[Treatment of sepsis with antibiotics].
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Biomedical subjects
Publications and source records attributed to T Ziegenfuss.
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We studied the effects of oral treatment with extracts from Rhodiola rosea (50 mg/kg) and Rhodiola crenulata (50 mg/kg) roots on the duration of exhaustive swimming and ATP content in mitochondria of skeletal muscles in rats. Treatment with R. rosea extract significantly (by 24.6%) prolonged the duration of exhaustive swimming in comparison with control rats and rats treated with R. crenullata. R. rosea extract activated the synthesis or resynthesis of ATP in mitochondria and stimulated reparative energy processes after intense exercise. Experiments proved different pharmacological characteristics of R. rosea and R. crenulata: R. rosea is most effective for improving physical working capacity.
BACKGROUND AND OBJECTIVE: This prospective, randomized, double-blinded study was designed to compare the effects of remifentanil or fentanyl on anaesthetic induction characteristics of propofol, thiopental or etomidate. METHODS: Seventy-two patients were enrolled in six groups of 12 individuals each. In three groups, fentanyl was given as a bolus dose of 1.5 microg kg(-1), whereas the others received a remifentanil infusion at 0.5 microg kg(-1) min(-1). Five minutes later, propofol, thiopental or etomidate were titrated to a state of unresponsiveness. Assessment included the amounts of drug necessary for induction, haemodynamics and the times to apnoea, loss of eyelash reflex, and the release of a water-filled syringe held in the patient's hand. RESULTS: Induction times to loss of the eyelash reflex were significantly shorter in the remifentanil than in the fentanyl groups: with propofol 50.7 +/- 13.6s (mean +/- SD) versus 74.9 +/- 27.0s (P < 0.01), with thiopental 42.9 +/- 16.8s versus 77.2 +/- 27.8s (P < 0.01) and with etomidate 54.7 +/- 17.6s versus 72.3 +/- 24.0s (P < 0.05). The times to respiratory arrest or for the syringe to fall were significantly shorter with remifentanil than with fentanyl for propofol and for thiopental, but not for etomidate. In terms of dosages per kg body weight necessary to achieve unresponsiveness, less propofol (-29%, P < 0.05), thiopental (-25%, P < 0.05) or etomidate (-32%, P < 0.01) was necessary with remifentanil than with fentanyl. Haemodynamic responses to tracheal intubation were controlled more effectively with remifentanil. However, within the remifentanil groups, mean arterial pressure significantly decreased during induction: -26% with propofol, -181% with thiopental and -14% with etomidate (all P < 0.01). CONCLUSIONS: During anaesthetic induction, a remifentanil infusion of 0.5 microg kg(-1) min(-1) over 5 min is a suitable alternative to a 1.5 microg kg(-1) bolus dose of fentanyl: induction times are shorter with reduced amounts of propofol, thiopental or etomidate.
OBJECTIVE: To evaluate the effects of prophylactic veno-venous hemofiltration (CVVH) in the absence of renal failure on multiple organ dysfunction syndrome after severe multiple trauma. DESIGN: Prospective, randomized study. SETTING: Intensive care unit (ICU) in a university hospital. PATIENTS: Twenty-four patients with severe multiple trauma (injury severity score > or = 27), no renal failure on admission and no contraindication for moderate heparinization. INTERVENTIONS: Twelve patients received conventional treatment while 12 patients were treated additionally with isovolemic CVVH for 5 days starting within 24 h following trauma. Signs of organ dysfunction were assessed daily including monitoring of systemic hemodynamic by means of pulmonary artery catheterization during the first 5 days after trauma. MEASUREMENTS AND MAIN RESULTS: Prophylactic CVVH did not affect the overall severity of organ dysfunction as assessed by MOF or APACHE II scores. However, the pattern of impaired organ systems was influenced by CVVH: while the post-traumatic decrease in platelet count in patients subjected to CVVH was more pronounced than in controls (e.g. day 4: control: 115,080 +/- 15,087, CVVH: 57,383 +/- 4,201 microliters-1; p < 0.05) the development of hyperdynamic circulatory failure was simultaneously attenuated, as reflected by a limited increased in cardiac output and an attenuated decrease in systemic vascular resistance and oxygen extraction ratio (e.g. systemic vascular resistance on day 4: control: 624.3 +/- 46.17, CVVH: 842.7 +/- 79.24 dyn.s.cm-5; p < 0.005). CONCLUSION: CVVH blunts the cardiovascular response to multiple trauma and increases tissue oxygen extraction. However, the concomitant decrease in platelet counts represents a limitation for the use of prophylactic CVVH in surgical patients.
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BACKGROUND: Rocuronium is a non-depolarising neuromuscular blocking agent structurally related to vecuronium. The compound has a rapid onset and an intermediate duration of action. The rapid onset is of importance in patients at risk for pulmonary aspiration, for elective induction of anaesthesia slower onset properties generally are accepted. In this context, we asked whether the induction dose of rocuronium may be reduced to doses smaller than 2 x ED95 in situations in which slower onset properties may be acceptable. METHODS: The time course of neuromuscular block and intubating conditions of two different doses rocuronium, 2 x ED95 (0.6 mg/kg) and 1.3 x ED95 (0.4 mg/kg), were investigated in 90 patients. We first determined the time course of neuromuscular block using electromyography (EMG), n = 15 for each group. In the second part the intubating conditions 3 min after injection of either rocuronium 0.6 mg/kg or rocuronium 0.4 mg/kg were evaluated, n = 30 for each group. RESULTS: In the present study reduction of the dose of rocuronium led to a slower onset (148 +/- 32 s vs. 220 +/- 30 s; P < 0.05) and a shorter clinical duration (21 min +/- 4 vs. 36 +/- 7 min; P < 0.05). The recovery index was modified by the dose reduction: 11 +/- 3 min after 0.6 mg/kg rocuronium and 9 +/- 2 min after 0.4 mg/kg. After both doses of rocuronium the intubating conditions were good to excellent, no difference between both rocuronium groups were found. CONCLUSION: In the present study dose reduction from 0.6 mg/kg rocuronium to 0.4 mg/kg rocuronium led to a slower onset and reduced clinical duration. However, the intubating conditions, evaluated 3 min after injection of the muscle relaxant were comparable. This offers new possibilities for muscle relaxation for surgical or diagnostic procedures of short duration and may reduce costs.
OBJECTIVE: To characterize the impact of abdominal aortic aneurysm repair (AAAR) on spontaneous as well as lipopolysaccharide (LPS)-induced gene expression of pro- and anti-inflammatory cytokines. DESIGN: Prospective, controlled in vivo/ex vivo study. SETTING: University hospital. PATIENTS AND INTERVENTIONS: Whole blood from 14 consecutive patients undergoing AAAR withdrawn prior to surgery (T1), at the end of ischemia (T2), 90 min after declamping (T3) and on the first postoperative day (T4) was cultured in the absence or presence of LPS. Five patients undergoing elective inguinal hernia repair served as controls. MEASUREMENTS AND RESULTS: While tumor necrosis factor (TNF), Interleukin (IL)-1 and IL-10 plasma concentrations did not increase significantly, IL-6 was elevated at each time point, as compared with T1. Despite the spontaneous release of trace amounts of IL-6, the ability of cultured whole blood to mount a cytokine response in vitro to LPS was impaired for all cytokines studied at T2 (TNF-62%, IL-1-51%, IL-6 -20%, IL-10-51%). The stimulated IL-6 response was restored early after declamping (T3: +56 %) and enhanced 1 day after operation (T4: +144%). In contrast, stimulated TNF and IL-1 responses remained depressed at T3 (TNF -48%, IL-1-64%) and T4 (TNF-40%, IL-1-24%). A biphasic pattern was observed for IL-10 with initial depression at T3 (-51%) and restoration at T4 (+40%). Among the different cytokines monitored, only impaired TNF responsiveness at early reperfusion (T3) correlated with the postoperative course, as reflected by APACHE II. Cytokine response to LPS was maintained or even increased during and after surgery in the whole blood from patients undergoing hernia repair. CONCLUSIONS: Despite consistent development of clinical signs of systemic inflammatory response syndrome (SIRS) and spontaneous release of IL-6 abdominal aortic aneurysm repair produces a state of impaired pro-inflammatory cytokine response upon a subsequent in vitro Gram-negative stimulus. This early impairment of TNF responsiveness seems to correlate with an unfavorable postoperative course.
We have investigated the dose-effect relationship of neostigmine in antagonizing vecuronium-induced neuromuscular block with and without magnesium sulphate (MgSO4) pretreatment. Neuromuscular block was assessed by electromyography with train-of-four (TOF) stimulation. First, we determined neostigmine-induced recovery in patients pretreated with MgSO4 (group A) or saline (group B) (n = 12 each). The height of T1, 5 min after neostigmine, was 43 (7)% in group A and 65 (6)% in group B (P < 0.01). Respective values after 10 min were 59 (7)% and 83 (5)% (P < 0.01). TOF ratio, 5 min after neostigmine, was 29 (6)% in group A and 29 (5)% in group B. Respective values after 10 min were 38 (11)% and 51 (7)% (P < 0.01). To gain insight into the mechanisms leading to delayed recovery after MgSO4, we calculated assisted recovery, defined as neostigmine-induced recovery minus mean spontaneous recovery. Spontaneous recovery was assessed in another 24 patients. Patients in group C received MgSO4/vecuronium and patients in group D vecuronium only (n = 12 each). Five minutes after neostigmine, assisted recovery was 22 (7)% in the MgSO4 pretreated patients and 28 (6)% in controls (P < 0.05). Ten minutes after neostigmine, values were 24 (7)% and 22 (6)%. Maximum assisted recovery was not influenced by MgSO4 pretreatment (27 (6)% in group A and 32 (6)% in group B) and time to maximum effect was comparable between groups: 6 (4-10) min and 7 (5-8) min, respectively. We conclude that neostigmine-induced recovery was attenuated in patients treated with MgSO4. This was mainly a result of slower spontaneous recovery and not decreased response to neostigmine.
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Innate and acquired immunity plays a pivotal role in the host defense response. Pain, stress, necrotic tissue and invading microorganisms are known modulators of the complex immune response of patients undergoing major surgery. Anaesthesia itself or perioperative interventions of the anaesthesiologist may substantially alter the immune function with potential impact on the postoperative course. For instance, transfusion of allogenic blood and administration of dopamine or metoclopramide may interfere with immunity. Stress and pain are associated with immune tolerance, increased susceptibility to infection and tumor spreading in animal models. Thus, anaesthesia may--through modulation of the neurohumoral stress response--indirectly affect immunity of the surgical patient. In particular epidural anaesthesia and/or administration of epidural or spinal opioids seem to attenuate the stress response with beneficial effects on cellular and humoral immunity. In addition, anaesthetics, such as etomidate, propofol, or thiopentone and opioid analgesics may directly affect function of immune competent cells. However, these actions may only be apparent with high or supraclinical concentrations and/or long-term exposure. Regarding the latter, evidence suggests that long-term sedation using thiopentone in neurosurgical patients is paralleled by infectious complications in a dose-dependent manner. At present, no data are available regarding the significance of the observed alterations associated with various anaesthetic procedures of the incidence of postoperative complications associated with impaired immunity, such as infection or metastatic spreading in oncological surgery.
OBJECTIVE: To determine the influence of gamma-hydroxy-butyrate (GHB) on spontaneous and lipopolysaccharide (LPS)-stimulated release of tumour necrosis factor-alpha (TNF), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and interleukin-10 (IL-10) in whole blood from patients undergoing coronary artery bypass grafting (CABG) with extracorporeal circulation (ECC). In addition, the pharmacological modulation on lipopolysaccharide (LPS)-stimulated cytokine release by GHB (GHB-Na and GHB-ethanolamide) was characterized in a separate in vitro-assay. METHODS: In a prospective, randomized, double-blinded study, 12 patients undergoing elective CABG were assigned to receive either saline (control) or GHB-Na (25 mg/kg as loading dose followed by 25 mg/kg/h) intraoperatively. Blood samples were obtained (A) preoperatively, (B) 20 min after ECC and (C) 24 h after ECC. Plasma levels (spontaneous release) as well as LPS-stimulated cytokine secretion were measured in a whole blood culture system ex vivo and correlated with mRNA-expression in peripheral blood mononuclear cells (PBMC). In addition, the dose-response characteristics of modulation of the cytokine response by GHB was studied in vitro in the same assay. RESULTS: Plasma IL-6 and IL-10 levels were significantly elevated after CABG, while TNF and IL-1 beta were detectable only occasionally in both groups. Expression of all cytokines studied was significantly reduced upon ex vivo LPS-stimulation at time point B. Despite maintained expression of TNF and IL-1 beta mRNA-transcripts upon ex vivo LPS-stimulation in patients treated with GHB, release of the cytokines in the supernatant was decreased to a similar degree as in the control group. Cytokine response upon LPS-stimulation was restored 24 h after CABG for the group mean, however, with substantial individual heterogeneity. In vitro, pharmacological doses of GHB-Na (2 mg/ml) attenuated LPS-induced IL-1 beta release. However, application of the GHB-receptor antagonist NCS-382 caused a nearly complete cessation of IL-1 beta release in vitro (to 2.5% of control). GHB-ethanolamide (LK 544) did not influence the LPS-stimulated release of the cytokines studied. CONCLUSION: The results suggest a biphasic response of stimulated PBMC cytokine gene expression during CABG with an initial tolerance to LPS-stimulation shortly after termination of ECC. However, whether or not PBMC express functional GHB receptors remains unclear in light of contradictory effects of the different ligands. In spite of the ex vivo and in vitro results, application of GHB-Na in doses which are primarily based on its use as an anesthetic agent do not seem to modulate the release of the cytokines studied.
We have assessed the effect of the choice of i.v. induction agent on intubation conditions, 60 s after administration of rocuronium 0.6 mg kg-1. We studied 60 adult patients, allocated randomly to one of two groups. Anaesthesia was induced with alfentanil 10 micrograms kg-1 followed by thiopental 5 mg kg-1 (AT-R group; n = 30) or etomidate 0.3 mg kg-1 (AE-R group; n = 30). Both groups received rocuronium 0.6 mg kg-1. Laryngoscopy was started 60 s later and intubation conditions were evaluated according to a standard score, which considered ease of laryngoscopy, condition of the vocal cords and reaction to intubation. In the AT-R group, overall intubation conditions were scored as excellent in 20 patients, good in nine and fair in the remaining patient. In the AE-R group, overall intubating conditions were excellent in 24 and good in six patients. The difference between the two groups was not significant. Of the three components of the intubation score assessed, response to intubation stimulus was significantly less pronounced in group AE-R compared with group AT-R (P < 0.05): group AE-R, no reaction in 24 patients, slight diaphragmatic movement in five and mild coughing in one patient; group AT-R, no reaction in 13, slight diaphragmatic movement in 14, mild coughing in two and severe coughing in one patient. We conclude that etomidate as part of an induction regimen containing alfentanil and rocuronium attenuated the reaction to intubation to a greater extent than thiopental.
The influence of coronary artery bypass grafting (CABG) on spontaneous and lipopolysaccharide (LPS)-stimulated release of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-10 as well as its modulation by pentoxifylline (PTF) were studied in a prospective, randomized, double-blinded study. 12 patients undergoing elective CABG were randomly assigned to receive either saline or PTF (1 mg/kg as a loading dose followed by 1 mg/kg/h) intraoperatively. Blood samples were obtained (A) preoperatively, (B) 20 min after CABG, and (C) 24 h after CABG. Cytokine plasma levels as well as LPS-stimulated cytokine secretion were measured in a whole blood culture system ex vivo and correlated with mRNA expression in peripheral blood mononuclear cells. In addition, the dose-response characteristics of modulation of the cytokine response by PTF were studied in cultured whole blood in vitro. Plasma IL-6 and IL-10-levels were significantly elevated after CABG, whereas neither TNF-alpha nor IL-1beta were detectable. In contrast to the spontaneous release of IL-6 and IL-10, the expression of all cytokines studied was significantly reduced upon ex vivo LPS stimulation early after CABG. Proinflammatory cytokine response upon LPS stimulation was restored 24 h after CABG for the group mean, however, with substantial interindividual heterogeneity. Therapeutic doses of PTF in vitro attenuated LPS-induced TNF-alpha (-50.5%) and most notably IL-10 (-83.9%) release, whereas IL-1beta was even increased (+45.7%). However, application of PTF during CABG neither inhibited the spontaneous production of IL-10 nor modulated cytokine production ex vivo. These results suggest a biphasic response of stimulated peripheral blood mononuclear cell cytokine gene expression during CABG with an initial tolerance to LPS stimulation. The application of PTF during CABG in doses that are primarily based on its use in occlusive arterial disease do not seem to modulate the release of the cytokines studied.
Adequate prehospital care of the severely traumatised patient is important to prevent or attenuate early as well as late life threatening complications, such as tissue hypoxia, ischemia/reperfusion injury and finally multiple organ failure. A mismatch of oxygen supply and oxygen demand is a hallmark in the pathophysiology of multiple trauma. Oxygen supply may be diminished by the following factors: shock-related decrease of cardiac output, anemia and hypoxia. On the other hand, oxygen demand may be increased by pain, panic, and agitation. Hence, it is a central point in prehospital care to reduce this supply-demand imbalance by identification and prompt reversal of the underlying causes. Most often, shock is caused by hypovolaemia and tissue injury ("traumatic-hemorrhagic shock"). However, shock may also be a result of central nervous system injury (neurogenic shock as a special form of distributive shock) or circulatory obstruction, e.g tension pneumothorax or cardiac tamponade (obstructive shock). Volume resuscitation by means of crystalloid or colloid solutions is an essential part in the therapy of the traumatic-haemorrhagic shock. In addition, catecholamines may be necessary in order to achieve an adequate arterial pressure. However, if bleeding cannot be controlled in the prehospital setting, only moderate volume support and permissive hypotension as well as rapid transportation into the next hospital may be preferable. This may be the case in penetrating thoracic or abdominal injuries as well as in traumatic amputations of the proximal limb. On the contrary, in patients with severe head injury, hypotension must be avoided by all means. Obstructive shock has to be treated urgently by insertion of a chest drain or drainage of the pericardium, respectively. Under all circumstances, it is an essential part of prehospital therapy to provide sufficient analgesia as soon as possible. Prehospital anesthesia, combined with artificial ventilation may be necessary for optimal patient management. Furthermore, ventilatory support is indicated when respiratory failure, loss of consciousness, or severe shock are present. Additional oxygen should be given whenever possible, even in the absence of an overt hypoxic state. Important additional measures are cervical spine immobilisation and reposition as well as splinting of long bone fractures or luxations, in order to avoid secondary injury of the spinal cord or ongoing tissue and vascular damage.
Multiple trauma often leads to systemic inflammatory reaction and multiple organ dysfunction. Modulation of this response may be promising. Several pharmacologic approaches, such as antioxidants (e.g. superoxidedismutase), calcium channel blockers (e.g. diltiazem), cytokines (e.g. interferone gamma), and modulators of intracellular signal transduction pathways (e.g. pentoxiphylline) have been shown to improve outcome in experimental models and/or in clinical pilot studies. However, up to now no definitive evidence has been provided in prospective, randomized, and blinded "intention to treat" trials that these agents are able to reduce mortality and morbidity of the traumatized patient. Hence, supportive care of failing organs, treatment of hypoxemia and maintenance of an appropriate systemic blood pressure remain the mainstay of critical care therapy. Widely accepted therapeutic measures are (i) immediate treatment of hypoxia by administration of oxygen and ventilatory support, if needed, to maintain an oxygen tension of 60 mmHg or higher (ii) maintenance of adequate oxygen content by transfusion of red packed cells in order to restore a hematocrit of 23-30% (iii) treatment of hypovolemia by infusion of crystalloids, colloids and blood products (iv) normoventilation and restoration of a normal or elevated blood pressure in patients with severe head injury (v) immobilisation and early administration of methylprednisolone in patients with spinal cord injury (vi) analgesia by administration of opioids, non-steroidal antiinflammatory drugs, or ketamine (vii) sedation with benzodiazepines, gamma-hydroxbutyrate or propofol (viii) early enteral nutrition (ix); antibiotic therapy of infections (x) pressure controlled ventilation in patients with acute lung injury (xi) continuous veno-venous hemofiltration in patients developing acute renal failure and (xii) early surgical interventions to control bleeding and/or to evacuate intracerebral hematomas.
Despite a high standard of preclinical, clinical and rehabilitative trauma care, the number and degree of injuries will remain a social and medical challenge. Improvements of trauma care in the future may be possible in respect to social, economic, organisational, clinical and research issues. Prevention of trauma will be of major impact and improvements may be possible by preventive legislation and technical developments. Organisation of trauma care should integrate high level trauma centres early-on including a national, regional and local quality control system. The future preclinical and clinical individual care of multiple trauma patients should consider the complex pathophysiological mechanisms at all levels, while the understanding of these mechanisms is increasing continuously.
OBJECTIVE: To determine the effects of a hydroxyethyl starch-deferoxamine conjugate on hepatic microcirculation in an isobaric, anesthetized rat model of hemorrhagic shock and asanguineous resuscitation. DESIGN: Prospective, randomized, controlled study. SETTING: Laboratory at a university hospital. SUBJECTS: Twenty-three female, inbred Lewis rats (190 to 215 g). INTERVENTIONS: After anesthesia (pentobarbital-sodium; 50 mg/kg), tracheotomy, and cannulation, animals were assigned to a hemorrhagic shock (mean arterial pressure at 40 +/- 3 mm Hg for 45 mins) or a time-matched sham protocol. Rats in the shock groups received either hydroxyethyl starch or a starch-deferoxamine conjugate for resuscitation. Liver microcirculation was assessed in vivo 60 mins after onset of volume therapy by epifluorescence microscopy. MEASUREMENTS AND MAIN RESULTS: Conventional resuscitation with the starch-vehicle failed to restore sinusoidal blood flow compared with either time-matched controls (71% of control value; p < .01) or the starch-deferoxamine-treated animals (89% of control value; p < .05 compared with starch-vehicle), although a comparable restoration of central hemodynamics was achieved with both starch preparations. Additionally, treatment with the starch-deferoxamine conjugate resulted in a significant attenuation of sinusoidal leukocyte margination (sham 72.4 +/- 11.0/mm2; starch-vehicle 194.5 +/- 19.0/mm2 [p < .01 compared with controls]; starch-deferoxamine conjugate 135.9 +/- 12.1/mm2 [p < .02 compared with sham and starch-vehicle]). CONCLUSIONS: Asanguineous resuscitation with conventional hydroxyethyl starch failed to restore hepatic microvascular blood flow, despite otherwise effective resuscitation. In contrast, the starch-deferoxamine conjugate improved volumetric blood flow and attenuated leukocyte margination in hepatic sinusoids compared with starch-vehicle, suggesting involvement of iron-dependent, oxygen-derived radicals in shock-induced hepatic microcirculatory disturbances.
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