Effects of early treatment with immunoglobulin on critical illness polyneuropathy following multiple organ failure and gram-negative sepsis

Objective: The evaluation of incidences and relating factors of severe persisting critical illness polyneuropathy (CIP) in survivors of multiple organ failure (MOF). Design: Prospective study with an entry period of 24 months. Electrophysiological studies for the diagnosis of CIP were performed 1 or 2 days before the patients were discharged from the intensive care unit (ICU). Factors which might have been related to the development of CIP were identified by a retrospective chart analysis. Setting: The interdisciplinary ICU of a university hospital. Patients: Thirty-three patients who survived MOF. Sixteen of these critically ill patients developed severe sepsis due to nosocomial infections with gram-negative bacteria. Results: In seven survivors of MOF and sepsis typical electrophysiological features of CIP, like spontaneous fibrillations and low compound muscle action potentials, were detectable at the time of discharge from the ICU. Seventeen patients with MOF following multiple trauma who developed no sepsis, and nine survivors of MOF with sepsis showed no signs of persisting CIP at the end of their ICU stay. Chart analysis revealed that eight survivors of MOF with sepsis and without the development of CIP had been treated with intravenous immunoglobulin (IVIG) with a dosage of 0.3 g/kg per day for 3 days immediately (within 24 h) after the diagnosis of sepsis. Four out of seven patients with MOF and sepsis who developed CIP were transferred to our ICU after the onset of sepsis and had not received IVIG treatment. The IVIG treatment in three patients was delayed for more than 24 h after the diagnosis of sepsis and was then omitted. Obviously not related to the development of CIP were aminoglycoside antibiotics, steroids, nutritional disturbances and episodes of hypotension or hypoxia. Neuromuscular blocking agents were not used during intensive care treatment. Conclusions: A high incidence of severe CIP persisting until the day of discharge from the ICU was related to gram-negative sepsis but not to MOF alone. Retrospective chart analysis suggested that early application of IVIG may prevent or mitigate this severe complication. However, these results have to be confirmed in a prospective, placebo-controlled study. Received: 22 April 1997 Accepted: 17 September 1997     

Early signs of critical illness polyneuropathy in ICU patients with systemic inflammatory response syndrome or sepsis

OBJECTIVE: To evaluate with electromyography the incidence and the time of appearance of neuromuscular abnormality in patients with systemic inflammatory response syndrome (SIRS) and/or sepsis. DESIGN: Follow-up study. SETTING: Intensive care unit of Helsinki University Hospital, Finland. PATIENTS: Nine mechanically ventilated patients with SIRS and/or sepsis. INTERVENTIONS: Electromyography and conduction velocity measurements on the 2nd-5th day after admission to the intensive care unit. MEASUREMENTS AND RESULTS: In all nine patients electromyography revealed signs of neuromuscular abnormality. The means of compound muscle action potential amplitudes of the median and ulnar nerves were decreased. Fibrillation was observed in four patients out of nine. CONCLUSION: Because neuromuscular abnormalities seem to develop earlier than previously reported, electroneuromyography should be used more frequently as a diagnostic test.     

A prospective, randomized, double-blinded, placebo-controlled trial of empirical teicoplanin in febrile neutropenia with persistent fever after imipenem monotherapy

Glycopeptide antibiotics are used extensively in the empirical treatment of febrile patients with neutropenia. To come to a more rational and restricted application of these expensive drugs and to reduce the risk of emergence of resistance, we carried out a prospective, double-blinded, placebo-controlled single-centre study to investigate whether the addition of teicoplanin improved the outcome of neutropenic patients who remained febrile after 72-96 h of imipenem monotherapy. Patients with known infections caused by imipenem-resistant microorganisms were excluded. From the 114 evaluable episodes (out of a total of 125) in 105 patients who met the eligibility criteria, 56 episodes were randomized to receive teicoplanin and 58 to placebo. At 72 h after the start of the assigned intervention, 52 (45.6%) of the patients were afebrile; at the end of the aplastic phase, 10 (8.8%) had succumbed. There was no difference between the two study arms. When febrile episodes were subdivided between microbiologically documented infections, clinically documented infections and fevers of unknown origin, again no significant differences were observed. With the exception of methicillin-resistant bacteria, Gram-positive infections seemed to respond well to imipenem monotherapy. It is concluded that the addition of teicoplanin on empirical grounds, i.e. for persistent fever only, is not necessary and that the use of glycopeptides should be restricted to well-defined clinical situations where methicillin-resistant bacteria are involved. Furthermore, it seems that many neutropenic patients respond slowly over more than 72-96 h even when they are treated with antibacterial drugs such as imipenem that are effective against the causative microorganism.     

Efficacy of oxycodone/paracetamol for patients with bone-cancer pain: a multicenter, randomized, double-blinded, placebo-controlled trial

What is known and Objective: Bone‐cancer pain is a common and refractory cancer pain. Opioids, on their own, do not control this type of pain well enough, and co‐analgesics are necessary. Methods: Patients with bone metastasis‐related pain at Numeric Rating Scale ≥4 were enrolled to this randomized placebo‐controlled trial. They had also received morphine or transdermal fentanyl patches for at least 1 week. During the 3‐day efficacy phase, patients received placebo or 1–3 tablets of oxycodone/paracetamol (5/325 mg), four times daily for 3 days. All patients kept a daily pain diary. The primary endpoint was the Pain Intensity Difference (PID). Secondary endpoints were cases of breakthrough pain and rescue morphine consumption. Additional analyses included the Short Form‐6 Dimensions (SF‐6D) quality‐of‐life scale and a general impression (GI) of patient satisfaction with treatment at the end of the phase. Results and Discussion: Of the 246 patients in the intent‐to‐treat set, 89·4% completed the 3‐day efficacy phase. PIDs were 0·9 and 0·3 in the oxycodone/paracetamol and placebo groups respectively, on day 1 (P < 0·001), and 1·5 and 0·3 respectively on day 3 (P < 0·001). Thirty‐eight patients in the treatment group, and 58 in the placebo group, suffered breakthrough pain on day 3 (P < 0·001). The SF‐6D score decreased to 21·2 ± 2·5 in the oxycodone/paracetamol group at the end of the phase (P = 0·001). In the oxycodone/paracetamol group, 67% rated GI as good, very good, or excellent. What is new and Conclusion: Patients with bone‐cancer pain, already on opioids, obtain clinically important, additional pain‐control, with regular oxycodone/paracetamol dosing.     

Ubiquinol (reduced Coenzyme Q10) in patients with severe sepsis or septic shock: a randomized,double-blind,placebo-controlled,pilot trial

IntroductionWe previously found decreased levels of Coenzyme Q10 (CoQ10) in patients with septic shock. The objective of the current study was to assess whether the provision of exogenous ubiquinol (the reduced form of CoQ10) could increase plasma CoQ10 levels and improve mitochondrial function.MethodsWe performed a randomized, double-blind, pilot trial at a single, tertiary care hospital. Adults (age ≥18 years) with severe sepsis or septic shock between November 2012 and January 2014 were included. Patients received 200 mg enteral ubiquinol or placebo twice a day for up to seven days. Blood draws were obtained at baseline (0 h), 12, 24, 48, and 72 h. The primary outcome of the study was change in plasma CoQ10 parameters (total CoQ10 levels, CoQ10 levels relative to cholesterol levels, and levels of oxidized and reduced CoQ10). Secondary outcomes included assessment of: 1) vascular endothelial biomarkers, 2) inflammatory biomarkers, 3) biomarkers related to mitochondrial injury including cytochrome c levels, and 4) clinical outcomes. CoQ10 levels and biomarkers were compared between groups using repeated measures models.ResultsWe enrolled 38 patients: 19 in the CoQ10 group and 19 in the placebo group. The mean patient age was 62 ± 16 years and 47 % were female. Baseline characteristics and CoQ10 levels were similar for both groups. There was a significant increase in total CoQ10 levels, CoQ10 levels relative to cholesterol levels, and levels of oxidized and reduced CoQ10 in the ubiquinol group compared to the placebo group. We found no difference between the two groups in any of the secondary outcomes.ConclusionsIn this pilot trial we showed that plasma CoQ10 levels could be increased in patients with severe sepsis or septic shock, with the administration of oral ubiquinol. Further research is needed to address whether ubiquinol administration can result in improved clinical outcomes in this patient population.

Trial registration

Clinicaltrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT01948063","term_id":"NCT01948063"}}NCT01948063. Registered on 18 February 2013.     

Decreased organ failure in patients with severe SIRS and septic shock treated with the platelet-activating factor antagonist TCV-309: a prospective, multicenter, double-blind, randomized phase II trial. TCV-309 Septic Shock Study Group

Sepsis and organ failure remain the main cause of death on the ICU. Sepsis is characterized by a severe inflammatory response, in which platelet-activating factor (PAF) is considered to play an important role. This study investigated whether treatment with the PAF-antagonist TCV-309 reduces morbidity and mortality in patients with septic shock. The study was conducted as a double-blind, randomized, placebo controlled multicenter study. The included patients had to fulfill the SIRS criteria with a clinical suspicion of infection, an admission APACHE II score greater than 15, and shock, defined as a mean arterial pressure <70 mmHg and/or a decrease > or =40 mmHg despite adequate fluid resuscitation. Patients received 1.0 mg/kg TCV-309 or placebo, twice daily, intravenously during 14 days. The prospectively set goals were MOF score, recovery from shock, mortality, and assessment of the safety of the medication. A total of 98 patients were included of which 97 were analyzed on an intention-to-treat basis. The overall survival at day 56 of TCV-309 treated patients was similar compared to placebo treated patients (51.0% vs. 41.7%, P = 0.47). In contrast, the mean percentage of failed organs per patient present after 14 days in the TCV-309 treated patients was significantly lower compared to the placebo treated patients (11.9% vs. 25.1%, P = 0.04), leading to a reduced need for vasopressors, dialysis, and ventilatory support. Furthermore, the mean APACHE-II score during treatment with TCV-309 was significantly lower and the number of patients recovered from shock after day 14 was significantly higher in the TCV-309 treated patient group (2/32 vs. 9/29, P = 0.01). The number of adverse events was not significantly different between the TCV-309 and placebo treated patients. TCV-309 did not change overall mortality of septic shock, however a substantial reduction in organ dysfunction and morbidity, frequently associated with septic shock was achieved, without significant adverse events.     

The addition of voice prompts to audiovisual feedback and debriefing does not modify CPR quality or outcomes in out of hospital cardiac arrest--a prospective, randomized trial

Aims

Chest compression quality is a determinant of survival from out-of-hospital cardiac arrest (OHCA). ERC 2005 guidelines recommend the use of technical devices to support rescuers giving compressions. This prospective randomized study reviewed influence of different feedback configurations on survival and compression quality.

Materials and methods

312 patients suffering an OHCA were randomly allocated to two different feedback configurations. In the limited feedback group a metronome and visual feedback was used. In the extended feedback group voice prompts were added. A training program was completed prior to implementation, performance debriefing was conducted throughout the study.

Results

Survival did not differ between the extended and limited feedback groups (47.8% vs 43.9%, p = 0.49). Average compression depth (mean ± SD: 4.74 ± 0.86 cm vs 4.84 ± 0.93 cm, p = 0.31) was similar in both groups. There were no differences in compression rate (103 ± 7 vs 102 ± 5 min(−1), p = 0.74) or hands-off fraction (16.16% ± 0.07 to 17.04% ± 0.07, p = 0.38). Bystander CPR, public arrest location, presenting rhythm and chest compression depth were predictors of short term survival (ROSC to ED).

Conclusions

Even limited CPR-feedback combined with training and ongoing debriefing leads to high chest compression quality. Bystander CPR, location, rhythm and chest compression depth are determinants of survival from out of hospital cardiac arrest. Addition of voice prompts does neither modify CPR quality nor outcome in OHCA. CC depth significantly influences survival and therefore more focus should be put on correct delivery. Further studies are needed to examine the best configuration of feedback to improve CPR quality and survival.

Registration

ClinicalTrials.gov (NCT00449969), http://www.clinicalTrials.gov.     

Hormone replacement therapy does not affect the 24-hour heart rate variability in postmenopausal women: results of a randomized, placebo-controlled trial with two regimens

Postmenopausal women are at greater risk of coronary heart disease. The results of previous studies of the effects of hormone replacement therapy (HRT) on cardiac autonomic modulation in postmenopausal women have been contradictory. This study examined whether continuous treatment for 3 months with estradiol alone (ERT) or with estradiol plus norethisterone (HRT), increases 24-hour heart rate variability (HRV) in postmenopausal women. In this double-blind, placebo-controlled trial, 40 healthy postmenopausal women, 46-63 years of age, were randomly assigned to (1) continuous 2 mg of estradiol plus 1 mg of norethisterone acetate daily (HRT, n = 13), or (2) 2 mg of estradiol daily (ERT, n = 14), or (3) placebo (n = 13). Before and after 3 months of therapy, blood estradiol concentrations were measured and 24-hour electrocardiograms recorded for evaluation of 24-hour time-domain indices of HRV, and indices derived from the three-dimensional return map. Both hormone replacement regimens significantly increased blood estradiol concentrations, while no change occurred in the placebo group. In the three treatment groups, multiple 24-hour time-domain indices of HRV and indices derived from the three-dimensional return map remained unchanged. In healthy postmenopausal women, HRT with estradiol or estradiol and norethisterone for 3 months did not modify cardiac autonomic activity evaluated by 24-hour indices of HRV. These findings are consistent with a lack of protective cardiovascular effect of HRT described in recent large randomized trials.     

危重病严重脓毒症/脓毒性休克患者早期规范化液体复苏治疗——多中心、前瞻性、随机、对照研究

目的 探讨早期目标导向治疗(EGDT)对严重脓毒症/脓毒性休克患者的影响.方法 采用多中心、前瞻性、随机、对照研究方法,选择2005年1月至2008年1月浙江省8家三级甲等医院重症监护病房(ICU)住院的314例严重脓毒症/脓毒性休克患者,按随机数字表法分为常规组(151例)和EGDT组(163例).常规组以中心静脉压(CVP)、收缩压(SBP)和平均动脉压(MAP)、尿量变化指导液体复苏;EGDT组在此基础上增加中心静脉血氧饱和度(ScvO2)为观测指标进行复苏;对患者进行输液、输血和强等治疗,6 h内达标.比较两组患者28 d生存率、ICU住院病死率(主要终点)以及ICU住院时间、机械通气时间、抗生素使用时间、新发感染率和疾病严重程度评分(次要终点)的差异.结果 可供分析的有效病例中EGDT组为157例,常规组为146例.EGDT组28 d生存率较常规组增高约17.7%(75.2%比57.5%,P=0.001),EGDT组ICU住院病死率较常规组降低约15.7%(35.0%比50.7%,p=0.035).与常规组比较,EGDT能明显善患者的急性生理学与慢性健康状况评分系统Ⅱ(APACHEⅡ)评分(分:14.4±8.5比18.0±7.1,P=0.043)、多器官功能障碍综合征(MODS)评分(分:5.8±3.1比8.9±3.7,P=0.014)和感染相关器官功能衰竭评分系统(SOFA)评分(分:5.6±2.9比10.4±3.7,P=0.001),减少抗生素使用时间(d:13.4±10.0比19.7±13.5,P=0.004),降低新发感染的发生率(37.6%比53.4%,p=0.014);EGDT对ICU住院时间、机械通气间均无明显影响.结论 EGDT能显著改善ICU中严重脓毒症/脓毒性休克患者28 d生存率和临床疾病严重程度评分,减少抗生素使用时间及降低新发感染的发生率.     

危重病严重脓毒症/脓毒性休克患者早期规范化液体复苏治疗——多中心、前瞻性、随机、对照研究

Objective To investigate the effect of early goal-directed therapy (EGDT) on treatment of critical patients with severe sepsis/septic shock.Methods A multi-center, prospective, randomized,controlled study was deployed.Totally 314 critical patients, from eight comprehensive hospitals in Zhejiang Province admitted during January, 2005 to January, 2008, suffering from severe sepsis/septic shock were randomized into conventional treatment group (n=151) and EGDT group (n = 163), the patients of the former underwent fluid resuscitation guided by central venous pressure (CVP), systolic blood pressure (SBP) or mean artery pressure (MAP) and urinary output (UO), and the latter guided by CVP, SBP orMAP and UO plus central venous oxygen saturation (ScvO2).The patients were treated with fluid, blood transfusions and cardiac stimulants in a period of 6 hours after enrollment to reach the goal.The difference of 28-day survival rate and intensive care unit (ICU) mortality (primary end points), the length of ICU stay,the duration of mechanical ventilation, duration of antibiotics treatment, incidence of newly occurredinfection, and severity scores (secondary end points) were compared between two groups.Results Finally,a total of 303 patients were eligible to enter this study, with 157 patients in EGDT group and 146 patients in conventional treatment group.In comparison with conventional treatment group, the 28-day survival rate of EGDT group was increased by 17.7% (75.2% vs.57.5%, P=0.001) and the ICU mortality of EGDT group was decreased by 15.7% (35.0% vs.50.7%, P=0.035), the acute physiology and chronic health evaluation Ⅱ(APACHE Ⅱ) score (14.4±8.5 vs.18.0±7.1, P=0.043), multiple organ dysfunction syndrome (MODS) score (5.8±3.1 vs.8.9±3.7, P=0.014) and sepsis-related organ failure assessment (SOFA) score (5.6 ± 2.9 vs.10.4 ± 3.7, P = 0.001) were significantly decreased in EGDT group.Meanwhile, a significant shortening of duration of using antibiotics was also found [(13.4±10.0) days vs.(19.7 ± 13.5) days, P = 0.004], with a lowering of incidence of occurrence of new infection (37.6% vs.53.4%, P=0.014).There were no differences in other parameters for secondary end points.Conclusion EGDT improves 28-day survival rate and clinical scores, and it shows beneficial effects on outcome of critical patients with severe sepsis/septic shock.     

危重病严重脓毒症/脓毒性休克患者早期规范化液体复苏治疗——多中心、前瞻性、随机、对照研究

Objective To investigate the effect of early goal-directed therapy (EGDT) on treatment of critical patients with severe sepsis/septic shock.Methods A multi-center, prospective, randomized,controlled study was deployed.Totally 314 critical patients, from eight comprehensive hospitals in Zhejiang Province admitted during January, 2005 to January, 2008, suffering from severe sepsis/septic shock were randomized into conventional treatment group (n=151) and EGDT group (n = 163), the patients of the former underwent fluid resuscitation guided by central venous pressure (CVP), systolic blood pressure (SBP) or mean artery pressure (MAP) and urinary output (UO), and the latter guided by CVP, SBP orMAP and UO plus central venous oxygen saturation (ScvO2).The patients were treated with fluid, blood transfusions and cardiac stimulants in a period of 6 hours after enrollment to reach the goal.The difference of 28-day survival rate and intensive care unit (ICU) mortality (primary end points), the length of ICU stay,the duration of mechanical ventilation, duration of antibiotics treatment, incidence of newly occurredinfection, and severity scores (secondary end points) were compared between two groups.Results Finally,a total of 303 patients were eligible to enter this study, with 157 patients in EGDT group and 146 patients in conventional treatment group.In comparison with conventional treatment group, the 28-day survival rate of EGDT group was increased by 17.7% (75.2% vs.57.5%, P=0.001) and the ICU mortality of EGDT group was decreased by 15.7% (35.0% vs.50.7%, P=0.035), the acute physiology and chronic health evaluation Ⅱ(APACHE Ⅱ) score (14.4±8.5 vs.18.0±7.1, P=0.043), multiple organ dysfunction syndrome (MODS) score (5.8±3.1 vs.8.9±3.7, P=0.014) and sepsis-related organ failure assessment (SOFA) score (5.6 ± 2.9 vs.10.4 ± 3.7, P = 0.001) were significantly decreased in EGDT group.Meanwhile, a significant shortening of duration of using antibiotics was also found [(13.4±10.0) days vs.(19.7 ± 13.5) days, P = 0.004], with a lowering of incidence of occurrence of new infection (37.6% vs.53.4%, P=0.014).There were no differences in other parameters for secondary end points.Conclusion EGDT improves 28-day survival rate and clinical scores, and it shows beneficial effects on outcome of critical patients with severe sepsis/septic shock.     

A placebo-controlled,double-blind,dose-escalation study to assess the safety,tolerability and pharmacokinetics/pharmacodynamics of single and multiple intravenous infusions of AZD9773 in patients with severe sepsis and septic shock

Introduction  

Tumor necrosis factor-alpha (TNF-α), an early mediator in the systemic inflammatory response to infection, is a potential therapeutic target in sepsis. The primary objective of this study was to determine the safety and tolerability of AZD9773, an ovine, polyclonal, anti-human TNF-α Fab preparation, in patients with severe sepsis. Secondary outcomes related to pharmacokinetic (PK) and pharmacodynamic (PD) parameters.     

4G/5G polymorphism of <Emphasis Type="Italic">PAI-1</Emphasis> gene is associated with multiple organ dysfunction and septic shock in pneumonia induced severe sepsis: prospective,observational, genetic study

Introduction  

Activation of inflammation and coagulation are closely related and mutually interdependent in sepsis. The acute-phase protein, plasminogen activator inhibitor-1 (PAI-1) is a key element in the inhibition of fibrinolysis. Elevated levels of PAI-1 have been related to worse outcome in pneumonia. We aimed to evaluate the effect of functionally relevant 4G/5G polymorphism of PAI-1 gene in pneumonia induced sepsis.