospital stay. METHODS Retrospective analysis of 160 propensity-matched patients undergoing elective coronary artery bypass grafting was performed comparing different perfusion strategies on perioperative blood transfusion and length of postoperative stay. Eighty patients who had rapid antegrade prime displacement and vacuum-assisted venous drainage (RAD-VAD) were compared with 80 patients who had conventional cardiopulmonary bypass with gravity drainage (CB). RAD-VAD involved displacing all or most of the prime in the circuit with the patients own blood prior to the initiation of cardiopulmonary bypass within a 15-20 s window. Within each group, 10 patients had intraoperative cerebral saturation measurements. RESULTS There were no differences in the baseline characteristics between the groups. Both groups had a significant fall (P < 0.05) in haematocrit during cardiopulmonary bypass from preoperative values, however, the fall in haematocrit was significantly less in the RAD-VAD group (P < 0.05). There was significantly (P < 0.05) less intraoperative and postoperative homologous blood transfusions in the RAD-VAD group (47.892 ml ± 8.14 and 76.58 ml ± 21.58) compared with the CB group (229.06 ml ± 105.03 and 199.91 ml ± 47.13). There was a significant fall in cerebral saturations within both groups (P < 0.05) but it was not significant between the groups. The postoperative stay was significantly (P < 0.05) shorter in the RAD-VAD group compared with the conventional group (7.74 days ± 0.51 vs 10.13 days ± 0.95). CONCLUSIONS RAD-VAD is associated with a significantly lower blood transfusion rate perioperatively and shorter hospital stays compared with CB.