Mayur B. Patel

Clinical and Pathologic Predictors of Survival in Patients With Thymoma

OBJECTIVE To evaluate the Johns Hopkins Hospital experience with 136 thymomas over the past 40 years. This number of patients allowed quantitative estimation of the independent influence of common clinicopathologic risk factors using multivariate analysis. SUMMARY BACKGROUND DATA Thymomas vary widely in terms of recurrence and influence on overall survival. Several series have indicated the importance of initial tumor invasion, as well as the extent of surgical resection, as predictors of recurrence and survival after thymoma resection. However, findings have been equivocal when other predictors of prognosis were examined. METHODS The authors evaluated 136 patients seen at the Johns Hopkins Hospital between 1957 and 1997 with a pathologic diagnosis of thymoma. Demographic information, clinical staging data, surgical and adjuvant treatment details, and patient follow-up data were obtained from the patient record and from detailed patient or family interviews. Microscopic sections of all 136 patients were reviewed by two pathologists blinded to the clinical data. All data were analyzed by multivariate Cox regression analysis, which allowed the quantification of the independent predictive value of 12 putative clinicopathologic prognostic indicators. RESULTS Completeness of follow-up was 99%, 99%, and 98% of eligible patients at 5, 10, and 15 years, respectively. Forty percent of the patients had associated myasthenia gravis and 27% had a secondary primary malignancy. Overall patient survival rates were 71%, 56%, 44%, 38%, and 33% at 5, 10, 15, 20, and 25 years, respectively. Overall, the thymoma-related mortality rate was 14%; the nonthymoma-related mortality rate was 26%. Incomplete resection, preoperative absence of myasthenia gravis, and advanced Lattes/Bernatz pathologic class were found to be independent predictors of poorer overall survival. CONCLUSIONS These findings support a policy of aggressive, complete surgical resection of all thymomas when feasible. Thymoma behaves as a rather indolent tumor, with most deaths from causes unrelated to thymoma or its direct treatment. Clinicians should have an increased awareness of the possibility of second primary malignancies in patients with thymoma.

Making the diagnosis of acute appendicitis: Do more preoperative CT scans mean fewer negative appendectomies? A 10-year study

PURPOSE To determine the frequency of preoperative computed tomography (CT) in the evaluation of patients suspected of having appendicitis at one institution during the past 10 years and to determine whether changes in CT utilization were associated with changes in the negative appendectomy rate. MATERIALS AND METHODS Institutional review board approval was obtained, and a waiver of informed consent was granted for this HIPAA-compliant study. A surgical database search yielded medical record numbers of 925 patients (526 [ 56.9%] men and 399 [43.1%] women; mean age, 38 years (range, 18-95 years]) who underwent urgent appendectomy between January 1998 and September 2007. Patients who were younger than 18 years of age at the time of surgery were excluded. CT, pathology, and surgery reports were reviewed. By using logistic regression, changes in the proportion of patients undergoing CT and in the proportion of patients undergoing each year appendectomy in which the appendix was healthy were evaluated. Subgroup analyses based on patient age (<or= 45 years or > 45 years) and sex also were performed. RESULTS Prior to urgent appendectomy, 18.5% of patients underwent preoperative CT in 1998 compared with 93.2% of patients in 2007. The negative appendectomy rate for women 45 years of age and younger decreased from 42.9% in 1998% to 7.1% in 2007. However, the timing of the decline in negative appendectomy rates for women 45 years and younger could not be proved to be associated with the increase in CT use. There was no significant trend toward a lower negative appendectomy rate for men regardless of age or for women older than 45 years of age with increased use of preoperative CT. The shift from single-detector CT to multidetector CT and the use of decreasing section thickness also correlated with a reduction in false-positive diagnoses. CONCLUSION Rising utilization of preoperative CT and advances in technology coincided with a decrease in the negative appendectomy rate for women 45 years and younger but not in men of any age or women older than 45 years.

Xanthine oxidase contributes to host defense against Burkholderia cepacia in the p47(phox-/-) mouse model of chronic granulomatous disease.

ABSTRACT Chronic granulomatous disease (CGD) is an inherited disorder of the NADPH oxidase in which phagocytes are defective in generating superoxide and downstream microbicidal reactive oxidants, leading to recurrent life-threatening bacterial and fungal infections. Xanthine oxidase (XO) is another enzyme known to produce superoxide in many tissues. Using the p47phox−/− mouse model of CGD, we evaluated the residual antibacterial activity of XO. Clearance of Burkholderia cepacia, a major pathogen in CGD, was reduced in p47phox−/− mice compared to that in wild-type mice and was further inhibited in p47phox−/− mice by pretreatment with the specific XO inhibitor allopurinol. Hepatic B. cepaciaburden was similar in the two genotypes, but allopurinol significantly reduced net hepatic killing and killing efficiency only in p47phox−/− mice. Clearance and killing of intravenous Escherichia coli was intact in p47phox−/− mice and was unaffected by pretreatment with allopurinol. In CGD, XO may contribute to host defense against a subset of reactive oxidant-sensitive pathogens.

Interaction of platelet activating factor, reactive oxygen species generated by xanthine oxidase, and leukocytes in the generation of hepatic injury after shock/resuscitation.

OBJECTIVE To evaluate the putative relation of platelet activating factor (PAF), xanthine oxidase, reactive oxidants, and leukocytes in the pathogenesis of hepatic injury after shock/resuscitation (S/R) in vivo. BACKGROUND Reactive oxygen metabolites generated by xanthine oxidase at reperfusion have been found to trigger postischemic injury in many organs, including the liver. However, the precise linear sequence of the mechanism of consequent hepatic injury after S/R remains to be characterized. METHODS Unheparinized male rats were bled to a mean blood pressure of 45 +/- 3 mmHg. After 2 hours of shock, they were resuscitated by reinfusion of shed blood (anticoagulated with citrate-phosphate-dextrose) and crystalloid and observed for the next 6 or 24 hours. RESULTS S/R caused the oxidation of hepatic glutathione and generated centrolobular leukocyte accumulation at 6 hours, followed by predominantly centrolobular hepatocellular injury at 24 hours. Each of these components was attenuated by PAF inhibition with WEB 2170, xanthine oxidase inhibition with allopurinol, antioxidant treatment with N-acetylcysteine, or severe leukopenia induced by vinblastine. In each case, the degree of leukocyte accumulation at 6 hours correlated with the hepatocellular injury seen at 24 hours. However, xanthine oxidase inhibition with allopurinol failed to attenuate further the small level of residual hepatocellular injury seen in leukopenic rats. CONCLUSION These findings suggest that reactive oxidants generated by xanthine oxidase at reperfusion, stimulated by PAF, mediate hepatocellular injury by triggering leukocyte accumulation, primarily within the centrolobular sinusoids.

Cervical spine collar clearance in the obtunded adult blunt trauma patient: A systematic review and practice management guideline from the Eastern Association for the Surgery of Trauma

BACKGROUND With the use of the framework advocated by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group, our aims were to perform a systematic review and to develop evidence-based recommendations that may be used to answer the following PICO [Population, Intervention, Comparator, Outcomes] question: In the obtunded adult blunt trauma patient, should cervical collar removal be performed after a negative high-quality cervical spine (C-spine) computed tomography (CT) result alone or after a negative high-quality C-spine CT result combined with adjunct imaging, to reduce peri-clearance events, such as new neurologic change, unstable C-spine injury, stable C-spine injury, need for post-clearance imaging, false-negative CT imaging result on re-review, pressure ulcers, and time to cervical collar clearance? METHODS Our protocol was registered with the PROSPERO international prospective register of systematic reviews on August 23, 2013 (Registration Number: CRD42013005461). Eligibility criteria consisted of adult blunt trauma patients 16 years or older, who underwent C-spine CT with axial thickness of less than 3 mm and who were obtunded using any definition. Quantitative synthesis via meta-analysis was not possible because of pre-post, partial-cohort, quasi-experimental study design limitations and the consequential incomplete diagnostic accuracy data. RESULTS Of five articles with a total follow-up of 1,017 included subjects, none reported new neurologic changes (paraplegia or quadriplegia) after cervical collar removal. There is a worst-case 9% (161 of 1,718 subjects in 11 studies) cumulative literature incidence of stable injuries and a 91% negative predictive value of no injury, after coupling a negative high-quality C-spine CT result with 1.5-T magnetic resonance imaging, upright x-rays, flexion-extension CT, and/or clinical follow-up. Similarly, there is a best-case 0% (0 of 1,718 subjects in 11 studies) cumulative literature incidence of unstable injuries after negative initial imaging result with a high-quality C-spine CT. CONCLUSION In obtunded adult blunt trauma patients, we conditionally recommend cervical collar removal after a negative high-quality C-spine CT scan result alone. LEVEL OF EVIDENCE Systematic review, level III.

Pathophysiology of acute brain dysfunction: what's the cause of all this confusion?

Purpose of reviewTo survey the recent medical literature examining the pathophysiology of acute brain dysfunction (delirium and coma) in the ICU. Recent findingsClinical risk factors for brain dysfunction in the ICU continue to be elucidated and prediction models developed. Multiple studies have identified sedatives, especially benzodiazepines, as modifiable risk factors for delirium. Imaging studies examining global brain disorders have demonstrated white matter lesions and brain atrophy to be associated with delirium. Endothelial dysfunction, increased blood–brain barrier permeability, and reduced blood flow have also been implicated in cerebral perfusion abnormalities associated with brain dysfunction. The response of the brain to inflammation, including activation of microglia and neuronal apoptosis, leads to synaptic and neurochemical disturbances. Decreased availability of acetylcholine during critical illness leads to decreased counter-regulatory activity in response to inflammatory disease states, likely causing additional injury and further neurotransmitter imbalances. Dopamine, norepinephrine, and serotonin excess and their respective amino acid precursors have also been associated with brain dysfunction. SummaryThe multifactorial pathophysiology of acute brain dysfunction remains incompletely understood. Multiple clinical risk factors have been identified and numerous pathophysiologic pathways have been hypothesized. Future research is required to investigate the roles of these pathways on differing clinical presentations, potential therapeutic options, and patient outcomes.

Intraoperative use of low-dose recombinant activated factor VII during thoracic aortic operations.

BACKGROUND Numerous studies have supported the effectiveness of recombinant activated factor VII (rFVIIa) for the control of bleeding after cardiac procedures; however safety concerns persist. Here we report the novel use of intraoperative low-dose rFVIIa in thoracic aortic operations, a strategy intended to improve safety by minimizing rFVIIa exposure. METHODS Between July 2005 and December 2010, 425 consecutive patients at a single referral center underwent thoracic aortic operations with cardiopulmonary bypass (CPB); 77 of these patients received intraoperative low-dose rFVIIa (≤60 μg/kg) for severe coagulopathy after CPB. Propensity matching produced a cohort of 88 patients (44 received intraoperative low-dose rFVIIa and 44 controls) for comparison. RESULTS Matched patients receiving intraoperative low-dose rFVIIa got an initial median dose of 32 μg/kg (interquartile range [IQR], 16-43 μg/kg) rFVIIa given 51 minutes (42-67 minutes) after separation from CPB. Patients receiving intraoperative low-dose rFVIIa demonstrated improved postoperative coagulation measurements (partial thromboplastin time 28.6 versus 31.5 seconds; p=0.05; international normalized ratio, 0.8 versus 1.2; p<0.0001) and received 50% fewer postoperative blood product transfusions (2.5 versus 5.0 units; p=0.05) compared with control patients. No patient receiving intraoperative low-dose rFVIIa required postoperative rFVIIa administration or reexploration for bleeding. Rates of stroke, thromboembolism, myocardial infarction, and other adverse events were equivalent between groups. CONCLUSIONS Intraoperative low-dose rFVIIa led to improved postoperative hemostasis with no apparent increase in adverse events. Intraoperative rFVIIa administration in appropriately selected patients may correct coagulopathy early in the course of refractory blood loss and lead to improved safety through the use of smaller rFVIIa doses. Appropriately powered randomized studies are necessary to confirm the safety and efficacy of this approach.

Decreasing adrenergic or sympathetic hyperactivity after severe traumatic brain injury using propranolol and clonidine (DASH After TBI Study): study protocol for a randomized controlled trial

BackgroundSevere TBI, defined as a Glasgow Coma Scale ≤ 8, increases intracranial pressure and activates the sympathetic nervous system. Sympathetic hyperactivity after TBI manifests as catecholamine excess, hypertension, abnormal heart rate variability, and agitation, and is associated with poor neuropsychological outcome. Propranolol and clonidine are centrally acting drugs that may decrease sympathetic outflow, brain edema, and agitation. However, there is no prospective randomized evidence available demonstrating the feasibility, outcome benefits, and safety for adrenergic blockade after TBI.Methods/DesignThe DASH after TBI study is an actively accruing, single-center, randomized, double-blinded, placebo-controlled, two-arm trial, where one group receives centrally acting sympatholytic drugs, propranolol (1 mg intravenously every 6 h for 7 days) and clonidine (0.1 mg per tube every 12 h for 7 days), and the other group, double placebo, within 48 h of severe TBI. The study uses a weighted adaptive minimization randomization with categories of age and Marshall head CT classification. Feasibility will be assessed by ability to provide a neuroradiology read for randomization, by treatment contamination, and by treatment compliance. The primary endpoint is reduction in plasma norepinephrine level as measured on day 8. Secondary endpoints include comprehensive plasma and urine catecholamine levels, heart rate variability, arrhythmia occurrence, infections, agitation measures using the Richmond Agitation-Sedation Scale and Agitated Behavior scale, medication use (anti-hypertensive, sedative, analgesic, and antipsychotic), coma-free days, ventilator-free days, length of stay, and mortality. Neuropsychological outcomes will be measured at hospital discharge and at 3 and 12 months. The domains tested will include global executive function, memory, processing speed, visual-spatial, and behavior. Other assessments include the Extended Glasgow Outcome Scale and Quality of Life after Brain Injury scale. Safety parameters evaluated will include cardiac complications.DiscussionThe DASH After TBI Study is the first randomized, double-blinded, placebo-controlled trial powered to determine feasibility and investigate safety and outcomes associated with adrenergic blockade in patients with severe TBI. If the study results in positive trends, this could provide pilot evidence for a larger multicenter randomized clinical trial. If there is no effect of therapy, this trial would still provide a robust prospective description of sympathetic hyperactivity after TBI.Trial registrationClinicalTrials.gov NCT01322048

Operative fixation of rib fractures after blunt trauma: A practice management guideline from the Eastern Association for the Surgery of Trauma

BACKGROUND Rib fractures are identified in 10% of all injury victims and are associated with significant morbidity (33%) and mortality (12%). Significant progress has been made in the management of rib fractures over the past few decades, including operative reduction and internal fixation (rib ORIF); however, the subset of patients that would benefit most from this procedure remains ill-defined. The aim of this project was to develop evidence-based recommendations. METHODS Population, intervention, comparison, and outcome (PICO) questions were formulated for patients with and without flail chest. Outcomes of interest included mortality, duration of mechanical ventilation (DMV), hospital and intensive care unit (ICU) length of stay (LOS), incidence of pneumonia, need for tracheostomy, and pain control. A systematic review and meta-analysis of currently available evidence was performed per the Grading of Recommendations Assessment, Development, and Evaluation methodology. RESULTS Twenty-two studies were identified and analyzed. These included 986 patients with flail chest, of whom 334 underwent rib ORIF. Rib ORIF afforded lower mortality; shorter DMV, hospital LOS, and ICU LOS; and lower incidence of pneumonia and need for tracheostomy. The data quality was deemed very low, with only three prospective randomized trials available. Analyses for pain in patients with flail chest and all outcomes in patients with nonflail chest were not feasible due to inadequate data. CONCLUSION In adult patients with flail chest, we conditionally recommend rib ORIF to decrease mortality; shorten DMV, hospital LOS, and ICU LOS; and decrease incidence of pneumonia and need for tracheostomy. We cannot offer a recommendation for pain control, or any of the outcomes in patients with nonflail chest with currently available data. LEVEL OF EVIDENCE Systematic review/meta-analysis, level III.

A Brief Report: The Use of High-frequency Oscillatory Ventilation for Severe Pulmonary Contusion

BACKGROUND Severe pulmonary contusions are a common cause of acute respiratory distress syndrome (ARDS) and are associated with significant morbidity. High frequency oscillatory ventilation (HFOV) is a ventilatory mode that employs a lung protective strategy consistent with the ARDSNet low tidal volume ventilation strategy and may result in reduced morbidity. The objective of this report is to examine the impact of HFOV on blunt trauma patients with severe pulmonary contusions who failed or were at a high risk of failing conventional mechanical ventilation. METHODS We undertook a retrospective chart review of all patients at our institution who received HFOV for severe pulmonary contusions. Patients were placed on HFOV when their mean airway pressure (mP(aw)) surpassed 30 cm H2O and their FIO2 was greater than 0.6. Baseline demographic data including injury severity score (ISS), length of time requiring HFOV, total ventilator days, and inhospital mortality were collected. Serial determinations of oxygenation index (OI) and the PaO2/FIO2 ratio (P/F) were made up to 72 hours after initiation of HFOV. A linear mixed model was used to analyze the slope (beta) of the regression line of P/F versus time and that of OI versus time. RESULTS Seventeen patients were identified who underwent HFOV for ARDS due primarily to pulmonary contusions. Mean ISS was 36.6, mean APACHE II score was 21.7, and the mean time before initiation of HFOV was 2.0 days. P/F increased significantly after HFOV was initiated (beta = 12.1; 95% confidence interval 7.9 to 16.4, p < 0.001). OI significantly decreased after HFOV implementation (beta = -1.8; 95% confidence interval -2.3 to -1.3, p < 0.001). Mortality rate was 17.6%. CONCLUSIONS The early use of HFOV appears to be safe and efficacious in blunt trauma patients sustaining pulmonary contusions, and results in a rapid improvement in OI and the P/F ratio.