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BACKGROUND Optimal resuscitation of hypotensive trauma patients has not been defined. This trial was performed to assess the feasibility and safety of controlled resuscitation (CR) versus standard resuscitation (SR) in hypotensive trauma patients. METHODS Patients were enrolled and randomized in the out-of-hospital setting. 19 EMS systems in the Resuscitation Outcome Consortium participated. Eligible patients had an out-of-hospital systolic blood pressure (SBP) ≤ 90 mmHg. CR patients received 250 cc of fluid if they had no radial pulse or a SBP < 70 mmHg and additional 250 cc boluses to maintain a radial pulse or a SBP ≥ 70 mmHg. SR group patients received 2 liters initially and additional fluid as needed to maintain a SBP ≥ 110 mmHg. The crystalloid protocol was maintained until hemorrhage control or 2 hours after hospital arrival. RESULTS 192 patients were randomized (97 CR and 95 SR). The CR and SR groups were similar at baseline. Average crystalloid volume administered during the study period was 1.0 liter (SD 1.5) in the CR group and 2.0 liters (SD 1.4) in the SR group, a difference of 1.0 liter (95% CI: 0.6 to 1.4). ICU-free days, ventilator-free days, renal injury and renal failure did not differ between groups. At 24 hours after admission, there were 5 deaths (5%) in the CR group and 14 (15%) in the SR group (adjusted odds ratio 0.39 [95% CI: 0.12, 1.26]). Among patients with blunt trauma, 24-hour mortality was 3% (CR) and 18% (SR) with an adjusted OR of 0.17 (0.03, 0.92). There was no difference among patients with penetrating trauma: 9% vs 9%, adjusted OR 1.93 (0.19, 19.17). CONCLUSION Controlled resuscitation is achievable in out-of-hospital and hospital settings and may offer an early survival advantage in blunt trauma. A large-scale, Phase III trial to examine its effects on survival and other clinical outcomes is warranted.

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Background Altered coagulation function after trauma may contribute to venous thromboembolism (VTE) development. Severe trauma impairs coagulation function, but the trajectory for recovery is not known. We hypothesized that enhanced, early recovery of coagulation function increases VTE risk in severely-injured trauma patients. Study Design Secondary analysis was performed on data from The Pragmatic Randomized Optimal Platelet and Plasma Ratio (PROPPR) trial, excluding patients who died within 24 hours and/or were on pre-injury anticoagulants. Patient characteristics, adverse outcomes, and parameters of platelet function (PF) and coagulation (thromboelastography; TEG) were compared from admission to 72 hours between VTE (n=83) and non-VTE (n=475) patients. p<0.05 indicated significance. Results Despite similar patient demographics, VTE patients exhibited hypercoagulable TEG parameters and enhanced PF at admission (p<0.05). Both groups exhibited hypocoagulable TEG parameters, platelet dysfunction and suppressed clot lysis (low LY30) 2HR following admission (p<0.05). VTE patients exhibited delayed coagulation recovery (a significant change compared to 2HR) of K (48 vs 24HR), α-angle (no recovery), MA (24 vs 12HR) and LY30 (48hrs vs 12HR). PF recovery mediated by arachidonic acid (72 vs 4HR), adensine-5’-diphosphate (72 vs 12HR), and collagen (48 vs 12HR) were delayed in VTE patients. VTE patients had lower mortality (4% vs 13%, p<0.05), but less hospital free days (0 (0–8) vs 10 (0–20), p<0.05) and higher complication rates (p<0.05). Conclusion Recovery from platelet dysfunction and coagulopathy following severe trauma were delayed in VTE patients. Suppressed clot lysis and compensatory mechanisms associated with altered coagulation that may potentiate VTE formation require further investigation.

Tacrolimus is a widely used immunosuppressive drug that inhibits the phosphatase calcineurin when bound to the 12 kDa FK506-binding protein (FKBP12). When this binding occurs in T cells, it leads to immunosuppression. Tacrolimus also causes side effects, however, such as hypertension and hyperkalemia. Previously, we reported that tacrolimus stimulates the renal thiazide-sensitive sodium chloride cotransporter (NCC), which is necessary for the development of hypertension. However, it was unclear if tacrolimus-induced hypertension resulted from tacrolimus effects in renal epithelial cells directly or in extrarenal tissues, and whether inhibition of calcineurin was required. To address these questions, we developed a mouse model in which FKBP12 could be deleted along the nephron. FKBP12 disruption alone did not cause phenotypic effects. When treated with tacrolimus, however, BP and the renal abundance of phosphorylated NCC were lower in mice lacking FKBP12 along the nephron than in control mice. Mice lacking FKBP12 along the nephron also maintained a normal relationship between plasma potassium levels and the abundance of phosphorylated NCC with tacrolimus treatment. In cultured cells, tacrolimus inhibited dephosphorylation of NCC. Together, these results suggest that tacrolimus causes hypertension predominantly by inhibiting calcineurin directly in cells expressing NCC, indicating thiazide diuretics may be particularly effective for lowering BP in tacrolimus-treated patients with hypertension. 27: 145627: -146427: , 201627: . doi: 10.1681 Tacrolimus, a widely prescribed calcineurin inhibitor, is an immunosuppressive drug often used to prevent the rejection of transplanted organs. 1 Its use, however, is frequently complicated by side effects, including hypertension, hyperkalemia, and CKD. 2 We reported previously that tacrolimus causes hypertension and increases the abundance of the phosphorylated, active, form of the renal sodium chloride cotransporter (NCC) in mice. We showed that NCC activity is essential for the full development of hypertension, and confirmed that tacrolimus increases the abundance of phosphorylated NCC (pNCC) in humans. 3 The molecular mechanisms, however, remain largely unknown. J Am Soc NephrolTo inhibit calcineurin, a serine/threonine phosphatase, tacrolimus must bind to an endogenous protein, the 12 kDa FK506-binding protein (FKBP12). 4 When this occurs in T cells, cytokine production is inhibited and it results in immunosuppression.

McCully BH, Brooks VL, Andresen MC. Diet-induced obesity severely impairs myelinated aortic baroreceptor reflex responses. Am J Physiol Heart Circ Physiol 302: H2083-H2091, 2012. First published March 9, 2012; doi:10.1152/ajpheart.01200.2011.-Diet-induced obesity (DIO) attenuates the arterial cardiac baroreceptor reflex, but the mechanisms and sites of action are unknown. This study tested the hypothesis that DIO impairs central aortic baroreceptor pathways. Normal chow control (CON) and high-fat-chow obesity-resistant (OR) and obesity-prone (OP) rats were anesthetized (inactin, 120 mg/kg) and underwent sinoaortic denervation. The central end of the aortic depressor nerve (ADN) was electrically stimulated to generate frequency-dependent baroreflex curves (5-100 Hz) during selective activation of myelinated (A-fiber) or combined (A-and C-fiber) ADN baroreceptors. A mild stimulus (1 V) that activates only A-fiber ADN baroreceptors induced robust, frequency-dependent depressor and bradycardic responses in CON and OR rats, but these responses were completely abolished in OP rats. Maximal activation of A fibers (3 V) elicited frequency-dependent reflexes in all groups, but a dramatic deficit was still present in OP rats. Activation of all ADN baroreceptors (20 V) evoked even larger reflex responses. Depressor responses were nearly identical among groups, but OP rats still exhibited attenuated bradycardia. In separate groups of rats, the reduced heart rate (HR) response to maximal activation of ADN A fibers (3 V) persisted in OP rats following pharmacological blockade of ␤1-adrenergic or muscarinic receptors, suggesting deficits in both parasympathetic nervous system (PNS) and sympathetic nervous system (SNS) reflex pathways. However, the bradycardic responses to direct efferent vagal stimulation were similar among groups. Taken together, our data suggest that DIO severely impairs the central processing of myelinated aortic baroreceptor control of HR, including both PNS and SNS components. obesity; autonomic nervous system; arterial baroreflex OBESITY IS ASSOCIATED WITH multisystem morbidity, including endocrine, immune, and autonomic manifestations (3,8,28), such as impairment of the baroreceptor reflex pathways. The depression of baroreceptor reflex sensitivity during weight gain in humans (4, 21) is replicated in animal models of obesity (9,24,25,39,40). Furthermore, the restoration of baroreflex function with weight loss suggests a dynamic interrelationship between diet, metabolic status, and cardiovascular autonomic control (4,21,41,42). Obesity not only increases sympathetic outflow (SNS) to muscle (1, 21) and kidneys (45), but it also decreases cardiac parasympathetic (PNS) drive (6, 36). Because a depressed cardiac PNS baroreflex is an important predictor of cardiac morbidity and mortality (29), independent of blood pressure changes, the mechanisms responsible for baroreflex modification during obesity are critical to understand.Changes in arterial pressure are transmitted via the arterial baroreceptors to the...

Obesity decreases baroreflex gain (BRG); however, the mechanisms are unknown. We tested the hypothesis that impaired BRG is related to the concurrent insulin resistance, and, therefore, BRG would be improved after treatment with the insulinsensitizing drug rosiglitazone. Male rats fed a high-fat diet diverged into obesity-prone (OP) and obesity-resistant (OR) groups after 2 weeks. Then, OP and OR rats, as well as control (CON) rats fed a standard diet, were treated daily for 2 to 3 weeks with rosiglitazone (3 or 6 mg/kg) or its vehicle by gavage. Compared with OR and CON rats, conscious OP rats exhibited reductions in BRG (OP, 2.9 Ϯ 0.1 bpm/mm Hg; OR, 4.0 Ϯ 0.2 bpm/mm Hg; CON, 3.9 Ϯ 0.2 bpm/mm Hg; P Ͻ 0.05) and insulin sensitivity (hyperinsulinemic euglycemic clamp; OP, 6.8 Ϯ 0.9 mg/kg ⅐ min; OR, 22.2 Ϯ 1.2 mg/kg ⅐ min; CON, 17.7 Ϯ 0.8 mg/kg ⅐ min; P Ͻ 0.05), which were well correlated (r 2 ϭ 0.49; P Ͻ 0.01). In OP rats, rosiglitazone dose-dependently improved (P Ͻ 0.05) insulin sensitivity (12.8 Ϯ 0.6 mg/kg ⅐ min at 3 mg/kg; 16.0 Ϯ 1.5 mg/kg ⅐ min at 6 mg/kg) and BRG (3.8 Ϯ 0.4 bpm/mm Hg at 3 mg/kg; 5.3 Ϯ 0.7 bpm/mm Hg at 6 mg/kg). However, 6 mg/kg rosiglitazone also increased BRG in OR rats without increasing insulin sensitivity, disrupted the correlation between BRG and insulin sensitivity (r 2 ϭ 0.08), and, in OP and OR rats, elevated BRG relative to insulin sensitivity (analysis of covariance; P Ͻ 0.05). Moreover, in OP rats, stimulation of the aortic depressor nerve, to activate central baroreflex pathways, elicited markedly reduced decreases in heart rate and arterial pressure, but these responses were not improved by rosiglitazone. In conclusion, diet-induced obesity impairs BRG via a central mechanism that is related to the concurrent insulin resistance. Rosiglitazone normalizes BRG, but not by improving brain baroreflex processing or insulin sensitivity.

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