Andrew C. Bernard

Human Polymerized Hemoglobin for the Treatment of Hemorrhagic Shock when Blood Is Unavailable: The USA Multicenter Trial

BACKGROUND Human polymerized hemoglobin (PolyHeme, Northfield Laboratories) is a universally compatible oxygen carrier developed to treat life-threatening anemia. This multicenter phase III trial was the first US study to assess survival of patients resuscitated with a hemoglobin-based oxygen carrier starting at the scene of injury. STUDY DESIGN Injured patients with a systolic blood pressure</=90 mmHg were randomized to receive field resuscitation with PolyHeme or crystalloid. Study patients continued to receive up to 6 U of PolyHeme during the first 12 hours postinjury before receiving blood. Control patients received blood on arrival in the trauma center. This trial was conducted as a dual superiority/noninferiority primary end point. RESULTS Seven hundred fourteen patients were enrolled at 29 urban Level I trauma centers (79% men; mean age 37.1 years). Injury mechanism was blunt trauma in 48%, and median transport time was 26 minutes. There was no significant difference between day 30 mortality in the as-randomized (13.4% PolyHeme versus 9.6% control) or per-protocol (11.1% PolyHeme versus 9.3% control) cohorts. Allogeneic blood use was lower in the PolyHeme group (68% versus 50% in the first 12 hours). The incidence of multiple organ failure was similar (7.4% PolyHeme versus 5.5% control). Adverse events (93% versus 88%; p=0.04) and serious adverse events (40% versus 35%; p=0.12), as anticipated, were frequent in the PolyHeme and control groups, respectively. Although myocardial infarction was reported by the investigators more frequently in the PolyHeme group (3% PolyHeme versus 1% control), a blinded committee of experts reviewed records of all enrolled patients and found no discernable difference between groups. CONCLUSIONS Patients resuscitated with PolyHeme, without stored blood for up to 6 U in 12 hours postinjury, had outcomes comparable with those for the standard of care. Although there were more adverse events in the PolyHeme group, the benefit-to-risk ratio of PolyHeme is favorable when blood is needed but not available.

General surgical operative duration is associated with increased risk-adjusted infectious complication rates and length of hospital stay.

BACKGROUND Studies of specific procedures have shown increases in infectious complications with operative duration. We hypothesized that operative duration is independently associated with increased risk-adjusted infectious complication (IC) rates in a broad range of general surgical procedures. STUDY DESIGN We queried the American College of Surgeons National Surgical Quality Improvement Program database for general surgical operations performed from 2005 to 2007. ICs (wound infection, sepsis, urinary tract infection, and/or pneumonia) and length of hospital stay (LOS) were evaluated versus operative duration (OD, ie, incision to closure). Multivariable regression adjusted for 38 patient risk variables, operation type and complexity, wound class and intraoperative transfusion. We also analyzed isolated laparoscopic cholecystectomies in patients of American Society of Anesthesiologists class 1 or 2, without intraoperative transfusion and with a clean or clean-contaminated wound class. RESULTS In 299,359 operations performed at 173 hospitals, unadjusted IC rates increased linearly with OD at a rate of close to 2.5% per half hour (chi-square test for linear trend, p < 0.001). After adjustment, IC risk increased for each half hour of OD relative to cases lasting <or=1 hour, almost doubling at 2.1 to 2.5 hours (odds ratio = 1.92; 95% CI, 1.82 to 2.03; p < 0.001). In isolated laparoscopic cholecystectomy, IC rates increased linearly with OD (n = 17,018, chi-square test for linear trend, p < 0.001) with rates for 1.1 to 1.5 hour cases (1.4%) doubling those lasting <or=0.5 hour (0.7%). Across all procedures, adjusted LOS increased geometrically with operative duration at a rate of about 6% per half hour (coefficient for natural log transformed LOS = 0.059 per half hour; 95% CI, 0.058 to 0.060; p < 0.001). CONCLUSIONS Operative duration is independently associated with increased ICs and LOS after adjustment for procedure and patient risk factors.

Arginase I Expression and Activity in Human Mononuclear Cells After Injury

ObjectiveTo determine the effect of trauma on arginase, an arginine-metabolizing enzyme, in cells of the immune system in humans. Summary Background DataArginase, classically considered an enzyme exclusive to the liver, is now known to exist in cells of the immune system. Arginase expression is induced in these cells by cytokines interleukin (IL) 4, IL-10, and transforming growth factor beta, corresponding to a T-helper 2 cytokine profile. In contrast, nitric oxide synthase expression is induced by IL-1, tumor necrosis factor, and gamma interferon, a T-helper 1 cytokine profile. Trauma is associated with a decrease in the production of nitric oxide metabolites and a state of immunosuppression characterized by an increase in the production of IL-4, IL-10, and transforming growth factor beta. This study tests the hypothesis that trauma increases arginase activity and expression in cells of the immune system. MethodsSeventeen severely traumatized patients were prospectively followed up in the intensive care unit for 7 days. Twenty volunteers served as controls. Peripheral mononuclear cells were isolated and assayed for arginase activity and expression, and plasma was collected for evaluation of levels of arginine, citrulline, ornithine, nitrogen oxides, and IL-10. ResultsMarkedly increased mononuclear cell arginase activity was observed early after trauma and persisted throughout the intensive care unit stay. Increased arginase activity corresponded with increased arginase I expression. Increased arginase activity coincided with decreased plasma arginine concentration. Plasma arginine and citrulline levels were decreased throughout the study period. Ornithine levels decreased early after injury but recovered by postinjury day 3. Increased arginase activity correlated with the severity of trauma, early alterations in lactate level, and increased levels of circulating IL-10. Increased arginase activity was associated with an increase in length of stay. Plasma nitric oxide metabolites were decreased during this same period. ConclusionsMarkedly altered arginase expression and activity in cells of the human immune system after trauma have not been reported previously. Increased mononuclear cell arginase may partially explain the benefit of arginine supplementation for trauma patients. Arginase, rather than nitric oxide synthase, appears to be the dominant route for arginine metabolism in immune cells after trauma.

Alterations in arginine metabolic enzymes in trauma

Arginine is the sole substrate for nitric oxide (NO) synthesis by NO synthases (NOS) and promotes the proliferation and maturation of human T-cells. Arginine is also metabolized by the enzyme arginase, producing urea and ornithine, the precursor for polyamine production. We sought to determine the molecular mechanisms regulating arginase and NOS in splenic immune cells after trauma. C3H/HeN mice underwent laparotomy as simulated moderate trauma or anesthesia alone (n = 24 per group). Six, 12, 24, or 48 h later, 6 animals from each group were sacrificed, and splenectomy was performed and plasma collected. Six separate animals had neither surgery nor anesthesia and were sacrificed to provide resting values (t = 0 h). Spleen arginase I and II and iNOS mRNA abundance, arginase I protein expression, and arginase activity were determined. Plasma NO metabolites (nitrite + nitrate) were also measured. Trauma increased spleen arginase I protein expression and activity (P = 0.01) within 12 and for at least 48 h after injury and coincided with up-regulated arginase I mRNA abundance at 24 h. Neither arginase II nor iNOS mRNA abundance in the spleen was significantly increased by trauma at 24 h. Plasma nitrite + nitrate was decreased in animals 48 h post-injury compared to anesthesia controls (P < 0.05). Trauma induces up-regulation of arginase I gene expression in splenic immune cells within 24 h of injury. Arginase II is not significantly up-regulated at that time point. Arginase I, rather than iNOS appears to be the dominant route for arginine metabolism in splenic immune cells 24 h after trauma.

Surgery induces human mononuclear cell arginase I expression

BACKGROUND Arginase is a metabolic enzyme for the amino acid arginine that participates in the immune response to trauma. We hypothesize that surgical trauma induces arginase expression and activity in the human immune system. METHODS Peripheral mononuclear cell (MNC) arginase activity and expression and plasma nitric oxide metabolites and interleukin (IL)-10 were measured in patients undergoing elective general surgery. Twenty-two healthy volunteers served as a comparison population. RESULTS MNC arginase activity increased within 6 hours of surgery (p < 0.05) and coincided with increased arginase I protein expression. Plasma nitric oxide metabolites decreased significantly postoperatively (p < 0.05). Patients lacking an elevation in IL-10 failed to demonstrate increased MNC arginase activity. CONCLUSION Increased MNC arginase expression may contribute to postsurgical immune dysfunction by affecting arginine use and availability and nitric oxide metabolism in the immune system. Plasma IL-10 may play a role in regulating MNC arginase activity.

Enteral nutrition and drug administration, interactions, and complications

The enteral route has become the standard of care to deliver nutrition support for hospitalized acute care and ambulatory care patients. The same access device is increasingly being used to deliver medications, which provides cost savings but also creates new challenges. Cost savings can be negated if the concomitant administration of nutrition elicits a decrease in bioavailability due to incompatibilities that alter drug or nutrition therapy. Feeding tubes can deliver nutrients and drugs to the stomach, small bowel, or both, with optimal efficacy of medications depending on delivery to the appropriate segment of the gastrointestinal tract. Liquid preparations are often the preferred formulation for enteral administration. Obstruction of the enteral access device may occur when specialized medication formulations are altered inappropriately. Occasionally, the enteral formula should be changed to modify the content of free water, fiber, electrolytes, or vitamins that may interfere with the drug therapy. Intolerance to enteral nutrition such as abdominal distention and diarrhea may be the result of the medication, and the causative agent should be identified to improve patient comfort. This article will address optimal drug delivery via enteral access devices and possible complications associated with therapy.

Imaging may delay transfer of rural trauma victims: a survey of referring physicians.

BACKGROUND Delayed transfer to a trauma center due to unnecessary imaging results in suboptimal patient outcome and increases healthcare costs. Unnecessary imaging may result from beliefs regarding trauma center requirements and legal concerns. We hypothesized that referring physicians consider factors other than clinical criteria when deciding to order imaging studies before transfer of trauma patients. METHODS A mail survey of 218 referring physicians to a level I trauma center elicited factors affecting decision to obtain imaging studies before transfer. Graded answers to six questions were obtained and demographics of the physician respondent. Statistical analysis was performed using Fishers exact test. RESULTS One hundred forty-nine of 218 surveys were returned (68.3%). One-third (33.1%) of respondents obtain imaging because of perceived expectations of the receiving trauma center, independent of patient acuity. Twenty percent incorrectly think that the law prohibits transfer before patients are stabilized. Twenty-eight percent obtain imaging because of liability concerns, even if that imaging delays transfer. Overall, 45% obtain imaging for either perceived requirement or liability concern. Non-advanced trauma life support (ATLS)-certified physicians are more likely to use all available resources before transfer than ATLS-certified physicians. CONCLUSIONS Factors other than patient care dictate imaging acquisition in almost half of those surveyed. Misperception of expectations, misunderstanding of legal imperatives, and liability concerns all delay transport of the injured. ATLS-certified individuals use imaging more appropriately, thus, promoting more timely transfer. State-wide protocols, education, and liability reform may reduce transport delays.

Conventional surgical tracheostomy as the preferred method of airway management

Tracheostomy was first described in the early Christian era.’ In 1909, Jackson standardized tracheostomy as we know it today.2 Although many modifications have been introduced since that time, Jackson’s conventional surgical technique has remained the gold standard, having been used in elective and emergent cases, in the operating room (OR) and in the intensive care unit (ICU).3-8 Indications for tracheostomy are the same regardless of the technique, including airway access for prolonged mechanical ventilation, facilitation of removal of tracheobronchial secretions, and elimination of upper airway obstruction. The last decade has seen a shift toward performing tracheostomy via Ciaglia et al’s percutaneous dilational technique,9 because studies have shown it to be safe, relatively easy to learn, and cost-effective when performed in the ICU (compared with conventional surgical tracheostomy in the operating room).10-28 However, surgeons should recognize that variability in performing a given technique adds error to any clinical comparison and potential bias to the literature. For example, in one trial, conventional surgical tracheostomies were performed by 18 different surgeons.18 This discussion supports conventional surgical tracheostomy as a safe technique that can be performed in the ICU, questions the trend away from conventional surgical tracheostomy toward percutaneous techniques for reasons of greater cost, suggests that conventional surgical tracheostomy is simple and can be performed quickly, and asserts that it is a fundamental surgical skill that should be mastered before performing alternative tracheostomy techniques.

Packed red blood cells suppress T-cell proliferation through a process involving cell-cell contact.

BACKGROUND Packed red blood cell (PRBC) transfusion suppresses immunity and increases morbidity and mortality. Leukocyte reduction has failed to abrogate these effects, thus implicating red blood cells themselves or their components. PRBC impair proliferation of immortal (Jurkat) T cells by depleting arginine from the extracellular environment. The effect of PRBC on isolated ex vivo T-cell proliferation has not been reported. We hypothesize that PRBCs depress mitogen-stimulated proliferation in isolated human and mouse T cells. METHODS Human peripheral T cells were isolated by Ficoll-Hypaque gradient, purified by magnetic separation, and stimulated with anti-CD3 or anti-CD28. DO11.10 transgenic mouse splenic T cells were stimulated with ovalbumin. Cells were cultured at 1 x 10(6)/mL in 96-well plates or in 24-transwell plates in the presence of PRBC (0.015-5% by volume, stored for 4-6 weeks). In culture media, arginine and citrulline were varied. Proliferation was measured at 72 hours by thymidine incorporation. T-cell viability, apoptosis, and receptor zeta chain were measured by flow cytometry. RESULTS PRBC significantly depressed human peripheral and mouse splenic T-cell proliferation in a dose-dependent manner. PRBC arginase blockade by N-omega-hydroxy-nor-l-arginine only partly restored proliferation. Cell contact was required in both cell types for maximal effect. Depressed zeta chain in human peripheral T cells was partly restored by arginase blockade. Salvage by high-dose arginine and citrulline was unsuccessful. Decreased proliferation was not related to cell death. CONCLUSION PRBC suppresses mitogen-stimulated human and antigen-stimulated mouse T-cell proliferation by mechanisms independent of arginine depletion. This is a novel mechanism for transfusion-associated immune suppression.

A placebo-controlled, double-blind, dose-escalation study to assess the safety, tolerability and pharmacokinetics/pharmacodynamics of single and multiple intravenous infusions of AZD9773 in patients with severe sepsis and septic shock

IntroductionTumor necrosis factor-alpha (TNF-α), an early mediator in the systemic inflammatory response to infection, is a potential therapeutic target in sepsis. The primary objective of this study was to determine the safety and tolerability of AZD9773, an ovine, polyclonal, anti-human TNF-α Fab preparation, in patients with severe sepsis. Secondary outcomes related to pharmacokinetic (PK) and pharmacodynamic (PD) parameters.MethodsIn this double-blind, placebo-controlled, multicenter Phase IIa study, patients were sequentially enrolled into five escalating-dose cohorts (single doses of 50 or 250 units/kg; multiple doses of 250 units/kg loading and 50 units/kg maintenance, 500 units/kg loading and 100 units/kg maintenance, or 750 units/kg loading and 250 units/kg maintenance). In each cohort, patients were randomized 2:1 to receive AZD9773 or placebo.ResultsSeventy patients received AZD9773 (n = 47) or placebo (n = 23). Baseline characteristics were similar across cohorts. Mean baseline APACHE score was 25.9. PK data demonstrated an approximately proportional increase in concentration with increasing dose and a terminal half-life of 20 hours. For the multiple-dose cohorts, serum TNF-α concentrations decreased to near-undetectable levels within two hours of commencing AZD9773 infusion. This suppression was maintained in most patients for the duration of treatment. AZD9773 was well tolerated. Most adverse events were of mild-to-moderate intensity and considered by the reporting investigator as unrelated to study treatment.ConclusionsThe safety, PK and PD data support the continued evaluation of AZD9773 in larger Phase IIb/III studies.