Patrick K. Kim

Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

IntroductionAcute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI.MethodsWe performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection.ResultsModerate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.ConclusionsTwo novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI.Trial registrationClinicalTrials.gov number NCT01209169.

An Acute Care Surgery Model Improves Outcomes in Patients With Appendicitis

Objective:To compare outcomes of appendectomy in an Acute Care Surgery (ACS) model to that of a traditional home-call attending surgeon model. Summary Background Data:Acute care surgery (ACS, a combination of trauma surgery, emergency surgery, and surgical critical care) has been proposed as a practice model for the future of general surgery. To date, there are few data regarding outcomes of surgical emergencies in the ACS model. Methods:Between September 1999 and August 2002, surgical emergencies were staffed at the faculty level by either an in-house trauma/emergency surgeon (ACS model) or a non-trauma general surgeon taking home call (traditional [TRAD] model). Coverage alternated monthly. Other aspects of hospital care, including resident complement, remained unchanged. We retrospectively reviewed key time intervals (emergency department [ED] presentation to surgical consultation; surgical consultation to operation [OR]; and ED presentation to OR) and outcomes (rupture rate, negative appendectomy rate, complication rate, and hospital length of stay [LOS]) for patients treated in the ACS and TRAD models. Questions of interest were examined using χ2 tests for discrete variables and independent sample t test for comparison of means. Results:During the study period, 294 appendectomies were performed. In-house ACS surgeons performed 167 procedures, and the home-call TRAD surgeons performed 127 procedures. No difference was found in the time from ED presentation to surgical consultation; however, the time interval from consultation to OR was significantly decreased in the ACS model (TRAD 7.6 hours vs. ACS 3.5 hours, P < 0.05). As a result, the total time from ED presentation to OR was significantly shorter in the ACS model (TRAD 14.0 hours vs. ACS 10.1 hour, P < 0.05). Rupture rates were decreased in the ACS model (TRAD 23.3% vs. ACS 12.3%, P < 0.05); negative appendectomy rates were similar. The complication rate in the ACS model was decreased (TRAD 17.4% vs. ACS 7.7%, P < 0.05), as was the hospital LOS (TRAD 3.5 days vs. ACS 2.3 days, P < 0.001). Conclusions:In patients with acute appendicitis, the presence of an in-house acute care surgeon significantly decreased the time to operation, rupture rate, complication rate, and hospital length of stay. The ACS model appears to improve outcomes of acute appendicitis compared with a TRAD home-call model. This study supports the efficacy and efficiency of the ACS model in the management of surgical emergencies.

INFLAMMATORY RESPONSES AND MEDIATORS

The host response to injury is usually appropriate in degree and is self-limited. In more severe injury, the host response may persist inappropriately, leading to SIRS and MODS and possibly multiple organ failure. The initial response to injury is mediated primarily by norepinephrine, and is directed toward preservation of circulation to the heart and brain at the expense of other vascular beds. If fluid resuscitation is adequate and necrotic tissue is débrided, a hypermetabolic state ensues, mediated by epinephrine and directed toward supporting repair of injured tissue by leukocytes. Inflammatory cells are recruited to the site of injury and elaborate cytokines, which promote repair locally, but in severe injury may be systemically released and trigger remote inflammation. Cytokine biology presently is poorly understood, and simple anticytokine strategies have failed to improve survival of critically ill patients. Current therapy of SIRS and MODS is directed toward symptoms. Presently, it is unclear how an abnormal stress response arises. Cytokine spillover into the systemic circulation may occur. Selective transcriptional failure may be the cellular basis of organ dysfunction. Inappropriate production of peroxynitrite or its precursor, NO, is implicated in mediating cellular injury in SIRS and MODS.

Intraabdominal sepsis down-regulates transcription of sodium taurocholate cotransporter and multidrug resistance-associated protein in rats.

Hepatic dysfunction in sepsis is characterized by hyperbilirubinemia and intrahepatic cholestasis. We hypothesize that sepsis causes decreased hepatic transcription of the bile acid transporter sodium taurocholate cotransporter (Ntcp) and the organic anion transporter multidrug resistance-associated protein (Mrp2) and that interleukin (IL)-6 is important in the down-regulation of Ntcp and Mrp2 expression. Male Sprague-Dawley rats underwent induction of mild, nonlethal sepsis by cecal ligation and single puncture (CLP) or fulminant sepsis by cecal ligation and double puncture (2CLP). Hepatic transcription of Ntcp and Mrp2 rapidly decreased after CLP or 2CLP. Seventy-two hours later, transcription was 60% of baseline in CLP and 14% of baseline in 2CLP. Serum bilirubin was elevated from 24 h onward and cholestasis was observed on fixed liver specimens at 24, 48, and 72 h after 2CLP but not after CLP. Steady-state Ntcp and Mrp2 mRNA was decreased in IL-6-treated cultured hepatocytes and in normal rats given 1 mg/kg intravenous IL-6. We conclude that 1) Ntcp and Mrp2 transcription is down-regulated transiently after CLP and persistently after 2CLP; 2) 2CLP results in hyperbilirubinemia and cholestasis, in part due to persistently decreased transcription of Ntcp and Mrp2; and 3) altered Ntcp and Mrp2 transcription is mediated in part by IL-6.

Effective Radiation Dose from Radiologic Studies in Pediatric Trauma Patients

Evaluation of the pediatric trauma patient frequently requires radiologic studies. Although low-dose radiation from diagnostic radiology is considered safe, lifetime risks per unit dose of radiation are increased in children compared to adults. The total effective dose of radiation to a typical pediatric trauma patient is unknown. We sought to estimate the total effective dose of radiation related to the radiologic assessment of injured children admitted to a pediatric Level I trauma center. We reviewed the radiology records of all children admitted directly to a trauma center in 2002 and tabulated all plain films, computed tomograms, angiographic/fluoroscopic studies, and nuclear medicine studies. Using age-adjusted effective doses (which incorporate biologic effects of radiation), we computed each patient’s total effective dose of radiation. Of 506 admitted patients, 394 (78%) underwent at least one radiologic study. The mean total effective dose per patient was 14.9 mSv (median: 7.2 mSv; interquartile range: 2.2–27.4 mSv). On average, computed tomography accounted for 97.5% of total effective dose. Age and injury severity score did not predict total effective dose. We conclude that in pediatric trauma patients, the estimated total effective dose of radiation varied widely. Computed tomography contributed virtually the entire total effective dose. Regarding radiographic evaluation of pediatric trauma patients, the risks and benefits of current practices should continue to be evaluated critically, because lifetime risks associated with radiation exposure are inversely proportional to age at exposure.

Complications following thoracic trauma managed with tube thoracostomy

INTRODUCTION Tube thoracostomy is a common procedure used to treat traumatic chest injuries. Although the mechanism of injury traditionally does not alter chest tube management, complication rates may vary depending on the severity of injury. The purpose of this study was to investigate the incidence of and risk factors associated with chest tube complications (CTCs) following thoracic trauma. METHODS A retrospective chart review of all trauma patients (≥16 years old) admitted to an urban level 1 trauma centre (1/2007-12/2007) was conducted. Patients who required chest tube (CT) therapy for thoracic injuries within 24 h of admission and survived until CT removal were included. CTCs were defined as a recurrent pneumothorax or residual haemothorax requiring CT reinsertion within 24 h after initial tube removal or addition of new CT >24 h after initial placement. Variables including demographic data, mechanism, associated injuries, initial vital signs, chest abbreviated injury score (AIS), injury severity score (ISS), Glasgow coma score (GCS) and length of stay (LOS) and CT-specific variables (e.g. indication, timing of insertion, and duration of therapy) were compared using the chi square test, Mann-Whitney test, and multivariate analysis. RESULTS 154 patients were included with 22.1% (n=34) developing a CTC. On univariate analysis, CTCs were associated with longer ICU and hospital LOS (p=0.02 and p<0.001), increased chest AIS (p=0.01), and the presence of an extrathoracic injury (p=0.047). Results of the multivariate analysis indicated that only increased chest AIS (OR 2.49; p=0.03) was a significantly independent predictor of CTCs. CONCLUSIONS CTCs following chest trauma are common and are associated with increased morbidity. The severity of the thoracic injury, as measured by chest AIS, should be incorporated into the development of CT management guidelines in order to decrease the incidence of CTCs.

Classifying errors in preventable and potentially preventable trauma deaths: a 9-year review using the Joint Commission's standardized methodology

BACKGROUND Benchmarking and classification of avoidable errors in trauma care are difficult as most reports classify errors using variable locally derived schemes. We sought to classify errors in a large trauma population using standardized Joint Commission taxonomy. METHODS All preventable/potentially preventable deaths identified at an urban, level-1 trauma center (January 2002 to December 2010) were abstracted from the trauma registry. Errors deemed avoidable were classified within the 5-node (impact, type, domain, cause, and prevention) Joint Commission taxonomy. RESULTS Of the 377 deaths in 11,100 trauma contacts, 106 (7.7%) were preventable/potentially preventable deaths related to 142 avoidable errors. Most common error types were in clinical performance (inaccurate diagnosis). Error domain involved primarily the emergency department (therapeutic interventions), caused mostly by knowledge deficits. Communication improvement was the most common mitigation strategy. CONCLUSION Standardized classification of errors in preventable trauma deaths most often involve clinical performance in the early phases of care and can be mitigated with universal strategies.

Transfer status: A risk factor for mortality in patients with necrotizing fasciitis

BACKGROUND Necrotizing fasciitis (NF) is a rapidly progressive disease that requires urgent surgical debridement for survival. Interhospital transfer (IT) may be associated with delay to operation, which could increase mortality. We hypothesized that mortality would be higher in patients undergoing surgical debridement for necrotizing fasciitis after IT compared to Emergency Department (ED) admission. METHODS We performed a retrospective cohort analysis from 2000-2006 using the Nationwide Inpatient Sample. Inclusion criteria were age >18 years, primary diagnosis of NF, and surgical therapy within 72 hours of admission. Logistic regression was used to assess the relationship between admission source, patient and hospital variables, and mortality. RESULTS We identified 9,958 cases over the study period. Patients in the ED group were more likely to be nonwhite and of lower income when compared with patients in the IT group. Unadjusted mortality was higher in the IT group than ED group (15.5% vs 8.7%, P < .001). After adjusting for potential confounders, odds of mortality were still greater in the IT (OR 2.04, CI 95% 1.60-2.59, P < .001). CONCLUSION Interhospital transfer is associated with increased risk of in-hospital mortality after surgical therapy for NF, a finding which persists after controlling for patient and hospital level variables.

Pancreatic injury in damage control laparotomies : Is pancreatic resection safe during the initial laparotomy?

OBJECTIVES While damage control (DC) techniques such as the rapid control of exsanguinating haemorrhage and gastrointestinal contamination have improved survival in severely injured patients, the optimal pancreatic injury management strategy in these critically injured patients requiring DC is uncertain. We sought to characterise pancreatic injury patterns and outcomes to better determine optimal initial operative management in the DC population. MATERIALS AND METHODS A two-centre, retrospective review of all patients who sustained pancreatic injury requiring DC in two urban trauma centres during 1997-2004 revealed 42 patients. Demographics and clinical characteristics were analysed. Study groups based on operative management (pack+/-drain vs. resection) were compared with respect to clinical characteristics and hospital outcomes. RESULTS The 42 patients analysed were primarily young (32.8+/-16.2 years) males (38/42, 90.5%) who suffered penetrating (30/42, 71.5%) injuries of the pancreas and other abdominal organs (41/42, 97.6%). Of the 12 patients who underwent an initial pancreatic resection (11 distal pancreatectomies, 1 pancreaticoduodenectomy), all distal pancreatectomies were performed in entirety during the initial laparotomy while pancreaticoduodenectomy reconstruction was delayed until subsequent laparotomy. Comparing the pack+/-drain and resection groups, no difference in mechanism, vascular injury, shock, ISS, or complications was revealed. Mortality was substantial (packing only, 70%; packing with drainage, 25%, distal pancreatectomy, 55%, pancreaticoduodenectomy, 0%) in the study population. CONCLUSIONS The presence of shock or major vascular injury dictates the extent of pancreatic operative intervention. While pancreatic resection may be required in selected damage control patients, packing with pancreatic drainage effectively controls both haemorrhage and abdominal contamination in patients with life-threatening physiological parameters and may lead to improved survival. Increased mortality rates in patients who were packed without drainage suggest that packing without drainage is ineffective and should be abandoned.

Intrahepatic nuclear factor-kappa B activity and alpha 1-acid glycoprotein transcription do not predict outcome after cecal ligation and puncture in the rat.

ObjectiveSepsis is the leading cause of death in critically ill surgical patients. Septic hepatic dysfunction, an important determinant of outcome, is poorly understood but includes inappropriate transcriptional down-regulation. This may be modulated by proinflammatory cytokines. We hypothesized that intrahepatic changes in tumor necrosis factor (TNF)/interleukin (IL)-1-linked processes, such as the activation of the p50 homodimeric and the p65/p50 heterodimeric isoforms of the transcription factor nuclear factor (NF)-&kgr;B or transcription of the acute phase reactant &agr;1-acid glycoprotein (AGP), would correlate with recovery from sepsis. DesignProspective experimental comparison of sham operation and nonlethal and lethal sepsis in male Sprague-Dawley rats. InterventionsNonlethal sepsis was induced by using single-puncture cecal ligation and puncture (CLP). Lethal sepsis was induced via double-puncture CLP. NF-&kgr;B DNA binding activity was determined by using electrophoretic mobility shift analysis with differentiation of p50/p50 and p50/p65 isoforms by using appropriate antibodies. AGP transcription was assessed with transcription elongation analysis, intrahepatic IL-1&bgr;, and TNF-&agr; abundance by using immunohistochemistry, and serum IL-1&bgr; was assessed by using ELISA. Main ResultsOverall NF-&kgr;B activity increased equivalently over time after both single- and double-puncture CLP, with a peak occurring 3 hrs after intervention. In single-puncture CLP, there was an increase in the binding of the p50 homodimer form over time. After double-puncture CLP, no such change was observed. AGP transcription was increased equivalently in both models. Intrahepatic IL-1&bgr; was detected 16 and 24 hrs after single-puncture CLP and 6 hrs after double-puncture CLP. After double-puncture CLP, intrahepatic TNF-&agr; was detected at 6, 16, and 24 hrs. Serum IL-1&bgr; was undetectable after both single- and double-puncture CLP. ConclusionsAlthough AGP transcription was similar in mild and fulminant sepsis, double-puncture CLP increased the binding activity of the p50 homodimer relative to binding of the p50/p65 NF-&kgr;B heterodimer. These results imply that transcriptional activity not linked to acute phase responses is an important determinant of outcome in sepsis.