Protocol adherence for continuously titrated interventions in randomized trials: an overview of the current methodology and case study.

BACKGROUND: The standard definition for protocol adherence is the proportion of all scheduled doses that are delivered. In clinical research, this definition has several limitations when evaluating protocol adherence in trials that study interventions requiring continuous titration. DISCUSSION: Building upon a specific case study, we analyzed a recent trial of a continuously titrated intervention to assess the impact of different definitions of protocol deviations on the interpretation of protocol adherence. The OVATION pilot trial was an open-label randomized controlled trial of higher (75-80 mmHg) versus lower (60-65 mmHg) mean arterial pressure (MAP) targets for vasopressor therapy in shock. In this trial, potential protocol deviations were defined as MAP values outside the targeted range for >4 consecutive hours during vasopressor therapy without synchronous and consistent adjustments of vasopressor doses. An adjudication committee reviewed each potential deviation to determine if it was clinically-justified or not. There are four reasons for this contextual measurement and reporting of protocol adherence. First, between-arm separation is a robust measure of adherence to complex protocols. Second, adherence assessed by protocol deviations varies in function of the definition of deviations and the frequency of measurements. Third, distinguishing clinically-justified vs. not clinically-justified protocol deviations acknowledges clinically sensible bedside decision-making and offers a clear terminology before the trial begins. Finally, multiple metrics exist to report protocol deviations, which provides different information but complementary information on protocol adherence. CONCLUSIONS: In trials of interventions requiring continuous titration, metrics used for defining protocol deviations have a considerable impact on the interpretation of protocol adherence. Definitions for protocol deviations should be prespecified and correlated with between-arm separation, if it can be measured.

Esophagectomy in esophageal perforations: an analysis.

This study aimed to study the factors that are associated with urgent esophagectomy for the treatment of esophageal perforations and the impact of this therapy. A retrospective review of all esophageal perforations treated at a tertiary care hospital from January 1984 to January 2012 was performed. Compiling demographics, cause and site of perforations, time to presentation, comorbidities, radiological tests, the length of perforation, the hemodynamic status of the patient, type of treatment required, and outcomes were performed. Univariate, multivariate, and Cox regression analyses were conducted. Of 127 cases of esophageal perforation, it was spontaneous in 44 (35%), iatrogenic in 53 (44%), foreign body ingestion in 22 (17%), and traumatic perforation in 7 (6%) cases. Overall, 85 of the 127 (67%) patients were managed operatively, 35 (27.6%) patients were treated conservatively, and 7 (6.3%) patients were treated by endoscopic stent placement. Of the 85 patients who were managed operatively, 21 (16.5%) required esophagectomies, 13 (15.3%) had esophagectomy with immediate reconstruction, 5 (5.9%) patients had esophagectomy followed by delayed reconstruction, and 3 (3.5%) patients failed primary repair and required an esophagectomy as a secondary definitive procedure. Multivariate analysis revealed that esophagectomy in esophageal perforations was associated with the presence of benign or malignant esophageal stricture (P = 0.001) and a perforation >5 cm (P = 0.001). Mortality was mainly associated with the presence of a benign or malignant esophageal stricture (P = 0.04). The presence of pre-existing benign or malignant stricture or large perforation (>5 cm) is associated with the need for an urgent esophagectomy with or without immediate reconstruction. Performing esophagectomy was not found to be a significant prognosticator for mortality.

Adjuvant sunitinib following chemoradiotherapy and surgery for locally advanced esophageal cancer: a phase II trial.

The prognosis for locally advanced esophageal cancer is poor despite the use of trimodality therapy. In this phase II study, we report the feasibility, tolerability and efficacy of adjuvant sunitinib. Included were patients with stage IIa, IIB or III cancer of the thoracic esophagus or gastroesophageal junction. Neoadjuvant therapy involved Irinotecan (65 mg/m2 ) + Cisplatin (30 mg/m2 ) on weeks 1 and 2, 4 and 5, 7 and 8 with concurrent radiation (50Gy/25 fractions) on weeks 4-8. Sunitinib was commenced 4-13 weeks after surgery and continued for one year. Sixty-one patients were included in the final analysis, 36 patients commenced adjuvant sunitinib. Fourteen patients discontinued sunitinib due to disease recurrence (39%) within the 12-month period, 12 (33%) discontinued due to toxicity, and 3 (8%) requested cessation of therapy. In the overall population, median survival was 26 months with a 2 and 3-year survival rate of 52% and 35%, respectively. The median survival for the 36 patients treated with sunitinib was 35 months and 2-year survival probability of 68%. In a historical control, a prior phase II study with the same trimodality therapy (n = 43), median survival was 36 months, with a 2-year survival of 67%. Initiation of adjuvant sunitinib is feasible, but poorly tolerated, with no signal of additional benefit over trimodality therapy for locally advanced esophageal cancer.

Toll-like receptors: exploring their potential connection with post-operative infectious complications and cancer recurrence.

Cancer is the leading cause of death in North America. Despite modern advances in cancer therapy, many patients will ultimately develop cancer metastasis resulting in mortality. Surgery to resect early stage solid malignancies remains the cornerstone of cancer treatment. However, surgery places patients at risk of developing post-operative infectious complications that are linked to earlier cancer metastatic recurrence and cancer mortality. Toll-like receptors (TLRs) are evolutionarily-conserved sentinel receptors of the innate immune system that are activated by microbial products present during infection, leading to activation of innate immunity. Numerous types of solid cancer cells also express TLRs, with their activation augmenting their ability to metastasize. Similarly, healthy host-tissue TLRs activated during infection induce a prometastatic environment in the host. Cancer cells additionally secrete TLR activating ligands that activate both cancer TLRs and host TLRs to promote metastasis. Consequently, TLRs are an attractive therapeutic candidate to target infection-induced cancer metastasis and progression.

Polymorphonuclear neutrophil (PMN) recruitment in a 2-front murine injury model: triage of PMNs to competing stimuli of recruitment.

BACKGROUND: Intensive care unit patients as a group have the highest rate of nosocomial infections, such as pneumonia, urinary tract infections, and wound infections. The triage of polymorphonuclear neutrophils (PMNs) during an acute inflammatory response was investigated to determine if the severity of injury or infection contributes to PMN delivery. METHODS: A murine cecal ligation and puncture-induced peritonitis model with polyvinyl sponge discs were used to collect the PMNs in the abdomen (primary site) and in the subcutaneous tissue of the dorsum (remote site). Eighty CD1 male mice--20 in each of 4 groups--were assigned to the following: cecal ligation and puncture (CLP), sham laparotomy with cecal manipulation (CM), polyvinyl sponge placement in the abdomen and back only (SP), and sponge placement in the back alone (CON [control]). After 24 hours, the sponges were harvested, and the PMNs were collected and counted on a hemocytometer. RESULTS: These data, reported as mean PMN cells x 10(5) +/- SEM, demonstrated that back sponges contained significantly fewer PMNs in the CLP group (3.29 +/- 1.1) than in the CM group (7.77 +/- 1.61, P = .04), the SP group (8.69 +/- 1.67, P = .01), and the CON group (11.04 +/- 1.91, P < .001). CONCLUSIONS: These results demonstrate that PMN delivery to sites of secondary injury are inversely correlated to the severity of the primary injury or peritonitis.

Reduction in neutrophil cell surface expression of tumor necrosis factor receptors but not Fas after transmigration: implications for the regulation of neutrophil apoptosis.

OBJECTIVES: To test the hypothesis that loss of polymorphonuclear neutrophil tumor necrosis factor alpha (TNF-alpha) receptors during transmigration renders the exudate neutrophil refractory to TNF-alpha-mediated stimulation of apoptosis; and to investigate the surface expression of Fas on both circulating and exudate neutrophils. DESIGN: A prospective cohort study. SETTING: Surgical laboratory of a tertiary care hospital. PARTICIPANTS: Twenty-one healthy human volunteers. INTERVENTIONS: All subjects had circulating neutrophils and exudate neutrophils collected by venipuncture and skin window methods, respectively. MAIN OUTCOME MEASURES: Circulating and exudate neutrophils were incubated in culture medium (1.0x10(6) neutrophils per milliliter) alone or with TNF-alpha (100 ng/mL). Apoptosis was evaluated by flow cytometry (annexin V-fluorescein isothiocyanate and propidium iodide). Tumor necrosis factor alpha-phycoerythrin and anti-human Fas-fluorescein isothiocyanate were used to evaluate neutrophil TNF-alpha receptors and surface expression of Fas. RESULTS: Exudate neutrophils had a significant delay in apoptosis rates when compared with circulating neutrophils. The percentage of neutrophils expressing TNF-alpha receptors was significantly diminished after exudation (80%+/-15% vs 33%+/-9%; P<.001), as was the median channel number of TNF-alpha phycoerythrin fluorescence (8.1+/-1.6 vs 5.2+/-0.5; P=.001). However, the expression of Fas was unchanged after transmigration (percentage positive for Fas: 98.7%+/-0.7% vs 92.8%+/-3.4%, P=.89; Fas antibody-fluorescein isothiocyanate median channel fluorescence: 12.2+/-1.1 vs 13.1+/-1.2; P=.80). Exposure of exudate neutrophils to TNF-alpha failed to increase their rate of apoptosis. CONCLUSIONS: Exudate polymorphonuclear neutrophils are confirmed to have delayed apoptosis. Loss of TNF-alpha receptors during transmigration is necessary for neutrophil survival in the extravascular inflammatory milieu.

Decreased systemic polymorphonuclear neutrophil (PMN) rolling without increased PMN adhesion in peritonitis at remote sites.

BACKGROUND: Previous in vitro studies have demonstrated that the host response to intra-abdominal infection produces increased generalized polymorphonuclear neutrophil (PMN) adherence to vascular endothelial cells (ECs), which may lead to subsequent endothelial damage, leaky capillaries, and organ dysfunction. There are scant data to demonstrate this enhanced systemic PMN adherence in vivo or the influence of PMN rolling on PMN endothelial adherence. HYPOTHESIS: Systemic PMN adherence in the animal with sepsis is increased. DESIGN: In vivo murine model of a 2-front infection using intravital microscopy of the cremasteric muscle to quantify PMN-EC adherence in a septic response. SETTING: Basic science laboratory and animal surgical facility. PATIENTS OR OTHER PARTICIPANTS: One hundred CD1 male mice. INTERVENTIONS: Animals underwent cecal ligation and puncture peritonitis, cremasteric muscle Escherichia coli infection, both infections, or neither (controls). Eighteen hours later, the mice underwent exteriorization of the cremasteric muscle under an intravital microscope for measurement of PMN-EC interactions. Blood was then drawn for calculation of circulating PMN counts. MAIN OUTCOME MEASURES: Adherence of PMNs, PMN rolling flux, PMN rolling velocity, and circulating PMN counts. RESULTS: Circulatory mechanics did not differ between the groups. Unlike static in vitro systems, we could not detect an increase in PMN adherence after peritonitis with this dynamic in vivo model. A local (cremasteric) infection was associated with marked PMN adherence. Peritonitis was associated with reduced PMN adherence at a local infection site as well as reduced rolling adhesion and PMN rolling velocity. CONCLUSIONS: The data suggest that intra-abdominal infection does not increase remote PMN adherence, and may actually result in reduction of systemic adherence via modulation of PMN rolling.

Do surgical residents rated as better teachers perform better on in-training examinations?

BACKGROUND: There have been no attempts to objectively compare resident teaching ability with resident knowledge level. METHODS: Resident teaching ability, as rated by medical students and junior surgical residents, was compared with resident knowledge level, estimated by in-training examination results, for 18 PGY5 and PGY4 surgical residents at McGill University (September 1996 to July 1997). RESULTS: There was a trend to suggest that greater teaching ability is associated with higher in-training examination scores; this did not achieve statistical significance. PGY4 residents were rated as better teachers than PGY5 residents. Resident self-evaluation revealed a high degree of interest in teaching; inadequate time was the principal deterrent to resident teaching; enjoyment and learning during teaching were found to be the most common incentives. CONCLUSIONS: Our results suggest an association between resident level of knowledge and teaching ability. The principal deterrent to teaching--inadequate time--must be addressed to effectively assist surgical resident teaching.

Hemorrhagic shock resuscitation with a low molecular weight starch reduces neutrophil-endothelial interactions and vessel leakage in vivo.

BACKGROUND: The polymorphonuclear neutrophil (PMN) has been implicated in the pathogenesis of endothelial cell (EC) damage and organ injury following hemorrhagic shock. Pentastarch (PTS), a low substituted medium molecular weight (MW) colloid, improves hemodynamics in hypovolemic shock and cardiac surgery. No data exist comparing the immunomodulation of PTS and Ringer's lactate (RL) on the activation of PMN in hemorrhagic shock in vivo. METHODS: Using an in vivo murine hemorrhagic shock model (blood withdrawal to maintain 50 mmHg x 45 min), circulating PMN were observed every 15 minutes using intravital microscopy on cremaster muscle. EC-PMN interactions (videorecorded and subsequently analyzed blindly), vessel leakage (live epifluorescence after injection of 50 mg/kg fluorescent albumin) and PMN expression of L-selectin (immunofluorescent monoclonal antibodies and flow cytometry) were evaluated in three resuscitation groups: PTS (7.14 mL/kg 10% pentastarch/0.9% NaCl + shed blood, n = 13), RL (RL [2 x shed blood volume] + shed blood, n = 13) and SHAM (0 hemorrhage, 0 resuscitation, n = 9). Significance was evaluated by ANOVA with Bonferroni correction. RESULTS: PMN rolling was significantly diminished in PTS and SHAM as compared to RL animals at all time points. Similar differences were found in PMN adherence to EC at most time points onwards from 15 minutes following resuscitation. In vivo vessel permeability was lowest in SHAM and PTS animals (mean 0.274 +/- 0.07 and 0.356 +/- 0.15, respectively, p > 0.05) and highest in RL animals (0.667 +/- 0.09, p < 0.001 vs PTS or SHAM). PMN L-selectin expression tended to be higher in the RL group than either SHAM and PTS groups. There were no flow-mechanics differences between groups (vessel diameter, mean red cell velocity, shear stress, shear rate). CONCLUSIONS: 10% pentastarch reduces RL-associated EC-PMN interactions and vessel leakage following hemorrhagic shock. These results support the use of low MW starches to resuscitate hemorrhagic shock, potentially reducing PMN-mediated tissue injury.

Segmentation and classification of capnograms: application in respiratory variability analysis.

Variability analysis of respiratory waveforms has been shown to provide key insights into respiratory physiology and has been used successfully to predict clinical outcomes. The current standard for quality assessment of the capnogram signal relies on a visual analysis performed by an expert in order to identify waveform artifacts. Automated processing of capnograms is desirable in order to extract clinically useful features over extended periods of time in a patient monitoring environment. However, the proper interpretation of capnogram derived features depends upon the quality of the underlying waveform. In addition, the comparison of capnogram datasets across studies requires a more practical approach than a visual analysis and selection of high-quality breath data. This paper describes a system that automatically extracts breath-by-breath features from capnograms and estimates the quality of individual breaths derived from them. Segmented capnogram breaths were presented to expert annotators, who labeled the individual physiological breaths into normal and multiple abnormal breath types. All abnormal breath types were aggregated into the abnormal class for the purpose of this manuscript, with respiratory variability analysis as the end-application. A database of 11,526 breaths from over 300 patients was created, comprising around 35% abnormal breaths. Several simple classifiers were trained through a stratified repeated ten-fold cross-validation and tested on an unseen portion of the labeled breath database, using a subset of 15 features derived from each breath curve. Decision Tree, K-Nearest Neighbors (KNN) and Naive Bayes classifiers were close in terms of performance (AUC of 90%, 89% and 88% respectively), while using 7, 4 and 5 breath features, respectively. When compared to airflow derived timings, the 95% confidence interval on the mean difference in interbreath intervals was ± 0.18 s. This breath classification system provides a fast and robust pre-processing of continuous respiratory waveforms, thereby ensuring reliable variability analysis of breath-by-breath parameter time series.

Multiple organ dysfunction syndrome: exploring the paradigm of complex nonlinear systems.

OBJECTIVES: The objectives of this article are to introduce and explore a novel paradigm based on complex nonlinear systems, and to evaluate its application to critical care research regarding the systemic host response and multiple organ dysfunction syndrome (MODS). DATA SOURCES: Published original work, review articles, scientific abstracts and books, as well as our personal files. STUDY SELECTION: Studies were selected for their relevance to the applications of nonlinear complex systems, to critical care medicine, and to the concepts presented. DATA EXTRACTION: We extracted all applicable data. DATA SYNTHESIS: Following a brief review of MODS, an introduction to complex nonlinear systems is presented, including clear concepts, definitions, and properties. By examining the multiple, nonlinear, interrelated, and variable interactions between the metabolic, neural, endocrine, immune, and inflammatory systems; data regarding interconnected antibody networks; and the redundant, nonlinear, interdependent nature of the inflammatory response, we present the hypothesis that the systemic host response to trauma, shock, or sepsis must be evaluated as a complex nonlinear system. This model provides a new explanation for the failure of trials using various antimediator therapies in the treatment of patients with sepsis and MODS. Understanding the host response as a complex nonlinear system offers innovative means of studying critical care patients, specifically by suggesting a greater focus on systemic properties. We hypothesize that analysis of variability and connectivity of individual variables offer a novel means of evaluating and differentiating the systemic properties of a complex nonlinear system. Current applications of evaluating variability and connectivity are discussed, and insights regarding future research are offered. CONCLUSION: The paradigm offered by the study of complex nonlinear systems suggests new insights to pursue research to evaluate, monitor, and treat patients with MODS.