Hemodynamic Instability Secondary to Vasopressin Withdrawal in Septic Shock.

RATIONALE: Vasopressors such as norepinephrine are first line for support of mean arterial pressure (MAP) in the management of septic shock. Their use, however, is commonly associated with many adverse events. These detriments frequently trigger the use of alternative, noncatecholamine therapies, including vasopressin. Vasopressin deficiency is a known physiologic consequence of septic shock, and while guidelines recommend vasopressin in addition to norepinephrine, no consensus exists on the duration of deficiency or ideal time of cessation. Studies have suggested that vasopressin discontinuation prior to other vasopressors may lead to hypotension; however, data are limited. This study evaluates the optimal sequence for the discontinuation of vasopressin therapy in septic shock. METHODS: This was a 1-year retrospective study of 152 patients admitted to the medical intensive care unit (ICU) with septic shock who received concurrent norepinephrine and vasopressin for vasoactive support. Patients were excluded if death occurred on vasopressors, within 24 hours after discontinuation of vasopressors, or within 48 hours of ICU admission. The primary outcome of hemodynamic instability included incidence of hypotension after vasopressor discontinuation (2 consecutive MAPs < 60 mm Hg), fluid bolus administration, greater than 0.05 µg/kg/min increase in norepinephrine requirements, or addition of an alternative vasopressor. Secondary outcomes included time to hypotension, total vasopressor duration, arrhythmias, mortality, and length of stay. RESULTS: Ninety-one patients met exclusion criteria, resulting in 61 patients for evaluation. Vasopressin was the first vasoactive therapy to be discontinued in 19 patients and last in 42 patients. Baseline characteristics and the use of potentially confounding treatments known to effect MAP were similar between groups. Discontinuation of vasopressin first was associated with a significant increase in hemodynamic instability (74% vs 16.7%, P < .01), with a shorter time to hemodynamic instability (5 vs 15 hours, P < .01). Secondary outcomes were similar. CONCLUSION: Vasopressin discontinuation prior to cessation of norepinephrine infusion was associated with an increased risk of hemodynamic instability.

Fever Burden in Patients With Subarachnoid Hemorrhage and the Increased Use of Antibiotics.

BACKGROUND: Fever occurs in the majority of subarachnoid hemorrhage (SAH) patients. Nearly 50% of SAH patients have noninfectious fevers. Data are lacking describing the effects of fever burden in the SAH patient population. METHODS: This was a single-center, retrospective observational cohort study in patients more or equal to 18 years of age with a diagnosis of nontraumatic SAH admitted to an ICU between January 1, 2010 and September 1, 2015. Exclusion criteria were SAH secondary to trauma or admission for more than 48 hours. Temperature measurements, demographic data, and other pertinent information were collected from Day 0 to Day 13. Daily fever burden was calculated for each patient by calculating an area under the curve. RESULTS: A total of 194 subjects were included. The mean study period maximum temperature (Tmax) for all 194 patients was 40.8 ± 0.83°C. The mean overall fever burden for all 194 patients was 89.2 ± 99.59°C h more than 37°C. The overall fever burden peaked on day 5 and declined thereafter. Fever burden, Tmax, and length of stay in the hospital were all significantly associated with receipt of antibiotics. Only Tmax was associated with poor outcome. The 31 patients who had fever but no identified cause of infection received 1000 doses of antibiotics or 32.25 doses per patient. CONCLUSION: Fever is common in SAH patients and is associated with antibiotic use, infection, vasospasm, and poor outcome. Some SAH patients may receive antibiotics unnecessarily for noninfectious fever. Clinicians should consider using site-specific parameters related to infection rather than systemic symptoms such as fever to evaluate infection in SAH patients.

Insidious Harm of Medication Diluents as a Contributor to Cumulative Volume and Hyperchloremia: A Prospective, Open-Label, Sequential Period Pilot Study.

OBJECTIVES: Although the potential dangers of hyperchloremia from resuscitation fluids continue to emerge, no study to date has considered the contribution of medication diluents to cumulative volume and hyperchloremia. This study compares saline versus dextrose 5% in water as the primary medication diluent and the occurrence of hyperchloremia in critically ill patients. DESIGN: Prospective, open-label, sequential period pilot study. SETTING: Medical ICU of a large academic medical center. PATIENTS: Adult patients admitted to the medical ICU were eligible for inclusion. Patients who were admitted for less than 48 hours, less than 18 years old, pregnant, incarcerated, or who had brain injury were excluded. INTERVENTIONS: Saline as the primary medication diluent for 2 months followed by dextrose 5% in water as the primary medication diluent for 2 months. MEASUREMENTS AND MAIN RESULTS: A total of 426 patients were included, 216 in the saline group and 210 in the dextrose 5% in water group. Medication diluents accounted for 63% of the total IV volume over the observation period. In the saline group, 17.9% developed hyperchloremia compared with 10.5% in the dextrose 5% in water group (p = 0.037), which was statistically significant in multivariable analysis (odds ratio, 0.50; 95% CI, 0.26-0.94; p = 0.031). In the saline group, 34.2% developed acute kidney injury versus 24.5% in the dextrose 5% in water group (p = 0.035); however, this was not statistically significant when adjusting for baseline covariates. No other significant differences in dysnatremias, insulin requirements, glucose control, ICU length of stay, or ICU mortality were observed. CONCLUSIONS: This study identified that medication diluents contribute substantially to the total IV volume received by critically ill patients. Saline as the primary medication diluent compared with dextrose 5% in water is associated with hyperchloremia, a possible risk factor for acute kidney injury.

A critical role for eukaryotic elongation factor 1A-1 in lipotoxic cell death.

The deleterious consequences of fatty acid (FA) and neutral lipid accumulation in nonadipose tissues, such as the heart, contribute to the pathogenesis of type 2 diabetes. To elucidate mechanisms of FA-induced cell death, or lipotoxicity, we generated Chinese hamster ovary (CHO) cell mutants resistant to palmitate-induced death and isolated a clone with disruption of eukaryotic elongation factor (eEF) 1A-1. eEF1A-1 involvement in lipotoxicity was confirmed in H9c2 cardiomyoblasts, in which small interfering RNA-mediated knockdown also conferred palmitate resistance. In wild-type CHO and H9c2 cells, palmitate increased reactive oxygen species and induced endoplasmic reticulum (ER) stress, changes accompanied by increased eEF1A-1 expression. Disruption of eEF1A-1 expression rendered these cells resistant to hydrogen peroxide- and ER stress-induced death, indicating that eEF1A-1 plays a critical role in the cell death response to these stressors downstream of lipid overload. Disruption of eEF1A-1 also resulted in actin cytoskeleton defects under basal conditions and in response to palmitate, suggesting that eEF1A-1 mediates lipotoxic cell death, secondary to oxidative and ER stress, by regulating cytoskeletal changes critical for this process. Furthermore, our observations of oxidative stress, ER stress, and induction of eEF1A-1 expression in a mouse model of lipotoxic cardiomyopathy implicate this cellular response in the pathophysiology of metabolic disease.

Novel therapy for liver cancer: direct intraarterial injection of a potent inhibitor of ATP production.

Most types of cancer are difficult to eradicate and some, like liver carcinomas, are almost always fatal. Significantly, we report here that direct intraarterial delivery of 3-bromopyruvate (3-BrPA), a potent inhibitorof cell ATP production, to liver-implanted rabbit tumors, inflicts a rapid, lethal blow to most cancer cells therein. Moreover, systemic delivery of 3-BrPA suppresses "metastatic" tumors that arise in the lungs. In both cases, there is no apparent harm to other organs or to the animals. Thus, intraarterial delivery of agents like 3-BrPA directly to the site of the primary tumor, followed by systemic delivery only when necessary, may represent a powerful new strategy for arresting the growth of liver and other cancers while minimizing toxic side effects.

Student Outcomes Associated with an Interprofessional Program Incorporating TeamSTEPPS®.

BACKGROUND: Interprofessional education (IPE) of health professions students is a starting point for developing collaborative-practice-ready healthcare professionals, ultimately leading to improved patient care. The purpose of this study was to develop and evaluate a novel, foundational, IPE pilot program that incorporates TeamSTEPPS® for health professions students. METHODS: Students representing 13 different health professions programs participated in successive Level 1 and Level 2 "Foundations of Interprofessional Collaboration: Introduction to TeamSTEPPS®" half-day activities (n = 241). Students' satisfaction with the pilot program, changes in attitudes toward teamwork from before to after participation, TeamSTEPPS® knowledge acquisition, and anticipated future interprofessional collaboration-oriented behavior change were assessed through online surveys. RESULTS: Overall, students were highly satisfied with the pilot program and reported that learning from other professions was valuable. Statistically significant positive changes were noted in attitudes toward teamwork, most notably with the Level 1 pilot. Greater than 80% of students who completed the surveys demonstrated acquisition of TeamSTEPPS® knowledge. Students also reported feeling more prepared to collaborate interprofessionally in their future practice. CONCLUSION: This study demonstrated that the two-level foundational pilot program is feasible and had the intended effects with regards to moving health professions students toward becoming collaborative-practice-ready healthcare professionals.

Optimal contrast agents for vascular imaging on computed tomography: iodixanol versus iohexol.

RATIONALE AND OBJECTIVES: Dimeric nonionic iodinated contrast has a lower osmolality than monomeric nonionic iodinated contrast but is available at lower iodine concentrations. Less dilution of intravascular fluid by influx from the extravascular space is proposed to occur with decreasing osmolality. The purpose of this study was to determine if a dimeric nonionic iso-osmolar contrast agent (iodixanol) gives equal vascular enhancement compared with a monomeric nonionic hyperosmolar contrast agent (iohexol). MATERIALS AND METHODS: A dynamic single-level computed tomography (CT) scan was performed of the abdominal aorta of 12 sedated rabbits using a four-row multidetector CT scanner following injection of 1.5 mL contrast/kg body weight at 2 mL/sec. The rabbits were injected with the dimeric contrast agent iodixanol (Visipaque 320; Amersham Health) or the monomeric contrast agent iohexol (Omnipaque 350; Amersham Health). The order of the type of contrast media injected was randomized for each rabbit, and the interval between injections was 2 weeks. Using the 2.5-mm detectors, four contiguous 3-mm contrast-enhanced scans were obtained at a single level every 5 seconds for 120 seconds (total of 24 scans) with a kVp of 120, mA.s of 110, field of view of 106 mm, and soft tissue reconstruction algorithm. A single level was chosen to measure the attenuation of the abdominal aorta at 5-second intervals. The mean attenuation and standard deviation values were recorded for the whole aorta, for the central half of the vessel, and for the peripheral half of the vessel. A log-log transformation of the data was performed and regression analysis was done on the outcomes of interest (e.g., mean, standard deviation) on time for each region. RESULTS: There was no statistically significant difference in mean attenuation for the whole aorta for iodixanol and iohexol (P = .918) even though the iodine content was 9.3% less with the dimeric iodixanol. The time-attenuation curve of iodixanol paralleled that of iohexol for all time points. The mean attenuation values of the central half of the aorta (P = .354) and peripheral half of the aorta (P = .758) were also not statistically different for the two contrast agents. CONCLUSION: The vascular attenuation provided by a 9.3% lower iodine concentration of iso-osmolar iodixanol is equal to that given by hyperosmolar iohexol. This suggests that there is less intravascular dilution of iso-osmolar contrast. The enhancement across the cross section of the vessel is also similar for both contrast agents. This suggests the vascular studies with iodixanol and iohexol are of equal quality even when a lower dose of iodine is given with iodixanol. It is relevant for patients with borderline or diminished renal function in whom less volume of contrast may be administered.

Local intracerebral administration of Paclitaxel with the paclimer delivery system: toxicity study in a canine model.

INTRODUCTION: Paclitaxel, a microtubule binding agent with potent anti-glioma activity in vitro, exhibits poor penetrance to the CNS when delivered systemically. To minimize toxicity and reach therapeutic concentrations in the CNS, paclitaxel was previously incorporated into biodegradable microspheres (Paclimer), and the efficacy of Paclimer was determined in a rat model of malignant glioma. In this study we report the safety of intracranial Paclimer in a canine dose escalation toxicity study to prepare its translation into clinical scenarios. METHODS: Twelve normal beagle dogs underwent a right parieto-occipital craniectomy and were randomized to receive either Paclimer at 2-mg/kg (n=5), empty microspheres at 2-mg/kg (n=1), Paclimer at 20-mg/kg (n=5), or empty microspheres at 20-mg/kg (n=1). Post-operatively, dogs were observed daily for signs of neurotoxicity. Complete blood counts and plasma levels of paclitaxel were obtained weekly. CSF levels and MRI scans were obtained on days 14-120. Paclitaxel concentrations were quantified by LC-MS. RESULTS: Animals treated with 20-mg/kg Paclimer had minimal paclitaxel levels in plasma (range 0-7.84 ng/ml) and CSF (range 0-1.16 ng/ml). Animals treated with 2 mg/kg Paclimer had undetectable levels of paclitaxel in plasma, CSF was not obtained to minimize animal suffering. All animals exhibited normal behavior and weight gain, and were alive post-operatively through the last day of the study (day 60-120) without signs of neurological toxicity. There was no evidence of systemic toxicity or myelosuppression. MR imaging was comparable between Paclimer animals and controls. Adverse effects included wound infections and a brain abscess, all of which responded to antibiotic therapy, and one ventriculomegaly due to communicating hydrocephalus. CONCLUSIONS: Paclimer-based delivery of paclitaxel is safe for intraparenchymal delivery at the tested doses in normal dogs.

The endoscopic transilluminator: an endoscopic device for identification of the proximal jejunum for transgastric endoscopic gastrojejunostomy.

BACKGROUND: Localization of the proximal jejunum is important for creation of gastrojejunal anastomosis to palliate gastric outlet obstruction or for treatment of obesity with gastric bypass. OBJECTIVE: To facilitate identification of the proximal jejunum during transgastric endoscopic gastrojejunostomy with the use of an endoscopic transilluminator (ET). DESIGN AND SETTING: Acute experiments in a live porcine model. INTERVENTIONS: The ET is a 3500-mm long, 6F radio-opaque tube with a fiberoptic core that lights up at its distal end. When situated in the intestinal lumen, it transilluminates the bowel wall. With the animal under general anesthesia with endotracheal intubation, a colonoscope was advanced to the proximal jejunum. A plastic tube (3500-mm long, 3.5 mm in diameter) was passed through the biopsy channel and placed into the small bowel. The colonoscope was withdrawn, leaving the tube in place. The ET was introduced into the jejunum through the tube. A gastric wall incision was made and the endoscope was advanced to the peritoneal cavity. The transilluminated loop of the proximal jejunum was identified and gastrojejunal anastomosis was made by use of a previously reported endoscopic technique. MAIN OUTCOME MEASUREMENTS: Identification of the proximal jejunum. RESULTS: Eleven pigs (average weight 55 kg) had ET placement. In all of the pigs, placement of the ET was performed easily to the proximal small bowel, and the proximal jejunum was successfully localized by either direct visualization of the transilluminated loop only or with the aid of fluoroscopy. The tip of the ET was usually located about 50 to 70 cm distal to the ligament of Treitz. There were no complications related to the use of ET. LIMITATIONS: The device has not yet been evaluated in humans. CONCLUSIONS: The ET is a safe instrument and can be used to identify the proximal jejunum to facilitate endoscopic gastrojejunostomy.

Peroral transgastric endoscopic ligation of fallopian tubes with long-term survival in a porcine model.

BACKGROUND: We have previously reported the feasibility and safety of the peroral transgastric endoscopic approach for diagnostic peritoneoscopy, liver biopsy, and gastrojejunostomy with long-term survival in a porcine model. This approach eliminates incisions of the abdominal wall, providing a less invasive alternative to diagnostic and therapeutic laparoscopy. We now report successful performance of peroral endoscopic transgastric ligation of Fallopian tubes with long-term survival in a porcine model. METHODS: Six female 50-kg pigs had general anesthesia and irrigation of the stomach with an antibiotic solution. Gastric puncture was performed with needleknife electrocautery followed by balloon dilatation of the tract with 20-mm TTS dilating balloon (Microvasive). A standard upper endoscope that underwent high-level disinfection and gas sterilzation was advanced into the peritoneal cavity through a sterile overtube. Both Fallopian tubes were identified and one was ligated using Olympus Endoloops. The other patent tube served as a control. Tubal patency was evaluated by hysterosalpingogram before and after ligation. After a follow-up period of 2-3 weeks, the pigs were sacrificed for postmortem examination. RESULTS: The Fallopian tubes were easily accessed, identified and ligated in all 6 pigs. In each pig, fluoroscopy confirmed complete obstruction of the ligated tube with preserved patency of the other tube. All pigs survived well and ate heartily without any ill-effects. Postmortem examination did not reveal any peritonitis or intra-abdominal adhesions. The Endoloops were in place with complete obstruction of the ligated tubes and patency of the controls. Histopathologic examination of the tubes showed chronic inflammatory infiltrates without abscesses. CONCLUSIONS: The peroral endoscopic transgastric approach to ligation of the Fallopian tubes with long-term survival is technically feasible and safe in a porcine model. The endoscopic transgastric approach to the peritoneal cavity has potential for a wide array of diagnostic and therapeutic procedures.

Endoscopic gastrojejunostomy with survival in a porcine model.

BACKGROUND: We have previously reported the feasibility and the safety of an endoscopic transgastric approach to the peritoneal cavity in a porcine model. We now report successful performance of endoscopic gastrojejunostomy with survival. METHODS: All procedures were performed on 50-kg pigs, with the pigs under general anesthesia, in aseptic conditions with sterilized endoscopes and accessories. The stomach was irrigated with antibiotic solution, and a gastric incision was performed with a needle-knife and a sphincterotome. A standard upper endoscope was advanced through a sterile overtube into the peritoneal cavity. A loop of jejunum was identified, was retracted into the stomach, and was secured with sutures while using a prototype endoscopic suturing device. An incision was made into the jejunal loop with a needle-knife, and the filet-opened ends of the jejunal wall were secured to the gastric wall with a second line of sutures, completing the gastrojejunostomy. OBSERVATIONS: Two pigs survived for 2 weeks. Endoscopy and a radiographic contrast study performed after gastrojejunostomy revealed a patent anastomosis with normal-appearing gastric and jejunal mucosa. Postmortem examination demonstrated a well-healed anastomosis without infection or adhesions. CONCLUSIONS: The endoscopic transgastric approach to create a gastrojejunostomy is technically feasible and can be performed, with survival, in a porcine model.

Intrasphincteric nitric oxide reduces sphincter of Oddi motility in an endoscopic porcine model.

Nitric oxide (NO), a potent nonadrenergic, noncholinergic mediator of gastrointestinal smooth muscle, causes relaxation of the category I pump like sphincter of Oddi (SO) (eg, opossum, rabbit) and category II resistor like SO (eg, pig, human). Topical administration of a NO donor induces SO relaxation in humans, and parenteral administration of sodium nitroprusside (SNP) decreases sphincter contractility in pig SO. The aim of this study is to evaluate the effect of intrasphincteric SNP injection on pig SO. Under general anesthesia, two pigs received intrasphincteric saline injection (1 ml) and six pigs received intrasphincteric SNP (0.5 microg/ml) injection into the SO. All injections were administered into the major papilla using a 5-mm sclerotherapy needle through the duodenoscope. Endoscopic biliary manometry was performed using the standard station pull-through technique and SO pressures were recorded before and after injection. Intrasphincteric saline injection did not significantly change the mean SO motility index (MI) (197 vs 198). However, intrasphincteric SNP reduced both the mean SO basal pressure (P = 0.002) and the mean SO MI (226 vs 109; P = 0.002). The effect of intrasphincteric SNP lasted up to 45 min and did not cause significant lowering of systemic blood pressure. This is the first study to demonstrate that intrasphincteric SNP results in significant reduction in both SO basal pressure and SO MI in the porcine model. The endoscopic intrasphincteric administration of NO donor drugs is technically feasible and without observed systemic side effects.

Experimental evaluation of a new transcatheter vascular embolization device in the swine model.

PURPOSE: To evaluate a new transcatheter device suitable for arterial embolization in an animal model. MATERIALS AND METHODS: A new prototype self-expanding braided embolic device (Embolizor), consisting of nitinol wire strands fixed at either end with platinum-iridium bands and covered with a film of polyethylene, was deployed through 5-F diagnostic catheters into renal artery branches in five swine. Standard stainless-steel spring coils were deployed in other renal branches and served as controls. The animals underwent follow-up selective renal arteriography to determine presence or absence of vessel recanalization or device migration 15-23 days after device deployment. Histopathologic evaluation of target vessels and peripheral renal parenchyma was also performed. RESULTS: Ten Embolizors and 10 stainless-steel coils were deployed in arteries ranging in size from 1.8 to 3.0 mm in diameter. The Embolizor was easily and precisely deployed. Angiographic evidence of vascular occlusion in the Embolizor group was noted within 30 seconds in eight device deployments and within 5 minutes in two. No early or delayed device migration was noted on follow-up arteriography. In the control group, seven of 10 previously occluded arteries were recanalized. No recanalization was noted in the Embolizor group. Light microscopy revealed evidence of infarction in all specimens examined. Whereas three specimens in the Embolizor group contained occasional giant cells, there were numerous multinucleated giant cells present within the interstices of all control spring coils. CONCLUSION: The Embolizor was easily, precisely, and successfully deployed through standard selective diagnostic angiographic catheters. Short-term follow-up demonstrated no recanalization or migration of the device. The Embolizor was shown on histopathologic analysis to have no significant foreign body reaction.

Flexible transgastric peritoneoscopy: a novel approach to diagnostic and therapeutic interventions in the peritoneal cavity.

BACKGROUND: A novel endoscopic peroral transgastric approach to the peritoneal cavity was tested in a porcine model in acute and long-term survival experiments. METHODS: Transgastric peritoneoscopy was evaluated in 50-kg pigs. After upper endoscopy, the peritoneal cavity was accessed by needle-knife puncture of the gastric wall, followed by extension of the incision either with a pull-type sphincterotome or by balloon dilation. The peritoneal cavity was examined, and a liver biopsy specimen was obtained. The gastric wall incision was closed with clips. OBSERVATIONS: Twelve acute and 5 survival experiments were performed. Both techniques of gastric wall incision were without complication. The acute experiments demonstrated the technical feasibility of the approach. In the survival experiments, all pigs recovered and gained weight. CONCLUSIONS: The peroral transgastric approach to peritoneal cavity technically is feasible and has the potential to be an alternative to laparoscopy and laparotomy.

Calcineurin and calcium/calmodulin-dependent protein kinase activate distinct metabolic gene regulatory programs in cardiac muscle.

To learn more about the targets of Cn (Cn) and calcium/calmodulin-dependent protein kinase in cardiac muscle, we investigated their actions in cultured cardiac myocytes and the hearts of mice in vivo. Adenoviral-mediated expression of constitutively active forms of either pathway induced expression of peroxisome proliferator-activated receptor gamma coactivator 1alpha, a transcriptional coactivator involved in the control of multiple cellular energy metabolic pathways in cardiac myocytes. Transcriptional profiling studies demonstrated that Cn and calcium/calmodulin-dependent protein kinase activate distinct but overlapping metabolic gene regulatory programs. Expression of the nuclear receptor, peroxisome proliferator-activated receptor alpha, was markedly increased by Cn, but not calcium/calmodulin-dependent protein kinase, providing one mechanism whereby cellular fatty acid utilization genes are selectively activated by Cn. Transfection experiments demonstrated that Cn directly activates the mouse peroxisome proliferator-activated receptor alpha gene promoter. Co-transfection "add-back" experiments demonstrated that the transcription factors, myocyte enhancer factors 2C or 2D, were sufficient to confer Cn-mediated activation of the peroxisome proliferator-activated receptor alpha gene. Cn was also shown to directly activate a known peroxisome proliferator-activated receptor alpha target, muscle-type carnitine palmitoyltransferase I, providing a second mechanism by which Cn activates genes of cellular fatty acid utilization. Lastly, the gene expression of peroxisome proliferator-activated receptor gamma coactivator 1alpha and peroxisome proliferator-activated receptor alpha was reduced in the hearts of mice with cardiac-specific ablation of the Cn regulatory subunit. These data support a role for calcium-triggered signaling pathways in the regulation of cardiac energetics and identify pathway-specific control of metabolic targets.