ABSTRACT
Sustained high-efficiency daily diafiltration using a mediator-adsorbing membrane (SHEDD-fA) is an effective, intensive modality for sepsis treatment. Here we describe the effectiveness of SHEDD-fA, which makes the best use of three principles: dialysis, filtration and adsorption, for mediator removal in the treatment of severe sepsis. SHEDD-fA was initiated after adequate fluid resuscitation and catecholamine support had been provided. A large (2.1 m(2)) polymethylmethacrylate membrane dialyzer was placed in the blood circuit. Operation conditions were as follows: blood flow rate 150 ml/min, filtration rate 1,500 ml/h (post-dilution), and dialysate flow rate 300-500 ml/min over 8-12 h daily. 55 consecutive patients with severe sepsis were studied. The following results were obtained: pressure catecholamine index significantly decreased at 3 h after initiation of septic shock, PaO(2)/F(IO2) significantly increased at 1 h after initiation of septic acute respiratory distress syndrome, a significant decrease in interleukin (IL)-6 level for 3 days was observed, and IL-6 was effectively adsorbed in one pass through the filter. The average sequential organ failure assessment score of patients was 10.1 and the mortality at 28 days was 16.4% (46 survived, 9 died). Because SHEDD-fA is an intensive and high-efficiency modality, removal of useful drugs or nutrients may be observed. Despite the fact that removal of useful substances cannot be ignored, we believe that an appropriate stage or timing can be identified so that we can avoid a vicious cycle and use blood purification with effective diffusion, filtration and adsorption. We demonstrate that SHEDD-fA may be an effective, intensive modality for the treatment of patients with severe sepsis and is a possible modality for cytokine modulation therapy.
Subject(s)
Hemodiafiltration/methods , Inflammation Mediators/blood , Membranes, Artificial , Polymethyl Methacrylate , Systemic Inflammatory Response Syndrome/therapy , Acute Kidney Injury/blood , Acute Kidney Injury/etiology , Acute Kidney Injury/therapy , Adsorption , Aged , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/therapeutic use , Catecholamines/classification , Catecholamines/therapeutic use , Combined Modality Therapy , Critical Care , Female , Fluid Therapy , HLA-DR Antigens/analysis , Hemodiafiltration/instrumentation , Humans , Interleukin-6/blood , Male , Middle Aged , Multiple Organ Failure/blood , Multiple Organ Failure/etiology , Multiple Organ Failure/therapy , Oxygen/blood , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/therapy , Retrospective Studies , Shock, Septic/blood , Shock, Septic/etiology , Shock, Septic/therapy , Survival Rate , Systemic Inflammatory Response Syndrome/blood , Systemic Inflammatory Response Syndrome/complications , Systemic Inflammatory Response Syndrome/drug therapy , Treatment OutcomeABSTRACT
RATIONALE: Serotonin transporter (SERT) knockout (-/-) mice have an altered phenotype in adulthood, including high baseline anxiety and depressive-like behaviors, associated with increased baseline extracellular serotonin levels throughout life. OBJECTIVES: To examine the effects of increases in serotonin following the administration of the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) in SERT wild-type (+/+), heterozygous (+/-), and -/- mice. RESULTS: 5-HTP increased serotonin in all five brain areas examined with approximately 2- to 5-fold increases in SERT+/+ and +/- mice, and with greater 4.5- to 11.7-fold increases in SERT-/- mice. Behaviorally, 5-HTP induced exaggerated serotonin syndrome behaviors in SERT-/-, mice with similar effects in male and female mice. Studies suggest promiscuous serotonin uptake by the dopamine transporter (DAT) in SERT-/- mice, and here, the DAT blocker GBR 12909 enhanced 5-HTP-induced behaviors in SERT-/- mice. Physiologically, 5-HTP induced exaggerated temperature effects in SERT-deficient mice. The 5-HT1A antagonist WAY 100635 decreased 5-HTP-induced hypothermia in SERT+/+ and +/- mice with no effect in SERT-/- mice, whereas the 5-HT7 antagonist SB 269970 decreased this exaggerated response in SERT-/- mice only. WAY 100635 and SB 269970 together completely blocked 5-HTP-induced hypothermia in SERT+/- and -/- mice. CONCLUSIONS: These studies demonstrate that SERT-/- mice have exaggerated neurochemical, behavioral, and physiological responses to further increases in serotonin, and provide the first evidence of intact 5-HT7 receptor function in SERT-/- mice, with interesting interactions between 5-HT1A and 5-HT7 receptors. As roles for 5-HT7 receptors in anxiety and depression were recently established, the current findings have implications for understanding the high anxiety and depressive-like phenotype of SERT-deficient mice.
Subject(s)
Brain Chemistry/drug effects , Serotonin Plasma Membrane Transport Proteins/deficiency , Serotonin/metabolism , 5-Hydroxytryptophan/pharmacology , 8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology , Animals , Brain/anatomy & histology , Brain/drug effects , Brain/metabolism , Catecholamines/antagonists & inhibitors , Catecholamines/classification , Clorgyline/pharmacology , Dopamine Uptake Inhibitors/pharmacology , Drug Synergism , Drug Therapy, Combination , Female , Hydroxyindoleacetic Acid/analysis , Hydroxyindoleacetic Acid/metabolism , Hypothermia/chemically induced , Male , Mice , Mice, Knockout , Monoamine Oxidase Inhibitors/pharmacology , Phenols/pharmacology , Piperazines/pharmacology , Piperazines/toxicity , Pyridines/pharmacology , Serotonin/analogs & derivatives , Serotonin/pharmacology , Serotonin 5-HT1 Receptor Antagonists , Serotonin Plasma Membrane Transport Proteins/genetics , Serotonin Receptor Agonists/pharmacology , Serotonin Syndrome/chemically induced , Sulfonamides/pharmacology , Tranylcypromine/pharmacologyABSTRACT
OBJECTIVES: Women with breast cancer are at risk for elevated depression, anxiety, and decreased natural killer (NK) cell number. Stress has been linked to increased tumor development by decreasing NK cell activity. The objectives of this study included examining massage therapy for women with breast cancer for (1) improving mood and biological measures associated with mood enhancement (serotonin, dopamine), (2) reducing stress and stress hormone levels, and (3) boosting immune measures. METHODS: Thirty-four women (M age=53) diagnosed with Stage 1 or 2 breast cancer were randomly assigned postsurgery to a massage therapy group (to receive 30-min massages three times per week for 5 weeks) or a control group. The massage consisted of stroking, squeezing, and stretching techniques to the head, arms, legs/feet, and back. On the first and last day of the study, the women were assessed on (1) immediate effects measures of anxiety, depressed mood, and vigor and (2) longer term effects on depression, anxiety and hostility, functioning, body image, and avoidant versus intrusive coping style, in addition to urinary catecholamines (norepinephrine, epinephrine, and dopamine) and serotonin levels. A subset of 27 women (n=15 massage) had blood drawn to assay immune measures. RESULTS: The immediate massage therapy effects included reduced anxiety, depressed mood, and anger. The longer term massage effects included reduced depression and hostility and increased urinary dopamine, serotonin values, NK cell number, and lymphocytes. CONCLUSIONS: Women with Stage 1 and 2 breast cancer may benefit from thrice-weekly massage therapy for reducing depressed mood, anxiety, and anger and for enhancing dopamine, serotonin, and NK cell number and lymphocytes.
Subject(s)
Affect/physiology , Anxiety , Breast Neoplasms , Catecholamines/urine , Depression , Dopamine/metabolism , Killer Cells, Natural/immunology , Lymphocytes/metabolism , Massage/methods , Serotonin/metabolism , Anxiety/immunology , Anxiety/metabolism , Anxiety/therapy , Breast Neoplasms/immunology , Breast Neoplasms/metabolism , Breast Neoplasms/surgery , Catecholamines/classification , Depression/immunology , Depression/metabolism , Depression/therapy , Female , Humans , Middle Aged , Neoplasm Staging , Postoperative PeriodABSTRACT
Splanchnic ischemia is frequent in sepsis and septic shock and is related to impairment in intestinal permeability, derangement in mucosal barrier functions and translocation of proinflammatory mediators. These changes can contribute to the pathogenesis of multiple organ failure. Vasoactive drugs such as dobutamine and dopexamine can improve splanchnic perfusion and gastric intramucosal pH during sepsis. However, contradictory results have been obtained with dopamine and norepinephrine. On the other hand, epinephrine further impairs splanchnic perfusion. In view of the contradictory effects of different vasoactive drugs, gastric tonometry must be measured during their use, to find the optimal drug combination that optimizes splanchnic blood flow
