Comparison of Differences in Cohort (Forward) and Case Control (Backward) Methodologic Approaches for Validation of the Hypotension Prediction Index.

BACKGROUND: The Hypotension Prediction Index (the index) software is a machine learning algorithm that detects physiologic changes that may lead to hypotension. The original validation used a case control (backward) analysis that has been suggested to be biased. This study therefore conducted a cohort (forward) analysis and compared this to the original validation technique. METHODS: A retrospective analysis of data from previously reported studies was conducted. All data were analyzed identically with two different methodologies, and receiver operating characteristic curves were constructed. Both backward and forward analyses were performed to examine differences in area under the receiver operating characteristic curves for the Hypotension Prediction Index and other hemodynamic variables to predict a mean arterial pressure (MAP) less than 65 mmHg for at least 1 min 5, 10, and 15 min in advance. RESULTS: The analysis included 2,022 patients, yielding 4,152,124 measurements taken at 20-s intervals. The area under the curve for the index predicting hypotension analyzed by backward and forward methodologies respectively was 0.957 (95% CI, 0.947 to 0.964) versus 0.923 (95% CI, 0.912 to 0.933) 5 min in advance, 0.933 (95% CI, 0.924 to 0.942) versus 0.923 (95% CI, 0.911 to 0.933) 10 min in advance, and 0.929 (95% CI, 0.918 to 0.938) versus 0.926 (95% CI, 0.914 to 0.937) 15 min in advance. No variable other than MAP had an area under the curve greater than 0.7. The areas under the curve using forward analysis for MAP predicting hypotension 5, 10, and 15 min in advance were 0.932 (95% CI, 0.920 to 0.940), 0.929 (95% CI, 0.918 to 0.938), and 0.932 (95% CI, 0.921 to 0.940), respectively. The R2 for the variation in the index due to MAP was 0.77. CONCLUSIONS: Using an updated methodology, the study found that the utility of the Hypotension Prediction Index to predict future hypotensive events is high, with an area under the receiver operating characteristics curve similar to that of the original validation method.

A retrospective study of the effects of a vasopressor bolus on systolic slope (dP/dt) and dynamic arterial elastance (Eadyn).

BACKGROUND: To enhance the utility of functional hemodynamic monitoring, the variables systolic slope (dP/dt) and dynamic arterial elastance (Eadyn) are calculated by the Hypotension Prediction Index (HPI) Acumen® Software. This study was designed to characterize the effects of phenylephrine and ephedrine on dP/dt and Eadyn. METHODS: This was a retrospective, non-randomized analysis of data collected during two clinical studies. All patients required intra-operative controlled mechanical ventilation and had an indwelling radial artery catheter connected to an Acumen IQ sensor. Raw arterial pressure waveform data was downloaded from the patient monitor and all hemodynamic measurements were calculated off-line. The anesthetic record was reviewed for bolus administrations of either phenylephrine or ephedrine. Cardiovascular variables prior to drug administration were compared to those following vasopressor administrations. The primary outcome was the difference for dP/dt and Eadyn at baseline compared with the average after the bolus administration. All data sets demonstrated non-normal distributions so statistical analysis of paired and unpaired data followed the Wilcoxon matched pairs signed-rank test or Mann-Whitney U test, respectively. RESULTS: 201 doses of phenylephrine and 100 doses of ephedrine were analyzed. All data sets are reported as median [95% CI]. Mean arterial pressure (MAP) increased from 62 [54,68] to 78 [76,80] mmHg following phenylephrine and from 59 [55,62] to 80 [77,83] mmHg following ephedrine. Stroke volume and cardiac output both increased. Stroke volume variation and pulse pressure variation decreased. Both drugs produced significant increases in dP/dt, from 571 [531, 645] to 767 [733, 811] mmHg/sec for phenylephrine and from 537 [509, 596] to 848 [779, 930] mmHg/sec for ephedrine. No significant changes in Eadyn were observed. CONCLUSION: Bolus administration of phenylephrine or ephedrine increases dP/dt but does not change Eadyn. dP/dt demonstrates potential for predicting the inotropic response to phenylephrine or ephedrine, providing guidance for the most efficacious vasopressor when treating hypotension. TRIAL REGISTRATION: Data was collected from two protocols. The first was deemed to not require written, informed consent by the Institutional Review Board (IRB). The second was IRB-approved (Effect of Diastolic Dysfunction on Dynamic Cardiac Monitors) and registered on ClinicalTrials.gov (NCT04177225).

The effects of an IV fluid bolus on mitral annular velocity and the assessment of diastolic function: a prospective non-randomized study.

BACKGROUND: Abnormal diastolic function is an independent predictor of adverse postoperative outcomes. Mitral annular tissue Doppler velocity (e') is a key parameter for assessing diastolic function. The purpose of this study was to confirm that an acute increase in preload did not significantly impact the intraoperative measurement of e' and secondarily evaluate the impact of this acute intravascular volume increase on the clinical assessment of diastolic function using a previously described simplified algorithm. METHODS: This was a prospective, non-randomized study in adult patients undergoing elective cardiac surgeries requiring transesophageal echocardiographic monitoring, arterial pressure and Swan-Ganz catheter placements as part of the surgical procedure. Following baseline echocardiographic and hemodynamic measurements, 500 ml of crystalloid solution was infused over 10 min. Hemodynamic and echocardiographic measurements were repeated 5 min after fluid administration. RESULTS: Complete data sets were available from 84 of the 100 patients who were enrolled in this study. There was no significant change in the values of e'. The average baseline was 7.8 ± 2.0 cm/s (95%CI: 7.4, 8.2) and 8.1 ± 2.4 (95%CI: 7.6, 8.6) following the fluid bolus (p = 0.10). All hemodynamic variables associated with increased intravascular volume (central venous pressure, pulmonary arterial pressures and stroke volume variation) changed significantly. The overall distribution of diastolic function grades did not change following fluid administration (p = 0.69). However, there were many individual patient differences. When using this simplified algorithm, functional grading changed in 35 patients. Thirty of these 35 changes were only a single grade shift. 22 patients had worse functional grading after fluid administration while 13 had improved grading. Nine patients with normal diastolic function at baseline demonstrated diastolic dysfunction after fluid administration while 6 patients with baseline dysfunction normalized following the fluid bolus. CONCLUSION: We confirmed that e' is a robust measurement that is reproducible in the intraoperative setting despite variable vascular volume loading conditions, however, the clinical assessment of diastolic function was still altered in 42% of the patients following an intravenous fluid bolus.

Performance of pulse oximeters as a function of race compared to skin pigmentation: a single center retrospective study.

Pulse oximetry (SpO2) is a critical monitor for assessing oxygenation status and guiding therapy in critically ill patients. Race has been identified as a potential source of SpO2 error, with consequent bias and inequities in healthcare. This study was designed to evaluate the incidence of occult hypoxemia and accuracy of pulse oximetry associated with the Massey-Martin scale and characterize the relationship between Massey scores and self-identified race. This retrospective single institute study utilized the Massey-Martin scale as a quantitative assessment of skin pigmentation. These values were recorded peri-operatively in patients enrolled in unrelated clinical trials. The electronic medical record was utilized to obtain demographics, arterial blood gas values, and time matched SpO2 values for each PaO2 ≤ 125 mmHg recorded throughout their hospitalizations. Differences between SaO2 and SpO2 were compared as a function of both Massey score and self-reported race. 4030 paired SaO2-SpO2 values were available from 579 patients. The average error (SaO2-SpO2) ± SD was 0.23 ± 2.6%. Statistically significant differences were observed within Massey scores and among races, with average errors that ranged from - 0.39 ± 2.3 to 0.53 ± 2.5 and - 0.55 ± 2.1 to 0.37 ± 2.7, respectively. Skin color varied widely within each self-identified race category. There was no clinically significant association between error rates and Massey-Martin scale grades and no clinically significant difference in accuracy observed between self-reported Black and White patients. In addition, self-reported race is not an appropriate surrogate for skin color.

Assisted Fluid Management Software Guidance for Intraoperative Fluid Administration.

BACKGROUND: Excessive or inadequate fluid administration causes complications, but despite this, fluid administration during noncardiac surgery is highly variable. Goal-directed management helps optimize the amount and timing of fluid administration; however, implementation is difficult because algorithms are complex. The authors therefore tested the performance of the Acumen Assisted Fluid Management software (Edwards Lifesciences, USA), which is designed to guide optimal intravenous fluid administration during surgery. METHODS: In this multicenter, prospective, single-arm cohort evaluation, the authors enrolled 330 adults scheduled for moderate- to high-risk noncardiac surgery that required arterial catheter insertion and mechanical ventilation. Clinicians chose a fluid strategy based on a desired 10%, 15%, or 20% increase in stroke volume (SV) in response to a fluid bolus. Dedicated fluid management software prompted "test" or "recommended" boluses, and clinicians were free to initiate a "user" bolus of 100 to 500 ml of crystalloid or colloid. Clinicians were free to accept or decline the software prompts. The authors primarily compared the fraction of software-recommended boluses that produced suitable increases in SV to a 30% reference rate. On an exploratory basis, we compared responses to software-recommended and clinician-initiated boluses. RESULTS: Four hundred twenty-four of 479 (89%) software-recommended fluid boluses and 508 of 592 (86%) clinician-initiated fluid boluses were analyzed per protocol. Of those, 66% (95% CI, 62 to 70%) of delivered fluid boluses recommended by the software resulted in desired increases in SV, compared with the 30% reference rate, whereas only 41% (95% CI, 38 to 44%) of clinician-initiated boluses did (P < 0.0001). The mean ± SD increase in SV after boluses recommended by the software was 14.2 ± 13.9% versus 8.3 ± 12.1% (P < 0.0001) for those initiated by clinicians. CONCLUSIONS: Fluid boluses recommended by the software resulted in desired SV increases more often, and with greater absolute SV increase, than clinician-initiated boluses. Automated assessment of fluid responsiveness may help clinicians optimize intraoperative fluid management during noncardiac surgery.

Oxygen Reserve Index: Utility as an Early Warning for Desaturation in High-Risk Surgical Patients.

BACKGROUND: Perioperative pulse oximetry hemoglobin saturation (Spo2) measurement is associated with fewer desaturation and hypoxia episodes. However, the sigmoidal nature of oxygen-hemoglobin dissociation limits the accuracy of estimation of the partial pressure of oxygen (Pao2) >80 mm Hg and correspondingly limits the ability to identify when Pao2 >80 mm Hg but falling. We hypothesized that a proxy measurement for oxygen saturation (Oxygen Reserve Index [ORI]) derived from multiwavelength pulse oximetry may allow additional warning time before critical desaturation or hypoxia. To test our hypothesis, we used a Masimo multiwavelength pulse oximeter to compare ORI and Spo2 warning times during apnea in high-risk surgical patients undergoing cardiac surgery. METHODS: This institutional review board-approved prospective study (NCT03021473) enrolled American Society of Anesthesiologists physical status III or IV patients scheduled for elective surgery with planned preinduction arterial catheter placement. In addition to standard monitors, an ORI sensor was placed and patients were monitored with a pulse oximeter displaying the ORI, a nondimensional parameter that ranges from 0 to 1. Patients were then preoxygenated until ORI plateaued. Following induction of anesthesia, mask ventilation with 100% oxygen was performed until neuromuscular blockade was established. Endotracheal intubation was accomplished using videolaryngoscopy to confirm placement. The endotracheal tube was not connected to the breathing circuit, and patients were allowed to be apneic. Ventilation was resumed when Spo2 reached 94%. We defined ORI warning time as the time from when the ORI alarm registered (based on the absolute value and the rate of change) until the Spo2 decreased to 94%. We defined the Spo2 warning time as the time for Spo2 to decrease from 97% to 94%. The added warning time provided by ORI was defined as the difference between ORI warning time and Spo2 warning time. RESULTS: Forty subjects were enrolled. Complete data for analysis were available from 37 patients. The ORI alarm registered before Spo2 decreasing to 97% in all patients. Median (interquartile range [IQR]) ORI warning time was 80.4 seconds (59.7-105.9 seconds). Median (IQR) Spo2 warning time was 29.0 seconds (20.5-41.0 seconds). The added warning time provided by ORI was 48.4 seconds (95% confidence interval [CI], 40.4-62.0 seconds; P < .0001). CONCLUSIONS: In adult high-risk surgical patients, ORI provided clinically relevant added warning time of impending desaturation compared to Spo2. This additional time may allow modification of airway management, earlier calls for help, or assistance from other providers. The potential patient safety impact of such monitoring requires further study.

Use of the Hypotension Prediction Index During Cardiac Surgery.

OBJECTIVE: The hypotension prediction index (HPI) is a novel parameter developed by Edwards Lifesciences (Irvine, CA) that is obtained through an algorithm based on arterial pressure waveform characteristics. Past studies have demonstrated its accuracy in predicting hypotensive events in noncardiac surgeries. The authors aimed to evaluate the use of the HPI in cardiac surgeries requiring cardiopulmonary bypass (CPB). DESIGN: Prospective cohort feasibility study. SETTING: Single university medical center. PARTICIPANTS: Sequential adult patients undergoing elective cardiac surgeries requiring CPB between October 1, 2018, and December 31, 2018. INTERVENTIONS: HPI monitor was connected to the patient's arterial pressure transducer. Anesthesiologists and surgeons were blinded to the monitor output. MEASUREMENTS AND MAIN RESULTS: HPI values and hypotensive events were recorded before and after CPB. The primary outcomes were the area under the curve (AUC) of the receiver operating characteristic curve, sensitivity, and specificity of HPI predicting hypotension. The AUC, sensitivity, and specificity for HPI lead time to hypotension five minutes before the event were 0.90 (95% confidence interval [CI]: 0.853-0.949), 84% (95% CI: 77.7-90.5), and 84% (95% CI: 70.9-96.8), respectively. Ten minutes before the event AUC, sensitivity, and specificity for HPI lead time to hypotension were 0.83 (95% CI: 0.750-0.905), 79% (95% CI: 69.8-88.1), and 74% (95% CI: 58.8-89.6), respectively. Fifteen minutes before the hypotensive event AUC, sensitivity, and specificity for HPI lead time to hypotension were 0.83 (95% CI: 0.746-0.911), 79% (95% CI: 68.4-89.0), and 74% (95% CI: 58.8-89.6), respectively. CONCLUSION: HPI predicted hypotensive episodes during cardiac surgeries with a high degree of sensitivity and specificity.

Study of early warning for desaturation provided by Oxygen Reserve Index in obese patients.

Acute hemoglobin desaturation can reflect rapidly decreasing PaO2. Pulse oximetry saturation (SpO2) facilitates hypoxia detection but may not significantly decrease until PaO2 < 80 mmHg. The Oxygen Reserve Index (ORI) is a unitless index that correlates with moderately hyperoxic PaO2. This study evaluated whether ORI provides added arterial desaturation warning in obese patients. This IRB approved, prospective, observational study obtained written informed consent from Obese (body mass index (BMI) kg m-2; 30 < BMI < 40) and Normal BMI (19 < BMI < 25) adult patients scheduled for elective surgery requiring general endotracheal anesthesia. Standard monitors and an ORI sensor were placed. Patient's lungs were pre-oxygenated with 100% FiO2. After ORI plateaued, general anesthesia was induced, and endotracheal intubation accomplished using a videolaryngoscope. Patients remained apneic until SpO2reached 94%. ORI and SpO2 were recorded continuously. Added warning time was defined as the difference between the time to SpO2 94% from ORI alarm start or from SpO2 97%. Data are reported as median; 95% confidence interval. Complete data were collected in 36 Obese and 36 Normal BMI patients. ORI warning time was always longer than SpO2 warning time. Added warning time provided by ORI was 46.5 (36.0-59.0) seconds in Obese and 87.0 (77.0-109.0) seconds in Normal BMI patients, and was shorter in Obese than Normal BMI patients difference 54.0 (38.0-74.0) seconds (p < 0.0001). ORI provided what was felt to be clinically significant added warning time of arterial desaturation compared to SpO2. This added time might allow earlier calls for help, assistance from other providers, or modifications of airway management.Trial registration ClinicalTrials.gov NCT03021551.

Stroke volume variation during acute normovolemic hemodilution.

BACKGROUND: The intravascular volume of surgical patients should be optimized to avoid complications associated with both overhydration and underresuscitation. In patients undergoing intraoperative acute normovolemic hemodilution, we investigated whether stroke volume variation (SVV) derived from an arterial pressure-based cardiac output (CO) monitor system (FloTrac/Vigileo, Edwards Lifesciences, Irvine, CA) tracked the changes associated with blood removal and replacement. We further evaluated the correlations between SVV and 3-dimensional (3D) transesophageal echocardiographic (TEE) left ventricular (LV) volume measurements. METHODS: Twenty-five patients had procedures during which acute normovolemic hemodilution was a planned part of the intraoperative management. We defined 7 measurement timepoints: baseline, after the removal of 5%, 10%, and 15% of the estimated blood volume (EBV) and after replacement with an equal volume of 6% hetastarch to -10%, -5%, and baseline EBV. At each timepoint, heart rate and systolic, diastolic, and mean arterial blood pressure were obtained from standard monitors, CO and SVV measurements were obtained from the FloTrac/Vigileo monitor, and TEE images were recorded for subsequent off-line reconstruction and determination of LV end-systolic and end-diastolic volumes. For statistical evaluations, we used a mixed models analysis of variance and Dunnett's test for post hoc comparisons with baseline values. Pearson's correlation was used to examine the relationships between SVV and LV volume. RESULTS: Analysis of variance demonstrated no significant change in heart rate or mean arterial blood pressure over the duration of study. CO decreased from 4.9 +/- 0.3 to 4.5 +/- 0.3 L/min after removal of 15% of the EBV and then increased to a final value of 5.4 +/- 0.3 L/min after replacement of 15% of the EBV. SVV increased from 9.2% +/- 0.9% to 20.3% +/- 2.0% (P < 0.001) after removal of 15% of the EBV and returned to a final value of 7.2% +/- 0.9% after replacement of 15% of the EBV. The indexed LV end-diastolic volume decreased from 42.1 +/- 8.3 to 36.9.3 +/- 8.3 mL/m(2) (P < 0.001) after removal of 15% of the EBV and then returned to a final volume of 45.9 +/- 10.3 mL/m(2) after replacement of 15% of the EBV. The measurements of SVV correlated inversely with the 3D TEE LV volume measurements. CONCLUSIONS: The SVV derived from the FloTrac/Vigileo system changes significantly as blood is removed and replaced during hemodilution. These changes correlate with 3D TEE measurements of LV volume. The utility of SVV in guiding optimization of intravascular volume merits further study.

Anesthetic preconditioning combined with postconditioning offers no additional benefit over preconditioning or postconditioning alone.

BACKGROUND: Recent investigations demonstrate that anesthetic preconditioning and postconditioning reduce myocardial infarct size to a degree comparable to that achieved with ischemic preconditioning. We hypothesized that the combination of sevoflurane preconditioning and postconditioning would result in greater preservation of myocardium. METHODS: Langendorff perfused rat hearts were divided into four groups: control, preconditioning, postconditioning, and preconditioning plus postconditioning. During reperfusion, left ventricular function (left ventricular developed pressure, left ventricular end diastolic pressure, and dp/dt) were measured. At the end of reperfusion, the infarct sizes were measured with 2,3,5 triphenyltetrazolium chloride staining. Nuclear magnetic resonance was used to measure intracellular pH, Na(+), and Ca(2+). RESULTS: Left ventricular developed pressure, left ventricular end diastolic pressure, left ventricular dp/dt(max) and dp/dt(min) were significantly improved in the treatment groups when compared with those in the controls. Myocardial infarct size (24% +/- 7%, 16% +/- 8%, and 22% +/- 7% in preconditioning, postconditioning, and pre-plus postconditioning groups versus 44% +/- 8% in the control group, P < 0.05) and intracellular Na(+) and Ca(2+) were significantly decreased in all experimental groups at the end of reperfusion when compared with those in control. However, there were no differences between these variables in each treatment group. CONCLUSION: Sevoflurane postconditioning is as effective as preconditioning in protecting myocardial function after global ischemia. The combination of sevoflurane preconditioning and postconditioning offered no additional benefit over either intervention alone.

The Utility of 3D Left Atrial Volume and Mitral Flow Velocities as Guides for Acute Volume Resuscitation.

Left ventricular end-diastolic pressure (LVEDP) is the foundation of cardiac function assessment. Because of difficulties and risks associated with its direct measurement, correlates of LVEDP derived by pulmonary artery (PA) catheterization or transesophageal echocardiography (TEE) are commonly adopted. TEE has the advantage of being less invasive; however TEE-based estimation of LVEDP using correlates such as left ventricular end-diastolic volume (LVEDV) has technical difficulties that limit its clinical usefulness. Using intraoperative acute normovolemic hemodilution (ANH) as a controlled hemorrhagic model, we examined various mitral flow parameters and three-dimensional reconstructions of left atrial volume as surrogates of LVEDP. Our results demonstrate that peak E wave velocity and left atrial end-diastolic volume (LAEDV) correlated with known changes in intravascular volume associated with ANH. Although left atrial volumetric analysis was done offline in our study, recent advances in echocardiographic software may allow for continuous display and real-time calculation of LAEDV. Along with the ease and reproducibility of acquiring Doppler images of flow across the mitral valve, these two correlates of LVEDP may justify a more widespread use of TEE to optimize intraoperative fluid management. The clinical applicability of peak E wave velocity and LAEDV still needs to be validated during uncontrolled resuscitation.

Comparison of postoperative hepatic function after laparoscopic versus open gastric bypass.

BACKGROUND: Pneumoperitoneum has been shown to reduce hepatic portal blood flow and alter postoperative hepatic transaminases. This study evaluated the changes in hepatic function after laparoscopic and open gastric bypass (GBP). METHODS: Thirty-six morbidly obese patients were randomly assigned to undergo either laparoscopic (n = 18) or open (n = 18) GBP. Liver function tests--total bilirubin (T Bil), gamma GT (GGT), albumin, alkaline phosphatase (ALP), aspartate transferase (AST), alanine transferase (ALT)--and creatine kinase levels were obtained preoperatively and at 1, 24, 48, and 72 hours postoperatively. RESULTS: The two groups were similar in age, sex, and body mass index. Albumin and ALP levels decreased while T Bil and GGT levels remained unchanged from baseline in both groups without significant difference between the two groups. After laparoscopic GBP, ALT and AST transiently increased by sixfold and returned to near baseline levels at 72 hours. After open GBP, ALT and AST transiently increased by fivefold to eightfold and returned to near baseline levels by 72 hours. Creatine kinase level was significantly lower after laparoscopic GBP than after open GBP at 48 and 72 hours postoperatively. There was no postoperative liver failure or mortality in either group. CONCLUSIONS: Laparoscopic GBP resulted in transient postoperative elevation of hepatic transaminase (ALT, AST) but did not adversely alter hepatic function to any greater extent than open GBP. Creatine kinase levels were lower after laparoscopic GBP reflecting its lesser degree of abdominal wall trauma.

Anticoagulation for patients with heparin-induced thrombocytopenia using recombinant hirudin during cardiopulmonary bypass.

Heparin-induced thrombocytopenia (HIT) is a common complication of heparin therapy. There are three types of HIT. In the majority of patients, thrombocytopenia is modest and resolves without sequelae (HIT I). In a smaller number of patients, the thrombocytopenia is severe (HIT II), and in still others, the thrombocytopenia is also associated with thrombosis (HITT). Administration of heparin to this latter group of patients causes platelet aggregation, thromboembolism, and thrombocytopenia. It is advisable that heparin not be administered in any form to patients with documented or suspected HIT II or HITT. This situation, of course, poses a problem for those patients requiring cardiopulmonary bypass (CPB) surgery. In this report, we summarize our experience with Lepirudin (Hoechst, Frankfurt Ammain, Germany), which is a recombinant hirudin (r-hirudin), as an alternative to heparin for systemic anticoagulation, as well as the use of the ecarine clotting time (ECT) for monitoring anticoagulation status during CPB.

Contact activation via ICAM-1 induces changes in airway epithelial permeability in vitro.

The role of ICAM-1 in contact activation of the bronchial epithelial cells is elucidated. Direct contact between epithelial cells and leukocytes is required to change transepithelial electrical resistance (TER) of the epithelium. Migration of human neutrophils across the layers of cultured human airway epithelial cells (Calu-3) or primary cow tracheal epithelial cells was induced by an fMLP gradient. Migrating neutrophils decreased TER and increased permeability to albumin. Monoclonal antibodies to ICAM-1 reduced neutrophil migration, thus reducing the changes in TER and changes in the epithelial permeability to albumin. By confocal microscopy, ERK1/2 was found to be locally activated in the epithelial cells at the sites of migration and cross-linking of ICAM-1. Blockade of ERK1/2 by PD98059 decreased the changes in TER which were induced by ICAM-1 cross-linking. Contact activation of the bronchial epithelial cells, involving ICAM-1 via local activation of ERK1/2, is an important mechanism of alteration of the bronchial epithelial permeability.

The mechanism and spread of pacemaker activity through myenteric interstitial cells of Cajal in human small intestine.

BACKGROUND & AIMS: It has been generally assumed that interstitial cells of Cajal (ICC) in the human gastrointestinal tract have similar functions to those in rodents, but no direct experimental evidence exists to date for this assumption. This is an important question because pathologists have noted decreased numbers of ICC in patients with a variety of motility disorders, and some have speculated that loss of ICC could be responsible for motor dysfunction. Our aims were to determine whether myenteric ICC (ICC-MY) in human jejunum are pacemaker cells and whether these cells actively propagate pacemaker activity. METHODS: The mucosa and submucosa were removed, and strips of longitudinal muscle were peeled away to reveal the ICC-MY network. ICC networks were loaded with the Ca(2+) indicator fluo-4, and pacemaker activity was recorded via high-speed video imaging at 36.5 degrees C +/- 0.5 degrees C. RESULTS: Rhythmic, biphasic Ca(2+) transients (6.03 +/- 0.33 cycles/min) occurred in Kit-positive ICC-MY. These consisted of a rapidly propagating upstroke phase that initiated a sustained plateau phase, which was associated with Ca(2+) spikes in neighboring smooth muscle. Pacemaker activity was dependent on inositol 1,4,5-triphosphate receptor-operated stores and mitochondrial function. The upstroke phase of Ca(2+) transients in ICC-MY appeared to result from Ca(2+) influx through dihydropyridine-resistant Ca(2+) channels, whereas the plateau phase was attributed to Ca(2+) release from inositol 1,4,5-triphosphate receptor-operated Ca(2+) stores. CONCLUSIONS: Each ICC-MY in human jejunum generates spontaneous pacemaker activity that actively propagates through the ICC network. Loss of these cells could severely disrupt the normal function of the human small intestine.

Septal interstitial cells of Cajal conduct pacemaker activity to excite muscle bundles in human jejunum.

BACKGROUND & AIMS: Like the heart, intestinal smooth muscles exhibit electrical rhythmicity, which originates in pacemaker cells surrounding the myenteric plexus, called interstitial cells of Cajal (ICC-MY). In large mammals, ICC also line septa (ICC-SEP) between circular muscle (CM) bundles, suggesting they might be necessary for activating muscle bundles. It is important to determine their functional significance, because a loss of ICC in humans is associated with disordered motility. Our aims were therefore to determine the role of ICC-SEP in activating the thick CM in the human jejunum. METHODS: The mucosa and submucosa were removed and muscle strips were cut and pinned in cross-section so that the ICC-MY and ICC-SEP networks and the CM could be readily visualized. The ICC networks and CM were loaded with the Ca(2+) indicator fluo-4, and pacemaker and muscle activity was recorded at 36.5 +/- 0.5( degrees )C. RESULTS: Ca(2+) imaging revealed that pacemaker activity in human ICC-MY can entrain ICC-SEP to excite CM bundles. Unlike the heart, pacemaker activity in ICC-MY varied in amplitude, propagation distance, and direction, leading to a sporadic activation of ICC-SEP. CONCLUSIONS: ICC-SEP form a crucial conduction pathway for spreading excitation deep into muscle bundles of the human jejunum, necessary for motor patterns underlying mixing. A loss of these cells could severely affect motor activity.

Cardiac output monitoring during off-pump coronary artery bypass grafting.

OBJECTIVE: To evaluate and compare monitors of cardiac output during repositioning and stabilization of the heart for off-pump coronary artery bypass (OPCAB) surgery. DESIGN: Prospective, observational, clinical study. SETTING: University teaching hospital. PARTICIPANTS: Consecutive patients scheduled to undergo elective OPCAB (n = 19). INTERVENTIONS: Monitoring, induction, and anesthesia followed a routine protocol for coronary artery bypass patients. This included the use of transesophageal echocardiography (TEE) and pulmonary artery catheter placement. MEASUREMENTS AND MAIN RESULTS: After positioning and stabilization for OPCAB surgery, the changes in descending aortic flow velocity (VTI) times heart rate (HR) and the mixed venous oxygen saturation (SvO(2)) could be used to predict the changes in thermodilution cardiac output (TDCO) using the following model: deltaTDCO((calc))=-13.15+0.35(deltaVTI*HR)+0.61(deltaSvO(2)) where Delta indicates the percentage change from baseline values. The changes in mean arterial pressure, mean pulmonary artery pressure, and continuous cardiac output did not correlate with the changes in TDCO. CONCLUSION: The use of the VTI*HR, as determined by TEE, in addition to the SvO(2) can strengthen clinical decision making during repositioning and stabilization of the heart during OPCAB. Changes in the VTI*HR and SvO(2) can be used as surrogate markers for changes in CO during OPCAB surgery.