A Prospective, Comparative Study to Evaluate the Diagnostic Accuracy of Mallampati Grading in Supine and Sitting Positions for Prediction of Difficult Airway.

Background & aim Difficult airway is a major concern for all anaesthesiologists because failure to secure airway could lead to devastating complications or may increase morbidity and mortality. Airway assessment, therefore, is of paramount importance and anticipating a difficult airway prior to anesthetic administration, could help us in better preparation as well as avoidance of life-threatening complications. There are various tests available to assess the airway, out of which, modified Mallampati test (MLPT) is one of the common, easy and reliable methods to predict difficult airway. Mallampati test, usually is done with patient in sitting position. However, in certain group of patients in whom sitting position is not possible (suspected cervical spine injury, pelvic injury, patients in shock, etc.), the Mallampati test can be done in supine position. Few studies were available which concluded that Mallampati test in supine position was not only reliable but also superior to sitting position, whereas, few other studies contradicted this opinion. We, therefore, wanted to address this issue and tried to find out whether Mallampati test in supine position could offer better diagnostic accuracy or not. Materials & methods Mallampati test (MLPT) in sitting position was done in 100 patients initially in preoperative period and subsequently in supine position inside operating room prior to induction of anesthesia. During laryngoscopy, Cormack-Lehane (CL) grading was noted in all patients. Correlation of Mallampati test in sitting and supine position with Cormack-Lehane grading was obtained. A receiver operating characteristics (ROC) analysis was done to determine the area under the curve, the sensitivity and the specificity. Positive predictive value (PPV) and negative predictive value (NPV) were also calculated to analyse the diagnostic accuracy of Mallampati score (MLPT) in sitting and supine position. Results A toal of 22.2% of patients had difficult intubation (CL grade 3) although MLPT of these patients in sitting position anticipated a non-difficult airway (MLPT 1 and 2) and there was no significant correlation between MLPT grade in sitting position with the Cormack-Lehane grade. In comparison to sitting position, MLPT in supine position had significant correlation with the Cormack-Lehane grading and all patients with supine MLPT 1 and 2 (non-difficult airway) had easy intubation (CL grade 1 and 2). ROC analysis also showed that MLPT grade in supine position had superior correlation and better diagnostic accuracy than MLPT in sitting position for assessment of airway as indicated by higher sensitivity and better positive as well as negative predictive values. Conclusion Mallampati test done in supine position has far greater sensitivity and is superior in predicting difficult intubation as compared to MLPT done in conventional sitting position.

Removal of Protein-Bound Uremic Toxins Using Binding Competitors in Hemodialysis: A Narrative Review.

Removal of protein-bound uremic toxins (PBUTs) during conventional dialysis is insufficient. PBUTs are associated with comorbidities and mortality in dialysis patients. Albumin is the primary carrier for PBUTs and only a small free fraction of PBUTs are dialyzable. In the past, we proposed a novel method where a binding competitor is infused upstream of a dialyzer into an extracorporeal circuit. The competitor competes with PBUTs for their binding sites on albumin and increases the free PBUT fraction. Essentially, binding competitor-augmented hemodialysis is a reactive membrane separation technique and is a paradigm shift from conventional dialysis therapies. The proposed method has been tested in silico, ex vivo, and in vivo, and has proven to be very effective in all scenarios. In an ex vivo study and a proof-of-concept clinical study with 18 patients, ibuprofen was used as a binding competitor; however, chronic ibuprofen infusion may affect residual kidney function. Binding competition with free fatty acids significantly improved PBUT removal in pre-clinical rat models. Based on in silico analysis, tryptophan can also be used as a binding competitor; importantly, fatty acids or tryptophan may have salutary effects in HD patients. More chemoinformatics research, pre-clinical, and clinical studies are required to identify ideal binding competitors before routine clinical use.

Changes in pre-dialysis blood pressure variability in the first year of dialysis associate with mortality in European hemodialysis patients: a retrospective cohort study on behalf of the MONDO Initiative.

Pre-hemodialysis systolic blood pressure variability (pre-HD SBPV) has been associated with outcomes. The association of a change in pre-HD SBPV over time with outcomes, and predictors of this change, has not yet been studied. Therefore, we studied this in a cohort of 8825 incident hemodialysis (HD) patients from the European Monitoring Dialysis Outcomes Initiative database. Patient level pre-HD SBPV was calculated as the standard deviation of the residuals of a linear regression model of systolic blood pressure (SBP) over time divided by individual mean SBP in the respective time periods. The pre-HD SBPV difference between months 1-6 and 7-12 was used as an indicator of pre-HD SBPV change. The association between pre-HD SBPV change and all-cause mortality in year 2 was analyzed by multivariate Cox models. Predictors of pre-HD SBPV change was determined by logistic regression models. We found the highest pre-HD SBPV tertile, in the first 6 months after initiation of HD, had the highest mortality rates (adjusted HR 1.44 (95% confidence intervals (95% CI): 1.15-1.79)). An increase in pre-HD SBPV between months 1-6 and 7-12 was associated with an increased risk of mortality in year 2 (adjusted HR 1.29 (95% CI: 1.05-1.58)) compared with stable pre-HD SPBV. A pre-HD SBPV increase was associated with female gender, higher mean pre-HD SBP and pulse pressure, and lower HD frequency.

A mathematical model of the four cardinal acid-base disorders.

Precise maintenance of acid-base homeostasis is fundamental for optimal functioning of physiological and cellular processes. The presence of an acid-base disturbance can affect clinical outcomes and is usually caused by an underlying disease. It is, therefore, important to assess the acid-base status of patients, and the extent to which various therapeutic treatments are effective in controlling these acid-base alterations. In this paper, we develop a dynamic model of the physiological regulation of an HCO3-/CO2 buffering system, an abundant and powerful buffering system, using Henderson-Hasselbalch kinetics. We simulate the normal physiological state and four cardinal acidbase disorders: Metabolic acidosis and alkalosis and respiratory acidosis and alkalosis. We show that the model accurately predicts serum pH over a range of clinical conditions. In addition to qualitative validation, we compare the in silico results with clinical data on acid-base homeostasis and alterations, finding clear relationships between primary acid-base disturbances and the secondary adaptive compensatory responses. We also show that the predicted primary disturbances accurately resemble clinically observed compensatory responses. Furthermore, via sensitivity analysis, key parameters were identified which could be the most effective in regulating systemic pH in healthy individuals, and those with chronic kidney disease and distal and proximal renal tubular acidosis. The model presented here may provide pathophysiologic insights and can serve as a tool to assess the safety and efficacy of different therapeutic interventions to control or correct acid-base disorders.

A model-based analysis of phenytoin and carbamazepine toxicity treatment using binding-competition during hemodialysis.

Hemodialysis (HD) has limited efficacy towards treatment of drug toxicity due to strong drug-protein binding. In this work, we propose to infuse a competitor drug into the extracorporeal circuit that increases the free fraction of a toxic drug and thereby increases its dialytic removal. We used a mechanistic model to assess the removal of phenytoin and carbamazepine during HD with or without binding-competition. We simulated dialytic removal of (1) phenytoin, initial concentration 70 mg/L, using 2000 mg aspirin, (2) carbamazepine, initial concentration 35 mg/L, using 800 mg ibuprofen, in a 70 kg patient. The competitor drug was infused at constant rate. For phenytoin (~ 13% free at t = 0), HD brings the patient to therapeutic concentration in 460 min while aspirin infusion reduces that time to 330 min. For carbamazepine (~ 27% free at t = 0), the ibuprofen infusion reduces the HD time to reach therapeutic concentration from 265 to 220 min. Competitor drugs with longer half-life further reduce the HD time. Binding-competition during HD is a potential treatment for drug toxicities for which current recommendations exclude HD due to strong drug-protein binding. We show clinically meaningful reductions in the treatment time necessary to achieve non-toxic concentrations in patients poisoned with these two prescription drugs.

Removal of Protein-Bound Uremic Toxins during Hemodialysis Using a Binding Competitor.

BACKGROUND AND OBJECTIVES: Current hemodialysis techniques fail to efficiently remove the protein-bound uremic toxins p-cresyl sulfate and indoxyl sulfate due to their high degree of albumin binding. Ibuprofen, which shares the same primary albumin binding site with p-cresyl sulfate and indoxyl sulfate, can be infused during hemodialysis to displace these toxins, thereby augmenting their removal. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We infused 800 mg ibuprofen into the arterial bloodline between minutes 21 and 40 of a conventional 4-hour high-flux hemodialysis treatment. We measured arterial, venous, and dialysate outlet concentrations of indoxyl sulfate, p-cresyl sulfate, tryptophan, ibuprofen, urea, and creatinine before, during, and after the ibuprofen infusion. We report clearances of p-cresyl sulfate and indoxyl sulfate before and during ibuprofen infusion and dialysate concentrations of protein-bound uremic toxins normalized to each patient's average preinfusion concentrations. RESULTS: We studied 18 patients on maintenance hemodialysis: age 36±11 years old, ten women, and mean vintage of 37±37 months. Compared with during the preinfusion period, the median (interquartile range) clearances of indoxyl sulfate and p-cresyl sulfate increased during ibuprofen infusion from 6.0 (6.5) to 20.2 (27.1) ml/min and from 4.4 (6.7) to 14.9 (27.1) ml/min (each P<0.001), respectively. Relative median (interquartile range) protein-bound uremic toxin dialysate outlet levels increased from preinfusion 1.0 (reference) to 2.4 (1.2) for indoxyl sulfate and to 2.4 (1.0) for p-cresyl sulfate (each P<0.001). Although median serum post- and predialyzer levels in the preinfusion period were similar, infusion led to a marked drop in serum postdialyzer levels for both indoxyl sulfate and p-cresyl sulfate (-1.0 and -0.3 mg/dl, respectively; each P<0.001). The removal of the nonprotein-bound solutes creatinine and urea was not increased by the ibuprofen infusion. CONCLUSIONS: Infusion of ibuprofen into the arterial bloodline during hemodialysis significantly increases the dialytic removal of indoxyl sulfate and p-cresyl sulfate and thereby, leads to greater reduction in their serum levels.

In silico comparison of protein-bound uremic toxin removal by hemodialysis, hemodiafiltration, membrane adsorption, and binding competition.

Protein-bound uremic toxins (PBUTs) are poorly removed during hemodialysis (HD) due to their low free (dialyzable) plasma concentration. We compared PBUT removal between HD, hemodiafiltration (HDF), membrane adsorption, and PBUT displacement in HD. The latter involves infusing a binding competitor pre-dialyzer, which competes with PBUTs for their albumin binding sites and increases their free fraction. We used a mathematical model of PBUT/displacer kinetics in dialysis comprising a three-compartment patient model, an arterial/venous tube segment model, and a dialyzer model. Compared to HD, improvements in removal of prototypical PBUTs indoxyl sulfate (initial concentration 100 µM, 7% free) and p-cresyl sulfate (150 µM, 5% free) were: 5.5% and 6.4%, respectively, for pre-dilution HDF with 20 L replacement fluid; 8.1% and 9.1% for post-dilution HDF 20 L; 15.6% and 18.3% for pre-dilution HDF 60 L; 19.4% and 22.2% for complete membrane adsorption; 35.0% and 41.9% for displacement with tryptophan (2000 mg in 500 mL saline); 26.7% and 32.4% for displacement with ibuprofen (800 mg in 200 mL saline). Prolonged (one-month) use of tryptophan reduces the IS and pCS time-averaged concentration by 28.1% and 29.9%, respectively, compared to conventional HD. We conclude that competitive binding can be a pragmatic approach for improving PBUT removal.

Association of Hip Radiograph Findings With Pain and Function in Patients Presenting With Low Back Pain.

BACKGROUND: Relationships between low back pain (LBP) and the hip in patient cohorts have been described primarily in patients with moderate to severe hip osteoarthritis (OA). Less is known about the links of LBP with hip radiographic findings of hip deformity and minimal OA. OBJECTIVE: To describe the incidence of radiographic hip deformity or hip OA; to describe and compare spine- and hip-related pain and function in the subset of patients who were found to have radiographic hip deformity or hip OA; and to compare patients with evidence of radiographic hip deformity or hip OA to patients without hip radiographic findings. DESIGN: Prospective cohort study with cross-sectional design. SETTING: Tertiary university. PATIENTS: A total of 63 patients (40 women, 23 men) with a mean age of 48.5 ± 14 years with LBP and a minimum of one positive provocative hip test. METHODS: Hip radiographs were assessed by an independent examiner for hip OA and deformity. MAIN OUTCOME MEASUREMENTS: Comparisons of hip and lumbar spine pain and function were completed for patients with radiographic findings of hip OA or deformity. RESULTS: Moderate to severe hip OA was found in 12 of 60 patients (20.0%). At least one measurement of femoroacetabular impingement (FAI) was found in 14 of 60 patients (23.3%) to 33 of 45 patients (73.3%). At least one measurement of developmental hip dysplasia (DDH) was found in 7 of 60 patients (11.6%) to 11 of 63 patients (17.4%). Greater pain and reduced hip and lumbar spine function were found in the patients with moderate to severe hip OA. Patients with LBP and FAI were found to have significantly greater extremes of pain and reduced lumbar spine function. CONCLUSION: Links between the hip and the spine affecting pain and function may be found in patients with LBP and hip deformity and before the onset of radiographic hip OA, and may be associated with hip deformity. Further investigation is needed to better understand these links and their potential impact on prognosis and treatment of LBP. LEVEL OF EVIDENCE: II.

An in silico method to predict net calcium transfer during hemodialysis.

International guidelines for chronic hemodialysis patients suggest a dialysate calcium concentration between 1.25 and 1.5 mmol/L. However, it is not certain if these dialysate calcium levels result in net calcium transfer into the patient. With ubiquitous prevalence of vascular calcification in hemodialysis patients, it is pertinent to model the mass balance of calcium during dialysis. To this end, we developed a two compartmental patient model and spatiotemporal representation of dialyzer model to investigate and quantify the calcium mass balance during dialysis. The model accounts for calcium-albumin binding and varying protein concentration; the latter accounts for the Gibbs-Donnan effect. The model simulations suggest that despite a lower dialysate calcium concentration of 1.25 mmol/L, some of our patients may be loaded with calcium during dialysis. This net calcium flux from dialysate to blood side may be a potential contributor to vascular calcification, a primary cause of cardiovascular mortality in hemodialysis patients.

A novel mathematical model of protein-bound uremic toxin kinetics during hemodialysis.

Protein-bound uremic toxins (PBUTs) are difficult to remove by conventional hemodialysis; a high degree of protein binding reduces the free fraction of toxins and decreases their diffusion across dialyzer membranes. Mechanistic understanding of PBUT kinetics can open new avenues to improve their dialytic removal. We developed a comprehensive model of PBUT kinetics that comprises: (1) a three-compartment patient model, (2) a dialyzer model. The model accounts for dynamic equilibrium between protein, toxin, and the protein-toxin complex. Calibrated and validated using clinical and experimental data from the literature, the model predicts key aspects of PBUT kinetics, including the free and bound concentration profiles for PBUTs and the effects of dialysate flow rate and dialyzer size on PBUT removal. Model simulations suggest that an increase in dialysate flow rate improves the reduction ratio (and removal) of strongly protein-bound toxins, namely, indoxyl sulfate and p-cresyl sulfate, while for weakly bound toxins, namely, indole-3-acetic acid and p-cresyl glucuronide, an increase in blood flow rate is advantageous. With improved dialyzer performance, removal of strongly bound PBUTs improves gradually, but marginally. The proposed model can be used for optimizing the dialysis regimen and for in silico testing of novel approaches to enhance removal of PBUTs.

Impact of fluid status and inflammation and their interaction on survival: a study in an international hemodialysis patient cohort.

In hemodialysis patients extracellular fluid overload is a predictor of all-cause and cardiovascular mortality, and a relation with inflammation has been reported in previous studies. The magnitude and nature of this interaction and the effects of moderate fluid overload and extracellular fluid depletion on survival are still unclear. We present the results of an international cohort study in 8883 hemodialysis patients from the European MONDO initiative database where, during a three-month baseline period, fluid status was assessed using bioimpedance and inflammation by C-reactive protein. All-cause mortality was recorded during 12 months of follow up. In a second analysis a three-month baseline period was added to the first baseline period, and changes in fluid and inflammation status were related to all-cause mortality during six-month follow up. Both pre-dialysis estimated fluid overload and fluid depletion were associated with an increased mortality, already apparent at moderate levels of estimated pre-dialysis fluid overload (1.1-2.5L); hazard ratio 1.64 (95% confidence interval 1.35-1.98). In contrast, post-dialysis estimated fluid depletion was associated with a survival benefit (0.74 [0.62-0.90]). The concurrent presence of fluid overload and inflammation was associated with the highest risk of death. Thus, while pre-dialysis fluid overload was associated with inflammation, even in the absence of inflammation, fluid overload remained a significant risk factor for short-term mortality, even following improvement of fluid status.

Hip and Lumbar Spine Physical Examination Findings in People Presenting With Low Back Pain, With or Without Lower Extremity Pain.

Study Design Prospective cohort study, cross-sectional design. Background The hip-spine syndrome is described in patients with known arthritis of the hip. This study describes the hip examination findings of people presenting with low back pain (LBP). Objectives To (1) report examination findings of the hip in patients with LBP and (2) compare pain and function in patients with positive hip examination findings to those in patients without positive hip examination findings. Methods An examination and validated questionnaires of spine and hip pain and function were completed. Pain and function scores were compared between patients with and without positive hip findings. Results Consecutive patients (68 women, 33 men) with a mean age of 47.6 years (range, 18.4-79.8 years) participated. On physical examination, 81 (80%) had reduced hip flexion; 76 (75%) had reduced hip internal rotation; and 25 (25%) had 1, 32 (32%) had 2, and 23 (23%) had 3 positive provocative hip tests. Patients with reduced hip flexion had worse LBP-related (mean modified Oswestry Disability Index, 35.3 versus 25.6; P = .04) and hip-related function (mean modified Harris Hip Score, 66.0 versus 82.0; P = .03). Patients with reduced hip internal rotation had worse LBP-related function (mean Roland-Morris questionnaire, 12.4 versus 8.2; P = .003). A positive provocative hip test was coupled with more intense pain (median, 9 versus 7; P = .05) and worse LBP-related (mean Roland-Morris questionnaire, 12.1 versus 8.5; P = .02) and hip-related function (mean modified Harris Hip Score, 65.8 versus 89.7; P = .005). Conclusion Physical examination findings indicating hip dysfunction are common in patients presenting with LBP. Patients with LBP and positive hip examination findings have more pain and worse function compared to patients with LBP but without positive hip examination findings. Level of Evidence Symptom prevalence, level 1b. J Orthop Sports Phys Ther 2017;47(3):163-172. Epub 3 Feb 2017. doi:10.2519/jospt.2017.6567.

Effect of cool vs. warm dialysate on toxin removal: rationale and study design.

BACKGROUND: Cool dialysate is often recommended for prevention of intra-dialytic hypotensive episodes in maintenance hemodialysis (HD) patients. However, its effect on toxin removal is not studied. It is known that inter-compartmental resistance is the main barrier for toxin removal. Cool dialysate can potentially increase this resistance by vasoconstriction and thus impair the toxin removal. The aim of this trial is to compare the toxin removal outcome associated with cool vs. warm dialysate. METHOD/DESIGN: This study is based on the hypothesis that dialysate temperature, a potential maneuver to maintain hemodynamic stability during HD, may influence inter-compartmental resistance and hence, toxin removal. Only stable HD patients will be recruited for this study. The quantum of removed toxins will be assessed by the total spent dialysate, which is a gold standard to quantify the efficacy of a single dialysis session. Collected samples will be analyzed for urea, creatinine, phosphate, ß2-microglobulin, and uric acid. The study is a single center, self-controlled, randomized prospective clinical research where 20 study subjects will undergo 2 dialysis sessions: (a) cool dialysis with dialysate at 35.5°C, and (b) warm dialysis with dialysate at 37°C. Pre- and post-dialysis blood samples will be collected to quantify the dialysis adequacy and toxin reduction ratio. DISCUSSION: This is the first clinical research to investigate the effect of dialysate temperature on removal of both small and large-sized toxins. Successful completion of this research will provide important knowledge pertaining to dialysate temperature prescription. Results can also lead to the hypothesis that cool dialysate may help in by preventing intra-dialytic hypotensive episodes, but prolonged prescription of cool dialysate may lead to comorbidities associated with excess toxin accumulation. The new knowledge will encourage for personalized dialysate temperature profiling. TRIAL REGISTRATION: Clinicaltrials.gov Identifier--NCT02064153.

Comparison of toxin removal outcomes in online hemodiafiltration and intra-dialytic exercise in high-flux hemodialysis: a prospective randomized open-label clinical study protocol.

BACKGROUND: Maintenance hemodialysis (HD) patients universally suffer from excess toxin load. Hemodiafiltration (HDF) has shown its potential in better removal of small as well as large sized toxins, but its efficacy is restricted by inter-compartmental clearance. Intra-dialytic exercise on the other hand is also found to be effective for removal of toxins; the augmented removal is apparently obtained by better perfusion of skeletal muscles and decreased inter-compartmental resistance. The aim of this trial is to compare the toxin removal outcome associated with intra-dialytic exercise in HD and with post-dilution HDF. METHODS/DESIGN: The main hypothesis of this study is that intra-dialytic exercise enhances toxin removal by decreasing the inter-compartmental resistance, a major impediment for toxin removal. To compare the HDF and HD with exercise, the toxin rebound for urea, creatinine, phosphate, and ß2-microglobulin will be calculated after 2 hours of dialysis. Spent dialysate will also be collected to calculate the removed toxin mass. To quantify the decrease in inter-compartmental resistance, the recently developed regional blood flow model will be employed. The study will be single center, randomized, self-control, open-label prospective clinical research where 15 study subjects will undergo three dialysis protocols (a) high flux HD, (b) post-dilution HDF, (c) high flux HD with exercise. Multiple blood samples during each study session will be collected to estimate the unknown model parameters. DISCUSSION: This will be the first study to investigate the exercise induced physiological change(s) responsible for enhanced toxin removal, and compare the toxin removal outcome both for small and middle sized toxins in HD with exercise and HDF. Successful completion of this clinical research will give important insights into exercise effect on factors responsible for enhanced toxin removal. The knowledge will give confidence for implementing, sustaining, and optimizing the exercise in routine dialysis care. We anticipate that toxin removal outcomes from intra-dialytic exercise session will be comparable to that obtained by standalone HDF. These results will encourage clinicians to combine HDF with intra-dialytic exercise for significantly enhanced toxin removal. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01674153.

A regional blood flow model for ß2-microglobulin kinetics and for simulating intra-dialytic exercise effect.

A kinetic model based on first principles, for ß(2)-microglobulin, is presented to obtain precise parameter estimates for individual patient. To reduce the model complexity, the number of model parameters was reduced using a priori identifiability analysis. The model validity was confirmed with the clinical data of ten renal patients on post-dilution hemodiafiltration. The model fit resulted in toxin distribution volume (V(d)) of 14.22 ± 0.75 L, plasma fraction in extracellular compartment (f(P)) of 0.39 ± 0.03, and inter-compartmental clearance of 44 ± 4.1 mL min(-1). Parameter estimates suggest that V(d) and f(P) are much higher in hemodialysis patients than in normal subjects. The developed model predicts larger removed toxin mass than that predicted by the two-pool model. On the application front, the developed model was employed to explain the effect of intra-dialytic exercise on toxin removal. The presented simulations suggest that intra-dialytic exercise not only increases the blood flow to low flow region, but also decreases the inter-compartmental resistance. Combined, they lead to increased toxin removal during dialysis and reduced post-dialysis rebound. The developed model can assist in suggesting the improved dialysis dose based on ß(2)-microglobulin, and also lead to quantitative inclusion of intra-dialytic exercise in the future.