Clinical usefulness of a host signature based on TRAIL, IP10, and CRP (MeMed BV) as infection biomarkers in intensive care units' patients. A retrospective observational study.

INTRODUCTION: Infection complications are common in intensive care unit patients, and early detection remains a diagnostic challenge. Procalcitonin (PCT) and C-reactive protein (CRP) are commonly used biomarkers. A novel diagnostic approach focuses on the host immune response. One of the approaches, the MMBV index, is based on measuring in a blood sample three parameters: (i) tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), (ii) interferon-γ-induced protein-10 (IP10), and (iii) CRP. This study aimed to evaluate the usefulness of MMBV as an infection biomarker in an ICU cohort. PATIENTS AND METHODS: Forty-six patients treated in the University Clinical Center in Gdansk ICU were enrolled in the study, and their clinical data were retrospectively analyzed. In total, 91 MMBV results were analyzed. RESULTS: Most of the patients had high MMBV values, suggesting bacterial etiology. A weak correlation between PCT and MMBV was observed, and no correlation between parameter changes was noted. There was a correlation between CRP/MMBV and between changes in CRP / changes in MMBV. CONCLUSION: It seems that MMBV is not valuable for ICU patients neither in diagnosing nor monitoring infection. Higher MMBV values may predict unfavorable treatment outcomes.

The Impact of Continuous Veno-Venous Hemodiafiltration on the Efficacy of Administration of Prophylactic Doses of Enoxaparin: A Prospective Observational Study.

BACKGROUND: Critically ill patients frequently require continuous renal replacement therapy (CRRT). During CRRT, particles up to 10 kDa in size, such as enoxaparin, may be removed. The aim of this study was to determine if patients receiving prophylactic doses of enoxaparin and treated with continuous veno-venous hemodiafiltration (CVVHDF) reach prophylactic values of anti-Xa factor activity. METHODS: In this observational trial, we compared two groups: 20 patients treated with CVVHDF and 20 patients not treated with CVVHDF. All of them received prophylactic doses of 40 mg of enoxaparin subcutaneously. Anti-Xa factor activity was determined on the third day of receiving a prophylactic dose of enoxaparin. The first blood sample was taken just before the administration of enoxaparin, and other samples were taken 3 h, 6 h, and 9 h after the administration of a prophylactic dose of enoxaparin. RESULTS: At 3 and 6 h after administration of enoxaparin in both groups, we observed a significant increase in anti-Xa factor activity from baseline, with the peak after 3 h of administration. There were no significant differences in the numbers of patients who had anti-Xa factor activity within the prophylactic range between CVVHDF and control groups. CONCLUSION: CVVHDF has only a mild effect on the enoxaparin prophylactic effect measured by anti-Xa factor activity. Thus, it seems there is no need to increase the dose of enoxaparin for patients requiring CVVHDF.

Escherichia coli bacteraemias in intensive care unit patients.

BACKGROUND: Although bacterial infections are common in critically ill patients, isolation of bacteria from the sample is not always unambiguous. The authors addressed Escherichia coli bacteraemia in patients treated in the Intensive Care Unit in the Teaching Hospital in Gdansk in 2002-2009. METHODS: Using a computer database, the names of Escherichia coli positive patients and dates of blood sampling were found, followed by a retrospective assessment whether positive blood cultures were accompanied by the clinical features of sepsis or asymptomatic bacteraemia. RESULTS: Positive cultures were found in 40 blood samples (36 patients). Bacteraemia was diagnosed in 11, sepsis in 10, severe sepsis in 6 and septic shock in 13 cases. In the bacteraemia group, the condition originated from the gastrointestinal tract - 4 cases; from the lungs - 1; while in 6 cases, the aetiology was not detected. In patients with an infection, the likely source was the gastrointestinal tract - 12 cases; the lungs - 4; and pyothorax - 2. In 11 cases, the aetiology remained unidentified. In 3 patients in the bacteraemia group, cultures of other microorganisms were found to be positive, while there were 4 cases among the septic patients. In the bacteraemia group, 8 patients died in the intensive care unit, without relation to bacteraemia. Amongst septic patients 17 died, including 12 whose death was probably attributable to Escherichia coli infection. CONCLUSIONS: Escherichia coli bacteraemias and infections have been and will remain an everyday problem in hospital wards. The differentiation of asymptomatic bacteraemia from infection is essential for rational antibiotic therapy, which is particularly important considering the increasing resistance of microorganisms.

Eye surgery in the elderly.

Extending life expectancy is a human achievement. It does however entail problems. Ophthalmic treatments are widely recognized as having a low risk of general complications. A classic example is cataract surgery, considered to be one of the safest and most frequently performed surgical procedures in the world. However, advanced age brings with it risks that should be considered before surgery. Eye operations, as with procedures on other organs, are largely dependent on the quality of surgical tissues. Therefore, the elderly are at increased risk of complications. Improved general health and postoperative follow-up with the use of noninvasive technologies such as optical coherence tomography translate into lower intraoperative risk and better postoperative prognosis. In this review, we discuss the impact of general health on operational prognosis, therapeutic problems, and technical difficulties which a surgeon and anesthesiologist may encounter in the process. We also consider new technology and strategies specifically aimed at treating eye conditions in the elderly.

The influence of epidural blockade on gut permeability in patients undergoing open surgical repair of abdominal aortic aneurysm.

BACKGROUND: Abdominal aortic clamping during aneurysm repair may cause a decrease in splanchnic blood flow and deterioration of gut barrier integrity. Epidural blocks have beneficial effects on vital organs during abdominal surgery, but sparse data are available on the influence on gut permeability during open aortic surgery. The aim of this study was to verify the hypothesis that epidural blocks may have beneficial effects on intestine permeability changes. METHODS: Seventy individuals undergoing elective open abdominal aortic aneurysm repair were randomly assigned to receive either balanced anaesthesia (continuous epidural and general anaesthesia, group E&G) or only general anaesthesia (group G). For group E&G, an epidural catheter was inserted into the epidural space before the induction of general anaesthesia. Ropivacaine was used for intraoperative and postoperative blocks. For both groups general anaesthesia was maintained with sevoflurane. For group G, analgesia was provided with remifentanil. The assessments of gut function were based on measurements of the absorption and percentages of urinary excretion of four sugars (m 3-O-methyl-D-glucose, D-xylose, L-rhamnose and lactulose) and the lactulose/rhamnose (L/R) ratio. RESULTS: No intergroup differences were observed for sugar recovery or L/R ratio. Significant decreases in 3-O-methyl-D-glucose, D-xylose, and L-rhamnose recoveries were revealed in both examined groups when comparing the results obtained at 12 and 24 hours following the administration of anaesthesia. The rate of blood pressure decrease was significantly higher in group E&G. CONCLUSIONS: Aortic clamping during open abdominal aortic repair led to unfavorable changes in intestinal permeability. Epidural block did not attenuate this deterioration.

The influence of epidural anesthesia on the electrical activity of heart atria.

INTRODUCTION: High thoracic epidural anesthesia (TEA) causes blockade of sympathetic fibers involved in innervation of the heart (segments T1-T4), which results in changes of cardiac electrophysiology. The anti-arrhythmic effects of TEA on supraventricular arrhythmias, mainly atrial fibrillation, are controversial. THE AIM OF THE STUDY: The aim of the study was to assess the influence of epidural anesthesia on the electrical function of heart atria, including proven markers of increased risk of perioperative atrial fibrillation, such as P wave dispersion and P wave maximum duration. MATERIAL AND METHODS: The study involved 50 male patients, without a history of previous heart diseases, scheduled for elective surgical procedures. Patients received thoracic epidural anesthesia (group T, n = 25) or lumbar epidural anesthesia (group L, n = 25). The measurements were obtained from a continuous recording of ECG before epidural anesthesia and after the detection of blockade (T1 or T8 segment sensory block in groups T and L, respectively). RESULTS: The statistical analysis of electrocardiographic parameters, including the maximum, minimum and mean P wave duration; P wave dispersion; the maximum, minimum and mean PR interval duration; and PR interval dispersion, did not show any inter- or intragroup differences at selected time points. CONCLUSIONS: Regardless of its location, epidural anesthesia and sympathetic blockade associated with this procedure do not significantly affect the electrical functions of the cardiac atria reflected in superficial ECG, including the electrocardiographic parameters that are considered to be markers of increased risk of perioperative atrial fibrillation, such as P wave dispersion and its maximum duration.

The influence of low flow anaesthesia on renal function in cancer patients previously treated with nephrotoxic chemotherapeutic agents.

BACKGROUND: The aim of this study was to assess renal morbidity, associated with the use of low flow anaesthesia (LFA), in cancer patients previously treated with nephrotoxic chemotherapeutic agents. METHODS: Seventy-five patients, aged 30-70 years, scheduled for elective surgery, were randomly allocated to three groups: Group A included those patients who had received nephrotoxic chemotherapeutic agents (cisplatin, carboplatin, methotrexate or cyclophosphamide) within 90 days before surgery, and who were anaesthetised with low flow (0.8(-1) L min(-1)) air-oxygen-sevoflurane (1-3 MAC) anaesthesia; Group B included similar patients who received high flow (6 L min-1) anaesthesia. Non-cancer patients receiving low flow anaesthesia served as controls. Blood was sampled for serum creatinine, BUN, cistatin C, and electrolytes (Na(+), K(+), Cl(-), Ca(2+), P(3+), Mg(2+)) before anaesthesia, and one, three and five days after. RESULTS: There were no statistically significant differences between the groups. CONCLUSIONS: The use of low flow sevoflurane anaesthesia is not associated with an increased risk of nephrotoxicity in those previously exposed to nephrotoxic chemotherapeutic agents.

Administration of CD4+CD25highCD127- regulatory T cells preserves ß-cell function in type 1 diabetes in children.

OBJECTIVE: Type 1 diabetes is a condition in which pancreatic islets are destroyed by self-reactive T cells. The process is facilitated by deficits in the number and suppressive activity of regulatory T cells (Tregs). Here, we show for the first time that the infusion of autologous Tregs prolongs remission in recently diagnosed type 1 diabetes in children. RESEARCH DESIGN AND METHODS: We have administered Tregs in 10 type 1 diabetic children (aged 8-16 years) within 2 months since diagnosis. In total, 4 patients received 10 × 10(6) Tregs/kg body wt, and the remaining 6 patients received 20 × 10(6) Tregs/kg body wt. The preparation consisted of sorted autologous CD3(+)CD4(+)CD25(high)CD127(-) Tregs expanded under good manufacturing practice conditions. RESULTS: No toxicity of the therapy was noted. A significant increase in the percentage of Tregs in the peripheral blood has been observed since the day of infusion. These patients were followed along with matched type 1 diabetic patients not treated with Tregs. Half a year after type 1 diabetes onset (4-5 months after Tregs infusion), 8 patients treated with Tregs still required <0.5 UI/kg body wt of insulin daily, with 2 patients out of insulin completely, whereas the remission was over in the nontreated group. In addition, plasma C-peptide levels were significantly higher in the treated group as compared with those not treated. CONCLUSIONS: This study shows that the administration of Tregs is safe and tolerable in children with recent-onset type 1 diabetes.

Laryngeal dystonia in the course of multiple system atrophy: a cause of postoperative respiratory insufficiency.

Multiple system atrophy (MSA) is an adult onset, incurable neurodegenerative disease, characterized by symptoms of nervous system failure. Occurrence of laryngeal dystonia indicates increased risk of sudden death caused by airway occlusion. We present the case report of 63-year-old patient with history of orthostatic hypotension, parkinsonism, progressive adynamia, and stridor. The patient was admitted to the hospital for diagnosis of orthostatic hypotension. A diagnosis of possible MSA was made. Because of patient's complaints, an X-ray of the hip joint was taken. It revealed femoral neck fracture. Endoprosthesis insertion under general anesthesia was performed. Two days later the patient presented progressive adynamy and respiratory insufficiency. Endotracheal intubation and respiratory support were required followed by extubation and one more intubation. After second extubation, stridor and acute respiratory insufficiency occurred. Urgent tracheostomy was performed. After 13 days in ICU, the patient was discharged to the rehabilitation center.

Analysis of intraoperative transfusions of red blood cell concentrates in adults.

BACKGROUND: Transfusion of red blood cell (RBC) concentrates is the most common allogeneic transplantation. The aim of the study was to analyse the indications for RBC transfusions, compared to the estimated intraoperative blood loss and the actual requirements for blood transfusion. METHODS: We retrospectively analysed the files of 250 adult patients who were transfused over the year 2006, during various general, oncologic, trauma, vascular, plastic and thoracic surgical procedures. Preoperative screening was done in a hospital laboratory, whereas postoperative haemoglobin concentration and haematocrit were assessed at the bedside using a co-oximeter. RESULTS: The majority of RBC transfusions were started at relatively high haemoglobin concentrations (mean 5.6 mmol L⁻¹), contrary to the current guidelines. A high correlation coefficient (r=0.82) was found between the estimated blood loss and the volume of RBCs transfused; therefore we concluded that the observed blood loss was the main factor in transfusion decisions. CONCLUSIONS: Despite enormous progress in transfusion science, the current practice in our institution is still far from ideal; RBCs are frequently transfused too early and without a real indication.

[Does the time of admission to ITU affect mortality?]. / Czy na smiertelnosc w oddziale intensywnej terapii ma wplyw czas przyjecia chorych do oddzialu?

BACKGROUND: Among many factors that may affect mortality among ITU patients, the time of admission has been reported to play some, but ill-defined role. In the retrospective study, we analysed the time of admission, severity of the underlying disease, clinical status on admission and mortality among adult patients treated in a single ITU over a six-year period. METHODS: We compared the mortality of patients who were admitted during daytime (7 a.m. to 6:59 p.m.) and at night (7 p.m. to 6:59 a.m.). We also compared those admitted on weekdays (Monday 7 p.m. to Friday 6:59 a.m.) to those admitted during weekends (Friday 7 p.m. to Monday 7 a.m.). The patients condition was assessed using the APACHE II scale. Brain dead organ donors and readmissions were excluded from the analysis. RESULTS: The retrospective study involved the data of 1789 patients. Mortality was higher in patients who were admitted during the night and during weekends, when compared to daytime and weekdays, respectively. Mortality was also higher in patients admitted directly from the operating theatre after emergency surgery, but only during nights and weekends. The following independent factors in ITU mortality have been identified: length of ITU stay (OR 1.015; % CI 1.005-1.024), admission from a hospital ward (OR 1.39; 95% CI 1.04-1.86) and APACHE II score (OR 1.177; 95% CI 1.156-1.198). CONCLUSION: Time of admission has not been identified as a single independent factor of ITU mortality, but admissions at night and during weekends were associated with higher mortality, probably because of emergency conditions.

Dexmedetomidine sedation for carotid endarterectomy.

BACKGROUND: General anaesthesia and deep sedation during endarterectomy exclude direct contact with the patient, required for safe performance of the surgery. The aim of the study was to assess sedation with dexmedetomidine and its cardiovascular effects. METHODS: Sixty-four adult patients, scheduled on internal carotid artery surgery under infiltration analgesia, were randomly divided to receive dexmedetomidine in the loading dose of 1 microg kg(-1) over 10 min, followed by 0.2 microg kg(-1) h(-1) continuous infusion (group D) or placebo (group P).The BIS score, heart rate (HR) and mean arterial pressure (MAP) were noted. RESULTS: In the group D, during carotid artery clamping (CAC) mean BIS scores were lower, compared to the baseline and to the values recorded in the group P. The BIS scores in the group P did not differ from baseline. In the group D, we did not observe cardiovascular reactions that could be attributed to CAC; in the group P, MAP and HR increased during CAC, and returned to normal 10 min after clamp release. Significant decrease of HR was observed after 12 min of dexmedetomidine infusion, at 10 and 15 min after CAC in group D. Urapidil and fentanyl were administered more often in the placebo group. CONCLUSIONS: The 0.2 microg kg(-1) h(-1) dexmedetomidine infusion, administered during carotid endarterectomy, secured cardiovascular stability and reduced the need for additional analgesia.

Effects of thoracic epidural anaesthesia on cardiac repolarization.

1. Prolongation of the QT interval is associated with a risk of life-threatening cardiac arrhythmias. In the present study, we examined whether reversible blockade of preganglionic sympathetic fibres of the heart, achieved by thoracic epidural anaesthesia, affects cardiac repolarization and thus confers an anti-arrhythmic effect. 2. Fifty-two men, aged between 28 and 65 years, were included in the study: 28 were patients scheduled for thoracic epidural anaesthesia (Group T) and 24 were patients scheduled for lumbar epidural anaesthesia (Group L). Epidural blockade was achieved with 0.5% isobaric bupivacaine solution. Measurements were taken from electrocardiogram fragments obtained before epidural anaesthesia and after detection of blockade (T1 or T8 segment sensory block in Groups T and L, respectively). Correction of the QT interval was calculated using Bazett's formula (QTcb), Fridericia's correction (QTcf) and the Framingham formula (QTcF). Transmural dispersion of repolarization (TDR) was determined using the Tpeak--Tend time, where Tpeak is the peak of the T wave and Tend is the end of the T wave. 3. Significant shortening of the QTcb interval and TDR was detected after blockade in Group T. However, there were no changes in the ECG parameters in Group L. 4. In conclusion, reversible blockade of preganglionic sympathetic fibres to the heart, achieved by thoracic epidural anaesthesia, results in a reduction in QTcb, as well as the TDR. These changes may explain the anti-arrhythmic action seen with central blockade.

Tracheal tube cuff pressure depends on the anaesthesiologist's experience. A follow-up study.

BACKGROUND: Excessive tracheal tube cuff pressure can cause ischemia of the tracheal mucosa, and possible serious complications, such as tracheal stenosis, formation of tracheo-oesophageal fistula or even life-threatening haemorrhage. Inadequate cuff pressure increases the risk of aspiration of gastric contents. METHODS: The cuff pressures were analysed on the basis of the anaesthesiologists' experience. The results were compared to those obtained during the previous study which had been conducted seven years earlier (2002). The physicians were divided into three groups, according to their experience: group I - less than 2 years of practice; group II--2 to 10 years of practice; and group III--over 10 years of practice. High-volume, low-pressure tubes were used for intubation. The anaesthesiologists were not informed of the planned audit. RESULTS: Statistical analysis demonstrated significant differences between cuff pressure readings in the respective study groups. Cuff pressures in group II (p < 0.05) and group III (p < 0.0005) were greater than those in group I. In 2002, no statistically significant differences had been observed between the three groups (p = 0.1156). When comparing results from 2002 and present one differences were observed inside individual groups, concerning group II (p < 0.05) and group III (p < 0.0005). CONCLUSION: There is a tendency to overinflation of endotracheal tube cuffs in all groups. This problem is more common in the group of highly experienced anaesthesiologists, and is more more prevalent at present than in 2002.

Ondansetron given intravenously attenuates arterial blood pressure drop due to spinal anesthesia: a double-blind, placebo-controlled study.

BACKGROUND AND OBJECTIVES: Side effects of spinal anesthesia include arterial hypotension and bradycardia. Both of them may be induced by sympathetic nerve blockade as well as by the Bezold-Jarisch reflex, which may be mediated by peripheral serotonin receptors (5-HT(3) type). The aim of this study was to verify the hypothesis that blockade of type 3 serotonin receptors by intravenous ondansetron administration might reduce hypotension and bradycardia induced by spinal anesthesia. METHODS: Seventy-one patients participated in the study; 36 in the ondansetron group (receiving 8 mg intravenous ondansetron), and 35 in the placebo group (receiving isotonic NaCl solution). Measurements of heart rate and arterial blood pressure were taken every 5 minutes after spinal anesthesia was performed with 4 mL 0.5% hyperbaric bupivacaine solution. RESULTS: Decreases in mean, systolic, and diastolic arterial pressure as well as in heart rate, compared with baseline values were observed in both groups. Minimal systolic and mean blood pressure values obtained over a 20-minute observation period were significantly higher in the ondansetron group. There were no significant differences in diastolic blood pressure and heart rate values between the groups. CONCLUSIONS: Ondansetron given intravenously attenuates the fall of systolic and mean blood pressure, but does not have an influence on diastolic blood pressure or heart rate.

Effect of anaesthetic agents on p-wave dispersion on the electrocardiogram: comparison of propofol and desflurane.

Anaesthetics influence cardiac electrical activity by various mechanisms; thus, they may have pro-arrhythmic or anti-arrhythmic actions. Increased P-wave dispersion is associated with a risk of paroxysmal atrial fibrillation. The aim of the present study was to analyse the impact of propofol and desflurane on changes in P wave dispersion, which may reflect the anti-arrhythmic effects of these drugs. Fifty patients undergoing scheduled surgery were included in the study. Patients were divided into two equal groups: a propofol group and a desflurane group. Patients in the propofol group were initially administered 2.5 mg/kg propofol, followed by infusion of 6 mg/kg per h propofol. Anaesthesia in the desflurane group was achieved using inhalation induction, with concentrations up to 8-12.5 vol%. When signs of adequate anaesthesia were observed, the concentration of desflurane was reduced to 6 vol%. An electrocardiogram (ECG) was obtained before induction and then again 1, 3 and 5 min after the initiation of propofol infusion or the induction of anaesthesia in the desflurane group; additional measurements were performed after tracheal intubation. P-wave dispersion was assessed by differences in maximal and minimal P-wave duration on a 12-lead ECG. P-wave dispersion did not change over time in the desflurane group. In the propofol group, there was a significant decrease in P-wave dispersion after 3 and 5 min of anaesthesia. Significant differences were observed between study groups after 1, 3 and 5 min of anaesthesia, and disappeared after tracheal intubation. Mean and maximal P-wave duration did not change in either group. In conclusion, propofol decreases P-wave dispersion and this seems to be connected with the anti-arrhythmic properties of the drug.

[The use of heart rate variability analysis to determine changes in autonomic nervous system activity induced by laryngoscopy and endotracheal intubation]. / Zastosowanie analizy zmiennosci rytmu serca do oceny zmian aktywnosci autonomicznego ukladu nerwowego wywolanych laryngoskopia i intubacja dotchawicza.

BACKGROUND: Laryngoscopy and intubation are associated with marked autonomic system activation that can be assessed by heart rate variability analysis (HRV)--a new method, comparing R-R intervals in 12-lead continuous ECG recording. METHODS: Fifty-two ASA I and II adults patients of both sexes were enrolled in the study. Patients were induced with fentanyl and thiopental, paralysed with vecuronium, and intubated. Continuous ECG was recorded and selected time-domain parameters (RMSSD, SDNN, NN50 and pNN50) were analyzed before and after intubation at 5- min intervals. RESULTS: Endotracheal intubation resulted in transient supraventricular and ventricular extrasystoles in six patients. Seven patients developed transient bigeminy. Equivocal changes of RMSSD, SDNN, NN50 and pNN50 were observed. CONCLUSION: Because of the large incidence of cardiac rhythm disturbances, the HRV proved to be useless for assessment of autonomic system changes.

Wernicke's syndrome after sleeve gastrectomy.

We report a case of Wernicke's encephalopathy after sleeve gastrectomy, which had been complicated by stomach wall edema and aggravated by dietary non-compliance. Despite intense parenteral nutrition, thiamine deficiency became clinically evident. It suggests that nutritional preparations used were unable to cover the increased thiamine requirement. After intense thiamine supplementation, gradual improvement occurred during the 6 months after the diagnosis, without permanent cognitive impairment. Clinicians involved in postoperative management of bariatric surgery patients must consider Wernicke's syndrome in hyper-emetic patients, who show unclear neurological deterioration. Early diagnosis and treatment can instantly improve the patient's condition without permanent sequelae.

Influence of spinal anesthesia on corrected QT interval.

BACKGROUND AND OBJECTIVES: Prolongation of the QT interval may result in grave cardiac arrhythmias, polymorphic ventricular tachycardia ("torsades de pointes"), and ventricular fibrillation. We assessed the influence of spinal anesthesia on the QTc interval and the potential arrhythmogenicity of this method of anesthesia. METHODS: Assessment was performed in 20 male unpremedicated patients, I or II American Society of Anesthesiologists physical status, who underwent spinal anesthesia for elective surgical procedures. Values of the QTc interval, heart rate, and arterial pressure were measured before spinal anesthesia as well as after 1, 3, 5, and 15 minutes of adequate blockade. RESULTS: Statistically significant lengthening of the QTc interval (compared with initial values) was observed in the first minute after blockade and in subsequent measurements. No differences were observed between mean values of the QTc interval after the onset of blockade. No significant changes in heart rate were noted. From the third minute on, significant decreases of the systolic, diastolic, and mean arterial blood pressure were observed as compared with baseline. These decreases in systolic, diastolic, and mean arterial blood pressure persisted for the entire study duration. No one patient developed clinically important cardiac arrhythmias. CONCLUSIONS: Spinal anesthesia provokes significant QTc interval prolongation in patients without cardiovascular disorders.