Polytrauma Increases Susceptibility to Pseudomonas Pneumonia in Mature Mice.

Pneumonia is the most common complication observed in patients with severe injuries. Although the average age of injured patients is 47 years, existing studies of the effect of injury on the susceptibility to infectious complications have focused on young animals, equivalent to a late adolescent human. We hypothesized that mature adult animals are more susceptible to infection after injury than younger counterparts. To test this hypothesis, we challenged 6 to 8-month-old mature mice to a polytrauma injury followed by Pseudomonas aeruginosa pneumonia and compared them to young (8-10-week-old) animals. We demonstrate that polytrauma injury increases mortality from pneumonia in mature animals (sham-pneumonia 21% vs. polytrauma-pneumonia 62%) but not younger counterparts. After polytrauma, pneumonia in mature mice is associated with higher bacterial burden in lung, increased incidence of bacteremia, and elevated levels of bacteria in the blood, demonstrating that injury decreases the ability to control the infectious challenge. We further find that polytrauma did not induce elevations in circulating cytokine levels (TNF-alpha, IL-6, KC, and IL-10) 24  h after injury. However, mature mice subjected to polytrauma demonstrated an exaggerated circulating inflammatory cytokine response to subsequent Pseudomonas pneumonia. Additionally, whereas prior injury increases LPS-stimulated IL-6 production by peripheral blood leukocytes from young (8-10-week-old) mice, injury does not prime IL-6 production by cell from mature adult mice. We conclude that in mature mice polytrauma results in increased susceptibility to Pseudomonas pneumonia while priming an exaggerated but ineffective inflammatory response.

Angiotensin Inhibition Is Associated with Preservation of T-Cell and Monocyte Function and Decreases Multiple Organ Failure in Obese Trauma Patients.

BACKGROUND: Obese patients are more prone to post-injury multiple organ failure (MOF). Obesity pathophysiology includes an adipose-tissue-derived, renin-angiotensin-aldosterone system affecting inflammatory responses via leukocyte angiotensin receptors. We hypothesized that obese patients receiving pre-injury angiotensin-converting enzyme inhibitor (ACE) or angiotensin receptor blocker (ARB) therapy would have decreased MOF and differences in immune cell frequencies. STUDY DESIGN: We analyzed the Inflammation and the Host Response to Injury trauma-related database. Patients receiving pre-injury ACE or ARB were stratified as obese (BMI >30 kg/m(2)) or nonobese (BMI <30 kg/m(2)). Groups were age, sex, and Injury Severity Score matched against patients not receiving this therapy. Primary end points were Marshall Multiple Organ Dysfunction Score, Denver-2 Postinjury MOF Score, leukocyte markers on T cells, and monocytes measured by flow cytometry. RESULTS: We evaluated 1,932 patients. One hundred and ten were receiving pre-injury ACE/ARB; 94 patients had data available to calculate BMI. Obese patients receiving ACE/ARB showed maximum Marshall (5.83 ± 2.87) and Denver-2 (2.45 ± 2.32) scores similar to nonobese patients receiving or not receiving ACE/ARB, and obese patients not receiving ACE/ARB had significantly higher Marshall (6.49 ± 2.57; p = 0.009) and Denver-2 (3.33 ± 2.21; p = 0.006) scores. Leukocyte analysis suggested improved T-cell function and monocyte maturation in obese patients on ACE/ARB. CONCLUSIONS: Obese patients receiving preinjury ACE/ARB therapy demonstrate post-injury MOF scores similar to nonobese patients; obese patients not receiving these medications have greater post-injury MOF. Leukocyte analysis demonstrates improved immune regulation. Modulation of the renin-angiotensin-aldosterone system pathway might represent a novel therapeutic target in severely injured obese patients.

Technique for repair of fractures and separations involving the cartilaginous portions of the anterior chest wall.

Internal fixation of the ribs has been shown in numerous studies to decrease complications following traumatic rib fractures. Anterior injuries to the chest wall causing cartilaginous fractures, although rare, can cause significant disability and can lead to a variety of complications and, therefore, pose a unique clinical problem. Here, we report the surgical technique used for four patients with internal fixation of injuries to the cartilaginous portions of the chest wall treated at our center. All patients had excellent clinical outcomes and reported improvement in symptoms, with no associated complications. Patients who have injuries to the anterior portions of the chest wall should be considered for internal fixation of the chest wall when the injuries are severe and can lead to clinical disability.

Improving enteral delivery through the adoption of the "Feed Early Enteral Diet adequately for Maximum Effect (FEED ME)" protocol in a surgical trauma ICU: a quality improvement review.

BACKGROUND: Despite the research supporting adequate enteral nutrition (EN) in intensive care unit (ICU) patients, underfeeding is still common. This quality improvement (QI) project was done to determine the effect of "volume-based" feeding on adequacy of EN delivery and provision of calories and protein in a surgical/trauma ICU (STICU). MATERIALS AND METHODS: Mechanically ventilated STICU patients (n = 111) fed at least 72 hours after achieving their target goal of EN during their first week of admission were reviewed retrospectively in a QI project. Data were obtained before (n = 54) and after (n = 56) initiation of a "volume-based" feeding protocol (FEED ME - Feed Early Enteral Diet adequately for Maximum Effect). RESULTS: The proportion of EN volume and calories delivered increased significantly (rate based, 63% ± 20%; FEED ME, 89% ± 9%; P < .0001), as did grams of protein/kg actual body weight (1.13 ± .29 to 1.26 ± .37; P = .036) using the FEED ME protocol. Groups were similar in patient demographics, clinical characteristics, and nutrition practices. Only slightly more diarrhea (rate based, 0; FEED ME, 6; P = .046) in gastric-fed patients was noted. The incidence of gastric residual volume >350 mL (rate-based, 20 episodes; FEED ME, 11 episodes; P = .34) and emesis (5 vs 2 episodes; P = .22) was similar. CONCLUSION: A change in standard of practice to an EN volume-based feeding approach in a STICU led to a significant improvement in adequacy of calories and protein delivered, with only a slight increase in diarrhea.

Implementation of a dexmedetomidine stewardship program at a tertiary academic medical center.

BACKGROUND: Brigham and Women's Hospital implemented a dexmedetomidine stewardship program in October 2010 beginning with an institution-specific prescribing guideline. To ensure continued adherence to the prescribing guideline, a pharmacist-driven quality assurance program was implemented in November 2011. OBJECTIVE: The primary objective of this study is to describe the role and impact of a dexmedetomidine stewardship program on dexmedetomidine use at a tertiary academic medical center. METHODS: This is a prospective descriptive analysis of a dexmedetomidine stewardship program. Dexmedetomidine stewardship data were collected prospectively from January 2012 through June 2012, in all intensive care units (ICUs) at a single academic medical center. Adult patients (>18 years old) receiving dexmedetomidine therapy continuously for sedation and in the ICU were included in the analysis. RESULTS: A total of 99 patients were identified during the study time frame, during which 71 (71.7%) were identified as compliant with the institutional guideline. The total number of patients receiving dexmedetomidine for greater than 24 hours was 13 (13.1%), of whom 10 (76.9%) received targeted interventions; 15 (15.2%) targeted interventions were made on all patients receiving dexmedetomidine during the study time frame. The total use of dexmedetomidine during the study period was 1310 vials, compared with 5404 vials during the equivalent time frame in 2010-a 76% reduction. CONCLUSIONS: A dexmedetomidine stewardship program, including an institution-specific prescribing guideline and a pharmacist-driven quality assurance program may ensure guideline compliance and decreased use of dexmedetomidine at an academic medical center.

Impact of an immunoglobulin G-specific enzyme-linked immunosorbent assay on the management of heparin-induced thrombocytopenia.

STUDY OBJECTIVE: To evaluate whether using an immunoglobulin G (IgG)-specific platelet factor 4 (PF4) test reduces the rate of positive PF4 results and has an impact on prescribing practices of nonheparin anticoagulants (direct thrombin inhibitors and fondaparinux) in patients assessed for heparin-induced thrombocytopenia (HIT). DESIGN: Single-center prospective cohort study with a historical control group. SETTING: Large academic medical center. PATIENTS: A total of 672 patients assessed for HIT. INTERVENTION: Patients were assessed for HIT by using either an IgG-specific PF4 enzyme-linked immunosorbent assay (ELISA; 336 patients) or a nonspecific PF4 ELISA (336 patients; historical control group). MEASUREMENTS AND MAIN RESULTS: No significant difference was noted in the proportion of patients with a low, intermediate, or high risk of HIT based on the 4Ts pretest clinical scoring system. The PF4 ELISA was positive in 6.9% versus 11.3% of patients (p=0.04) in the IgG-specific and nonspecific cohorts, respectively. A smaller proportion of patients were prescribed a direct thrombin inhibitor in the IgG-specific cohort (19.4% vs 25.9%; p=0.04). No significant difference in fondaparinux use was noted between the cohorts. The duration of direct thrombin inhibitor therapy, bleeding events, hospital length of stay, and in-hospital mortality was similar in both cohorts. CONCLUSION: Use of an IgG-specific PF4 ELISA was associated with a lower rate of positive PF4 test results. Direct thrombin inhibitor prescribing was also significantly lower during the time period where the IgG-specific PF4 ELISA was used, with no significant differences noted in safety outcomes.

Neurologic adverse effects of ranolazine in an elderly patient with renal impairment.

Ranolazine, an antianginal agent, has activity at muscle and neuronal sodium channels. Congenital genetic mutations to sodium channels in humans and supratherapeutic ranolazine concentrations in animal models have produced similar neurologic adverse reactions. We describe a case of neurologic adverse effects in an 81-year-old woman with coronary artery disease, renal impairment, and mild neurologic disease who received ranolazine for symptomatic control of a non-ST-segment elevation myocardial infarction. Just over 48 hours after a dose increase, she experienced new-onset dysarthia, dysmetria, hallucinations, worse tremors, and difficulty with word finding. Her workup for acute stroke and infectious causes was negative. Her symptoms abated 2 days after ranolazine was discontinued. The patient was at risk for ranolazine adverse effects due to the high dose administered and her advanced age, renal impairment, and baseline mild neurologic disease. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 5) between the patient's neurologic adverse events and the ranolazine therapy. To our knowledge, this is the first case report illustrating rare but debilitating neurologic adverse effects of ranolazine. Health care practitioners should be aware of the adverse effects of ranolazine and avoid doses greater than 500 mg twice/day in patients older than 80 years or those with a creatinine clearance of less than 30 ml/minute.

Pulmonary contusion is associated with toll-like receptor 4 upregulation and decreased susceptibility to pseudomonas pneumonia in a mouse model.

Pulmonary contusion is a major cause of respiratory failure in trauma patients. This injury frequently leads to immune suppression and infectious complications such as pneumonia. The mechanism whereby trauma leads to an immune-suppressed state is poorly understood. To further study this phenomenon, we developed an animal model of pulmonary contusion (PC) complicated by pneumonia and assessed the effect of PC and pneumonia on toll-like receptor expression in alveolar macrophages. Using a mouse model, PC was induced on the right lung, and pneumonia was induced with Pseudomonas aeruginosa (Pa) injected intratracheally 48 h after injury. Susceptibility to pneumonia was assessed by mortality at 7 days. Uninjured animals were used as controls. Bronchoalveolar lavage fluid and blood were assayed 48 h after injury and 24 h after Pa instillation to look at markers of systemic inflammation. Toll-like receptor expression in the initial inflammatory response was analyzed by flow cytometry. Unexpectedly, injured animals subjected to intratracheal injection of Pa at 48 h after PC demonstrated increased survival compared with uninjured animals. Bronchoalveolar lavage cytokine expression was increased significantly after Pa administration but not after PC alone. Toll-like receptor 4 expression on alveolar macrophages was significantly elevated in the injured group compared with sham but not in neutrophils. Animals subjected to PC are more resistant to mortality from infection with Pa and display an enhanced cytokine response when subsequently subjected to Pa. Increased expression of toll-like receptor 4 on alveolar macrophages and enhanced innate immunity are a possible mechanism of increased cytokine production and decreased susceptibility to pneumonia.

Reversal of secondary pulmonary hypertension by axial and pulsatile mechanical circulatory support.

BACKGROUND: Pulmonary hypertension associated with chronic congestive heart failure posses a significant risk of morbidity and death after heart transplantation. Isolated observations suggest that chronic ventricular unloading may lead to normalization of pulmonary pressures and thus render a patient likely to be a heart transplant candidate. METHODS: This study is a retrospective analysis of 9 heart failure patients with secondary pulmonary hypertension (transpulmonary gradient [TPG] > 15 mm/Hg). Two were treated with a pulsatile left ventricular assist device (LVAD) and 7 with an axial-flow LVAD. RESULTS: After LVAD support, mean pulmonary artery pressure decreased from 39 +/- 7 to 31 +/- 5 mm Hg, and the TPG decreased from 19 +/- 3 to 13 +/- 4 mm Hg (p < 0.01). The 1-year Kaplan-Meier survival curve for patients with pre-LVAD TPG > 15 mm Hg vs those with TPG < 15 mm Hg showed no difference in survival (p = 0.6). This finding was supported by analysis of a large multi-institutional cohort obtained from the Organ Procurement and Transplantation Network database, where no differences in survival were found in the same groups. CONCLUSIONS: Pulmonary hypertension that is secondary to congestive heart failure, as defined by a TPG > 15 mm Hg can be reversed by the use of pulsatile and axial-flow LVADs; furthermore, post-transplant survival for patients with secondary pulmonary hypertension treated with an LVAD was no different than for those without pulmonary hypertension who received LVAD support.

Conventional intramuscular sedatives versus ziprasidone for severe agitation in adolescents: case-control study.

OBJECTIVE: The objective of this study was to compare intramuscular (IM) ziprasidone to conventional IM medications (haloperidol combined with lorazepam) for the treatment of severe agitation in adolescents (age 12-17). METHODS: We retrospectively identified consecutive severe agitation episodes (defined as requiring physical restraint) in adolescents treated with either IM ziprasidone or conventional IM agents in a psychiatric emergency room. For ziprasidone, the dosage was 20 mg for 23 episodes and 10 mg for 5 episodes. For 24 episodes treated with combined haloperidol and lorazepam, the dosages were 4.8 +/- 0.3 SEM mg and 1.9 +/- 0.4 mg respectively. Outcomes were the duration of restraint and need for adjunctive "rescue" medications within 60 minutes. These outcomes were decided prior to reviewing any records. RESULTS: No difference was found in restraint duration (ziprasidone, N = 28, 55 +/- 5 minutes; haloperidol with lorazepam N = 24, 65 +/- 7 minutes, P = NS). Use of "rescue" medications did not differ between the two groups. No changes in blood pressure were found, but pulse decreased 8.3 +/- 2.4 for haloperidol with lorazepam and 8.9 +/- 4.24 for ziprasidone (P = NS). No instances of excessive sedation or extra-pyramidal symptoms were documented. CONCLUSION: In this study, IM ziprasidone appeared effective, well tolerated, and similar in clinical profile to combined conventional IM medications for treating severe agitation in adolescents. Given the reportedly favorable acute side effect profile of parenteral atypical agents, they may provide an alternative to conventional antipsychotics for treating acute agitation in both adult and adolescent populations. Future randomized, controlled studies are needed.

Decorin-mediated transforming growth factor-beta inhibition ameliorates adverse cardiac remodeling.

BACKGROUND: Implantation of a left ventricular assist device (LVAD) has been shown to induce regression of fibrosis in patients with congestive heart failure (CHF) and improve myocardial function. The mechanism of reverse remodeling after mechanical circulatory support (MCS), however, has not been fully characterized. In this study we examined the anti-fibrotic effects of decorin, an extracellular matrix (ECM) proteoglycan, on the transforming growth factor-beta (TGF-beta) pathway. METHODS: Human myocardial tissue samples were obtained from patients undergoing LVAD implantation and again following subsequent transplantation after a sustained period of MCS. The specimens were examined by utilizing different molecular and histologic techniques, including human cardiac fibroblast in vitro studies. We assessed gene expression, mRNA and protein levels. RESULTS: We found a significant decrease in interstitial fibrosis after MCS, with a decrease in collagen mRNA transcription rates, serving as an indirect measurement of collagen synthesis. Both the mRNA and protein levels of decorin were significantly increased after a period of MCS. Decorin mRNA was up-regulated by 44% after MCS (p < 0.01), which paralleled the increase in interstitial decorin deposition (p < 0.001). In addition, p-SMAD2, a molecular marker downstream of the TGF-beta pathway, was found to be inactivated after MCS (p < 0.02). Moreover, cultured human cardiac fibroblasts exposed to TGF-beta demonstrated decreased collagen production when exogenous decorin was added (p < 0.03). CONCLUSIONS: The decorin molecule is potentially involved in reverse cardiac remodeling, by directly inhibiting the TGF-beta pathway and its pro-fibrotic effects on the failing human heart.

A pooled analysis of posttransplant survival following combined heart-liver transplantation.

Because no single center has accumulated a large experience with this complex operation, the effectiveness of combined orthotopic heart transplantation (OHT) and orthotopic liver transplantation (OLT) in achieving long-term survival has been unknown. Cases of OHT-OLT were pooled from a U.S. transplant recipient registry and from previously published literature. Aggregate data from these sources was used for survival analysis. Thirty-six patients having undergone OHT-OLT were listed in the national registry; the one- and five-year patient survival rates of these patients were 88% and 78%, respectively. Many patients remain alive at 8+ years after transplantation. An analysis of the pooled results of previously-published cases estimated a one-year patient survival rate of 84%. In selected disease processes, OHT-OLT can correct underlying metabolic deficiencies. While rarely indicated, OHT-OLT is a successful treatment for patients with end-stage heart and liver disease, with survival comparable to that seen after isolated orthotopic heart or orthotopic liver transplantation.

Early mobilization of LVAD recipients who require prolonged mechanical ventilation.

Early mobilization and aggressive physical therapy are essential in patients who receive left ventricular assist devices (LVADs) due to long-term, end-stage heart failure. Some of these patients remain ventilator dependent for quite some time after device implantation. We report our regimen of mobilization with the aid of a portable ventilator, in patients with cardiac cachexia and LVAD implantation. Further, we describe the specific physical therapy interventions used in an LVAD patient who required prolonged mechanical ventilation after device implantation. The patient was critically ill for 5 weeks before the surgery and was ventilator dependent for 48 days postoperatively. There were significant functional gains during the period of prolonged mechanical ventilation. The patient was able to walk up to 600 feet by the time he was weaned from the ventilator and transferred out of the intensive care unit. He underwent successful heart transplantation 6 weeks after being weaned from the ventilator We believe that improving the mobility of LVAD patients who require mechanical ventilation has the potential both to facilitate ventilator weaning and to improve the outcomes of transplantation.

Rupture of inlet graft of the HeartMate System: a case report.

As the implantation of left ventricular assist devices (LVADs) as destination therapy for patients with heart failure increases in frequency, device durability and malfunction present an increasing concern. Complications such as inflow valve regurgitation, outflow valve distortion, and problems with power cable or pump motors place the LVAD recipient at increased risk for morbidity and mortality. To offset the risk of complications related to the inflow cannula, modifications to the valve conduit were made to the SNAP VE device in November 2002. These modifications were intended to improve durability with cycle performance of up to 6 times longer than the old inflow valve during in vitro testing. We describe here a patient who sustained disruption of the Dacron inlet graft after implantation of the Heart-Mate XVE System as a destination therapy.

Impact of left ventricular assist device (LVAD)-mediated humoral sensitization on post-transplant outcomes.

BACKGROUND: Humoral sensitization, defined as a panel-reactive antibody (PRA) screen of >10%, places heart transplant recipients at a greater risk of acute rejection and mortality. Previous studies have suggested an increased sensitization in left ventricular assist device (LVAD) recipients, although neither the impact of device selection nor the clinical importance of elevated PRA in these patients has been completely described. METHODS: Using the registry of the International Society for Heart and Lung Transplantation (ISHLT), we compared PRA levels in 7,686 heart transplant recipients to determine the impact of LVAD therapy on humoral sensitization, acute rejection and mortality. To determine the impact of device selection on sensitization, we compared data from the ISHLT registry as well as from our own institution. RESULTS: Elevated PRA levels were found in 16.6% of LVAD recipients, compared with 7.6% of non-LVAD controls (p < 0.0001). Sensitization differed by device type, being present in 21.9% of Thoratec recipients, 14.4% of HeartMate recipients, and 15.5% of Novacor recipients (p = 0.01). Despite these findings, LVAD use had no impact on rejection rates. LVAD use was associated with a small increase (4.4% and 4.3%, respectively) in 1- and 2-year mortality. CONCLUSIONS: These findings support the concept that mechanical circulatory support increases the rate of humoral sensitization. However, these differences in sensitization do not translate to substantial differences in the clinical outcomes of rejection and mortality.

Rapid-acting IM ziprasidone in a psychiatric emergency service: a naturalistic study.

Atypical antipsychotics have gained acceptance as first-line treatment for psychotic disorders. Rapid-acting intramuscular (IM) atypicals may supplant benzodiazepine and/or neuroleptic alternatives. IM atypical ziprasidone studies excluded severe psychiatric agitation (PSYCH), or that due to the abuse of alcohol (ETOH) or other substances (SUBS). We report Behavioral Activity Rating Scale agitation scores (range, 1-7) and duration of physical restraints in a naturalistic study in a psychiatric emergency service using IM ziprasidone 20 mg and various doses for conventional antipsychotics. Baseline scores were high for PSYCH, ETOH and SUBS patients (mean, 6.5, 6.9 and 6.6, respectively). Agitation decreased rapidly from baseline with ziprasidone [mean, 5.6, 5.3 and 5.8, respectively, at 15 min (P<.05 for all), and 4.2, 4.1 and 4.1, respectively, at 30 min (P<.01 for all)]. At 2 h, scores were 2.6, 2.1 and 2.3 (P<.01 for all versus baseline). For 9 patients receiving conventional IM antipsychotics, scores were 6.6 (baseline), 5.7 (15 min), 4.2 (30 min) and 2.9 (2 h) (P<.02 versus ziprasidone). Compared with restraint durations from 80 patients receiving conventional IM agents 1 month prior to this study, restraint duration decreased from 91+/-4 to 54+/-3 min with ziprasidone (n=77; P<.01) and varied with conventional IM agents (mean, 60+/-12 min; n=4; P=NS). None of the 19 ziprasidone patients who received electrocardiograms showed prolonged QTc; one had a dystonic reaction. IM ziprasidone appears effective for severe agitation, including agitation associated with alcohol or substance intoxication, and may reduce time in restraints.

Placement of a left ventricular assist device in a patient with dextrocardia.

Dextrocardia most commonly presents in the setting of situs inversus, but it may occur as an isolated anomaly with normal position of the abdominal organs. Herein we present a 54-year-old man with ischemic cardiomyopathy and dextrocardia with normal position of the abdominal organs who presented with an exacerbation of congestive heart failure requiring inotropic support as well as mechanical ventilation. An implantable, wearable left ventricular assist device was placed in this patient to allow for ambulation and eventual discharge home. The patient survived 4 months before he developed pneumonia and expired.

Organ-specific regulation of pro-inflammatory molecules in heart, lung, and kidney following brain death.

BACKGROUND: Nonspecific inflammatory events following brain death may increase the intensity of the immunological host response. The present study investigated the course of pro-inflammatory molecules in heart, lung, kidney, and plasma after brain death induction. MATERIALS AND METHODS: Brain death was induced in five pigs by inflation of an intracranial Foley catheter and five pigs were sham-operated as controls. Each experiment was terminated 6 h after brain death/sham operation and the organs were harvested. We measured the mRNA and protein levels for TNF-alpha, IL-1beta, and IL-6 in heart, lung, kidney, and plasma. Additionally, the mRNA expression for IL-6R, ICAM-1, MCP-1, and TGF-beta was determined in each organ. RESULTS: After 6 h, the plasma cytokine levels were higher in the brain-dead animals than in the sham-operated. In heart, lung, and kidney there was an increase in IL-6 and IL-1beta following brain death, while TNF-alpha was up-regulated in lung only (P < 0.05). MCP-1 and TGF-beta were significantly higher in heart and lung and IL-6R increased in heart after brain death (P < 0.05). CONCLUSIONS: Brain death was associated with non-uniform cytokine expression patterns in the investigated organs. These expression patterns may cause variable pro-inflammatory priming resulting in different degrees of damage and explain the organ-specific variation in outcomes after transplantations.