Duration of Antibiotic Therapy for Early VAP Trial: Study Protocol for a Surgical Infection Society Multicenter, Pragmatic, Randomized Clinical Trial of Four versus Seven Days of Definitive Antibiotic Therapy for Early Ventilator-Associated Pneumonia in Surgical Patients.

Background: Current guidelines recommend a seven-day course of antibiotic therapy for patients with ventilator-associated pneumonia (VAP). However, clinical and microbiologic resolution of infection may occur much sooner than seven days, particularly in patients with early VAP. Shortening the course of antibiotic therapy for early VAP likely results in lower antibiotic-associated complications, but it is unclear whether VAP recurrence rates will be higher in patients receiving fewer days of therapy. We propose to compare four days versus seven days of antibiotic therapy for early VAP in surgical patients in a multicenter, pragmatic, randomized clinical trial. Patients and Methods: Eligible patients admitted to a surgical intensive care unit with early VAP, defined as VAP occurring within two to seven days of intubation, will be randomized to receive four or seven days of antibiotic therapy. The two primary outcomes are: VAP recurrence, defined as VAP occurring two to 14 days after completion of initial therapy and antibiotic-free days, defined as the number of days without receiving any antibiotic agents within 30 days from completion of initial therapy. Data will be analyzed using both intention-to-treat and per-protocol strategies. Power analysis was performed assuming non-inferiority of four days vs. seven days for VAP recurrence and superiority of four days versus seven days for antibiotic-free days. The total sample size to detect a 10% difference between groups with 80% power and assuming a 10% dropout rate is 458 patients. Three separate data analyses are planned throughout the trial and sample size will be re-calculated at each interim analysis. Conclusions: The Duration of Antibiotic Therapy for Early VAP (DATE) Trial will enroll surgical patients with early VAP to analyze whether a shorter duration of antibiotic therapy results in similar clinical outcomes while decreasing antibiotic exposure.

Heart rate variability is an independent predictor of morbidity and mortality in hemodynamically stable trauma patients.

BACKGROUND: Reduced heart rate variability (HRV) reflects autonomic dysfunction and can triage patients better than routine trauma criteria or vital signs. However, there is questionable specificity and no consensus measurement technique. The purpose of this study was to analyze whether factors that alter autonomic function affect the specificity of HRV for assessing traumatic injury. METHODS: We evaluated 216 hemodynamically stable adults (3:1 M:F; 97:3 blunt:penetrating; age 49 years ± 1 year, mean ± standard error) undergoing computed axial tomography (CT) scan to rule out traumatic brain injury (TBI). All were prospectively instrumented with a Mars Holter system (GE Healthcare, Milwaukee, WI). HRV was determined offline using time domain (standard deviation of normal-normal intervals, root-mean-square successive difference) and frequency domain (very low frequency [VLF], LF, wideband frequency, high frequency [HF], low to HF index ratio) calculations from 15-minute electrocardiogram and correlated with routine vital signs, mortality, TBI, morbidity, length of stay (LOS), and comorbidities. Significance (p ≤ 0.05) was determined using nonparametric analysis, Student's t test, analysis of variance, or multiple logistic regression. RESULTS: VLF alone predicted survival, severity of TBI, intensive care unit LOS, and hospital LOS (all p < 0.05). Beta-blockers or diabetes had no effect, whereas age, sedation, mechanical ventilation, spinal cord injury, and intoxication influenced one or more of the variables with age being the most powerful confounder (all p < 0.05). Except for the Glasgow Coma Scale, no other routine trauma or hemodynamic criteria correlated with any of these outcomes. CONCLUSIONS: Decreased VLF is an independent predictor of mortality and morbidity in hemodynamically stable trauma patients. Other time and other frequency domain variables correlated with some, but not all, outcomes. All were heavily influenced by factors that alter autonomic function, especially patient age.

Heart rate variability as a triage tool in patients with trauma during prehospital helicopter transport.

BACKGROUND: Prehospital triage of patients with trauma is routinely challenging, but more so in mass casualty situations and military operations. The purpose of this study was to prospectively test whether heart rate variability (HRV) could be used as a triage tool during helicopter transport of civilian patients with trauma. METHODS: After institutional review board approval and waiver of informed consent, 75 patients with trauma requiring prehospital helicopter transport to our level I center (from December 2007 to November 2008) were prospectively instrumented with a 2-Channel SEER Light recorder (GE Healthcare, Milwaukee, WI). HRV was analyzed with a Mars Holter monitor system and proprietary software. SDNN (standard deviation [SD] of the normal-to-normal R-R interval), as an index of HRV, was correlated with prehospital trauma triage criteria, base deficit, seriousness of injury, operative interventions, outcome, and other data extracted from the patients' medical records. There were no interventions or medical decisions based on HRV. Data were excluded only if there was measurement artifact or technical problems with the recordings. RESULTS: The demographics were mean age 47 years, 63% men, 88% blunt, 25% traumatic brain injury, 9% mortality. Prehospital SDNN predicted patients with base excess < or = -6, those defined as seriously injured and benefiting from trauma center care, as well as patients requiring a life-saving procedure in the operating room. No other available data, including prehospital en-route vital signs, predicted any of these. The sensitivity, specificity, positive predictive value, and negative predictive value were 80%, 75%, 33%, 96%, respectively, with and an overall accuracy of 76% for predicting a life-saving intervention in the operating room. CONCLUSIONS: This is the first demonstration that prehospital HRV (specifically SDNN) predicts base excess and operating room life-saving opportunities. HRV triages and discriminates severely injured patients better than routine trauma criteria or en-route prehospital vital signs. HRV may be a useful civilian or military triage tool to avoid unnecessary helicopter evacuation for minimally injured patients. A prospective, randomized trial in a larger patient population is indicated.

Aerosolized tobramycin in the treatment of ventilator-associated pneumonia: a pilot study.

OBJECTIVE: To evaluate the efficacy and safety of inhaled tobramycin (TOBI) in the treatment of ventilator-associated pneumonia (VAP) in a randomized, double-blind pilot study. PATIENTS AND METHODS: Ten patients from a cohort of 108 mechanically ventilated patients with documented clinical and bacteriological evidence of VAP caused by Pseudomonas aeruginosa or Acinetobacter spp. in the surgical and trauma intensive care units of a university teaching hospital were randomized to receive either TOBI (n = 5) or intravenous tobramycin (TOBRA; n = 5). The two groups were similar in their Acute Physiology and Chronic Health Evaluation (APACHE) score, Clinical Pulmonary Infection Score (CPIS), and Multiple Organ Dysfunction Score (MODS) prior to randomization. The primary outcome measure was resolution of pneumonia. The CPIS and MODS were used as objective indicators of clinical progress. RESULTS: All TOBI patients had clinical resolution of VAP. Two TOBRA patients were considered failures. One had deterioration in MODS, and the other had doubling of his serum creatinine concentration. The patients treated with TOBI may have had more ventilator-free days than those receiving TOBRA, but the difference was not statistically significant owing to the small sample size (24 +/- 3 vs. 14 +/- 13 days; p = 0.12). CONCLUSION: Aerosolized tobramycin for the treatment of VAP appeared safe and effective in this pilot study. A larger study is warranted to determine if aerosolized tobramycin will lead to better outcomes than intravenous tobramycin when used for the treatment of VAP.

Recent Advances in Forward Surgical Team Training at the U.S. Army Trauma Training Department.

U.S. Army Forward Surgical Teams (FSTs) are elite, multidisciplinary units that are highly mobile, and rapidly deployable. The mission of the FST is to provide resuscitative and damage control surgery for stabilization of life-threatening injuries in austere environments. The Army Trauma Training Center began in 2001 at the University of Miami Ryder Trauma Center under the direction of COL T. E. Knuth, MC USA (Ret.), as a multimodality combination of lectures, laboratory exercises, and clinical experiences that provided the only predeployment mass casualty and clinical trauma training center for all FSTs. Each of the subsequent five directors has restructured the training based on dynamic feedback from trainees, current military needs, and on the rapid advances in combat casualty care. We have highlighted these evolutionary changes at the Army Trauma Training Center in previous reviews. Under the current director, LTC J. M. Seery, MC USA, there are new team-building exercises, mobile learning modules and simulators, and other alternative methods in the mass casualty exercise. This report summarizes the latest updates to the state of the art training since the last review.

Magnetic resonance cholangiopancreatography accurately detects common bile duct stones in resolving gallstone pancreatitis.

BACKGROUND: There is controversy about the optimal method to detect common bile duct (CBD) stones in patients with mild resolving gallstone pancreatitis. The aim of this study was to evaluate magnetic resonance cholangiopancreatography (MRCP) in detecting choledocholithiasis in this group of patients. STUDY DESIGN: A prospective randomized trial was conducted. Patients randomized to group 1 (n = 34) underwent laparoscopic cholecystectomy (LC) and intraoperative cholangiography (IOC). Those randomized to group 2 (n = 29) had preoperative MRCP, of these, patients with negative MRCP underwent LC and IOC, patients with positive MRCP had preoperative ERCP followed by LC. RESULTS: Sixty-three patients were randomized (34 to group 1 and 29 to group 2). CBD stones were found in 5 patients in group 1. CBD exploration was performed in 2 patients, preoperative ERCP in 1, and postoperative ERCP in the other 2. MRCP showed CBD stones in 4 patients in group 2. There were two false-positive MRCPs. Four patients with a negative MRCP did not have IOC or ERCP, the remaining 21 patients with a negative MRCP had a negative IOC. The MRCP sensitivity was 100% (95% CI, 16-100%), specificity 91% (95% CI, 72-99%), positive predictive value 50% (95% CI, 7-93%), negative predictive value 100% (95% CI, 84-100%), and accuracy 92% (95% CI, 74-99%). CONCLUSIONS: Patients with resolving gallstone pancreatitis and a negative MRCP do not need preoperative ERCP or IOC. Only patients with a positive MRCP will require preoperative ERCP.

The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study.

BACKGROUND: Despite the large body of evidence suggesting a beneficial role of fever in the host response, antipyretic therapy is commonly employed for febrile critically ill patients. Our objective was to evaluate the impact of antipyretic therapy strategies on the outcomes of critically ill patients. METHODS: Patients admitted to the Trauma Intensive Care Unit over a nine-month period were eligible for inclusion, except those with traumatic brain injury. Patients were randomized on day three of the ICU stay into aggressive or permissive groups. The aggressive group received acetaminophen 650 mg every 6 h for temperature of >38.5 degrees C and a cooling blanket was added for temperature of >39.5 degrees C. The permissive group received no treatment for temperature of >38.5 degrees C, but instead had treatment initiated at temperature of >40 degrees C, at which time acetaminophen and cooling blankets were used until temperature was <40 degrees C. Patient demographics, daily temperatures, systemic inflammatory response syndrome (SIRS) scores, multiple organ dysfunction syndrome (MODS) scores, and infections and complications were recorded. RESULTS: Between December, 2002 and September, 2003, 572 patients were screened, of whom 82 met criteria for enrollment. Forty-four patients were randomized to the aggressive group and 38 patients were randomized to the permissive group for a total of 961 and 751 ICU days, respectively. There were 131 infections in the aggressive group and 85 infections in the permissive group (4 +/- 6 vs. 3 +/- 2 infections per patient, p = 0.26). There were seven deaths in the aggressive group and only one death in the permissive group (p = 0.06, Fisher Exact Test). The study was stopped after the first interim analysis due to the mortality difference, related to the issues of waiver of consent and the mandate for minimal risk. CONCLUSIONS: Aggressively treating fever in critically ill patients may lead to a higher mortality rate.

Coagulation Profile Changes Due to Thromboprophylaxis and Platelets in Trauma Patients at High-Risk for Venous Thromboembolism.

We hypothesize there are coagulation profile changes associated both with initiation of thromboporphylaxis (TPX) and with change in platelet levels in trauma patients at high-risk for venous thromboembolism (VTE). A total of 1203 trauma intensive care unit patients were screened with a VTE risk assessment profile. In all, 302 high-risk patients (risk assessment profile score ≥ 10) were consented for weekly thromboelastography. TPX was initiated between initial and follow-up thromboelastography. Seventy-four patients were analyzed. Upon admission, 87 per cent were hypercoagulable, and 81 per cent remained hypercoagulable by Day 7 (P = 0.504). TPX was initiated 3.4 ± 1.4 days after admission; 68 per cent received unfractionated heparin and 32 per cent received low-molecular-weight heparin. The VTE rate was 18 per cent, length of stay 38 (25-37) days, and mortality of 17.6 per cent. In all, 76 per cent had a rapid clotting time at admission versus 39 per cent at Day 7 (P < 0.001); correcting from 7.75 (6.45-8.90) minutes to 10.45 (7.90-15.25) minutes (P < 0.001). At admission, 41 per cent had an elevated maximum clot formation (MCF) and 85 per cent had at Day 7 (P < 0.001); increasing from 61(55-65) mm to 75(69-80) mm (P < 0.001). Platelets positively correlated with MCF at admission (r = 0.308, R(2) = 0.095, P = 0.008) and at Day 7 (r = 0.516, R(2) = 0.266, P < 0.001). Change in platelet levels correlated with change in MCF (r = 0.332, R(2) = 0.110, P = 0.005). In conclusion, hypercoagulability persists despite the use of TPX. Although clotting time normalizes, MCF increases in correlation with platelet levels. As platelet function is a dominant contributor to sustained trauma-evoked hypercoagulability, antiplatelet therapy may be indicated in the management of severely injured trauma patients.

Insertion of central venous catheters induces a hypercoagulable state.

BACKGROUND: Central venous catheters (CVCs) increase the risk of venous thromboembolism. We have previously demonstrated that pulmonary artery catheters are associated with a hypercoagulable state in an animal model and in patients. The purpose of this study is to determine whether the insertion of a CVC is associated with a similar response. ANIMAL: 7F femoral artery catheters were placed in healthy anesthetized swine (N = 16). Serial arterial blood samples were drawn immediately before and after an 8.5F jugular vein CVC and then for 3 hours after CVC removal. Samples were analyzed using kaolin-activated thromboelastography (TEG) at precisely 2 minutes. Human: An institutional review board-approved prospective observational trial was conducted, with informed consent, in patients with critical illness (N = 8) at a Level I trauma center. Blood was drawn from indwelling arterial catheters immediately before and 60 minutes after CVC insertion. Samples were stored in sodium citrate for 15 minutes before TEG. Routine and special coagulation tests were performed on stored samples in the hospital pathology laboratory. RESULTS: Insertion of a CVC decreased TEG clotting time (R) by 55% in swine and by 29% in humans (p < 0.001 and 0.019, respectively). Initial clot formation time (K) was reduced by 41% in swine and by 36% in humans (p = 0.003 and 0.019). Fibrin cross-linking (α) was accelerated by 28% in swine and by 17% in humans (p = 0.007 and 0.896), but overall clot strength (maximum amplitude) was not affected. There was no change in routine or special coagulation factors, including von Willebrand factor, antithrombin III, prothrombin time, international normalized ratio, or activated partial thromboplastin time. In animals, the hypercoagulable TEG response was persistent for 3 hours after CVC removal and was prevented by pretreatment with enoxaparin (n = 4) but not heparin (n = 2). CONCLUSION: In healthy swine and patients with critical illness, a systemic hypercoagulable state occurred after CVC insertion, and this may partially account for an increased risk of venous thromboembolism. However, because the sample size was small and not powered to detect changes in coagulation proteins, no inferences can be made about the mechanism for the hypercoagulable response.

First report on safety and efficacy of hetastarch solution for initial fluid resuscitation at a level 1 trauma center.

BACKGROUND: For logistics, the US Army recommends Hextend (Hospira; 6% hetastarch in buffered electrolyte, HET) for battlefield resuscitation. To support this practice, there are laboratory data, but none in humans. To test the hypothesis that HET is safe and effective in trauma, we reviewed our first 6 months of use at a civilian level 1 trauma center. STUDY DESIGN: From June 2008 to December 2008, trauma patients received standard of care (SOC) +/- 500 to 1,000 mL of HET within 2 hours of admission at surgeon discretion. Each case was reviewed, with waiver of consent. RESULTS: There were 1,714 admissions; 805 received HET and 909 did not. With HET versus SOC, overall mortality was 5.2% versus 8.9% (p = 0.0035) by univariate analysis. Results were similar after penetrating injury only (p = 0.0016) and in those with severe injury, defined by Glasgow Coma Scale <9 (p = 0.0013) or Injury Severity Score >26 (p = 0.0142). After HET, more patients required ICU admission (40.9% vs. 34.5%; p = 0.0334) and transfusions of blood (34.4% vs. 20.2%; p = 0.0014) or plasma (20.7% vs. 12.2%; p = 0.0251), but there were no treatment-related differences in prothrombin time or partial thromboplastin time. The 24-hour urine outputs and requirements for blood, plasma, and other fluids were similar. However, increased early deaths with SOC implicate possible selection bias. If that factor was controlled for with multivariate analysis, the same trends were present, but the apparent treatment effects of HET were no longer statistically significant. CONCLUSIONS: In the first trial to date in hemodynamically unstable trauma patients, and the largest trial to date in any population of surgical patients, initial resuscitation with HET was associated with reduced mortality and no obvious coagulopathy. A randomized blinded trial is necessary before these results can be accepted with confidence.