Pharmacokinetics and clearance of ganciclovir during continuous hemodiafiltration.

OBJECTIVE: To evaluate the ganciclovir pharmacokinetics and clearance during continuous venovenous hemodiafiltration. DESIGN: Case report. SETTING: General intensive care unit of a tertiary care emergency department. PATIENTS: A 63-yr-old female who has a history of active behçet's disease that has been controlled with oral prednisolone, and who has chronic renal failure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A 5-mg/kg dosage of ganciclovir was administered intravenously over a 60-min period under continuous venovenous hemodiafiltration. Samples from the arterial and venous blood catheters and from the ultradiafiltrate were collected over the next 12 hrs to calculate pharmacokinetic parameters and clearance of hemodiafiltration. The pharmacokinetic parameters were as follows: half-life of elimination phase 12.6 hrs; total clearance 0.55 mL/min/kg; and volume distribution of steady state 27.07 L. The clearance of hemodiafiltration was 0.63 mL/min/kg. CONCLUSION: Continuous venovenous hemodiafiltration is effective in removing ganciclovir from the blood.

Participation of tissue factor and thrombin in posttraumatic systemic inflammatory syndrome.

OBJECTIVE: To determine the roles of tissue factor and thrombin on the systemic inflammatory response syndrome (SIRS) in posttrauma patients, as well as to investigate the relationship between SIRS and sepsis. DESIGN: Prospective, cohort study. SETTING: General intensive care unit of a tertiary care emergency department. PATIENTS: Forty trauma patients were classified into subgroups, according to the duration of SIRS: non-SIRS patients (n = 9); patients with SIRS for < 2 days (n = 15); and patients with SIRS for > 3 days (n = 16). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Tissue factor antigen concentration, prothrombin fragment F1+2, thrombin antithrombin complex, fibrinopeptide A, and cross-linked fibrin degradation products (D-dimer) were measured on the day of admission, and on days 1 through 4 after admission. Simultaneously, the number of SIRS criteria that the patients met and the disseminated intravascular coagulation score were determined. The results of these measurements, frequency of acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome, sepsis, and outcome were compared among the groups. The values of all five hemostatic molecular markers in the patients with SIRS for > 3 days were significantly more increased than those molecular marker values measured in the other groups on the day of admission. These values continued to be markedly high up to day 4 of admission. The occurrence rates of disseminated intravascular coagulation in these patient groups were significantly higher than those rates in the other two groups (p = .0001), and the disseminated intravascular coagulation scores did not improve during the study period. The occurrence rates of ARDS (p < .05) and multiple organ dysfunction syndrome (p < .01) were higher in patients with SIRS for > 3 days compared with those rates in the other groups, and the patients with SIRS for > 3 days had a poor outcome. No significant difference was noted in the frequency of sepsis among the groups. CONCLUSIONS: Sustained SIRS is the main determinant for ARDS, multiple organ dysfunction syndrome, and outcome in posttrauma patients. Disseminated intravascular coagulation associated with massive thrombin generation and its activation is involved in the pathogenesis of sustained SIRS. Sepsis has a small role in early posttrauma multiple organ dysfunction syndrome.

Increased neutrophil elastase, persistent intravascular coagulation, and decreased fibrinolytic activity in patients with posttraumatic acute respiratory distress syndrome.

BACKGROUND: To investigate the role of plasma neutrophil elastase (elastase-alpha1-proteinase inhibitor complex), plasminogen activator inhibitor-1 (PAI-1), and disseminated intravascular coagulation (DIC) in patients with posttraumatic acute respiratory distress syndrome (ARDS) and to explore the time course of the changes of these factors after trauma, we performed a prospective case-control study. METHODS: The study subjects consisted of 41 trauma patients, 5 with ARDS, 7 at risk for but not developing the syndrome, and 29 control patients without or with no risk for ARDS. Plasma neutrophil elastase, PAI-1 activity, and PAI-1 antigen concentration were measured on the day of the injury and on days 1, 3, and 5 after admission. DIC was measured on the basis of the DIC score. The results of these measurements and demographic data were compared among the three groups. RESULTS: Neutrophil elastase, PAI-1 activity, and PAI-1 antigen concentration for the ARDS patients continued to be markedly high until the fifth day of admission, and the values on the fifth day were significantly higher than those of the other two groups. All patients with ARDS developed DIC. A decrease in the DIC score was found for the control patients and also for the patients at risk for ARDS; however, for the patients with ARDS, the DIC score did not improve during the study period (p = 0.5809). CONCLUSION: We provide precise information on the time course of neutrophil elastase, PAI-1, and DIC in trauma patients with ARDS and those at risk of developing this syndrome. Neutrophil activation and persistent intravascular coagulation as well as impaired fibrinolysis may play a role in the pathogenesis of posttraumatic ARDS.

Massive fibrin formation with consecutive impairment of fibrinolysis in patients with out-of-hospital cardiac arrest.

Hypoxia and ischaemia influence blood coagulation and fibrinolysis. This study has been made to determine whether human cardiopulmonary arrest causes fibrin formation and reduction of fibrinolysis. Serial levels of fibrinopeptide A (FPA), fibrinopeptide B beta 15-42 (FPB beta 15-42), D-dimer, tissue plasminogen activator antigen concentration (t-PA antigen), t-PA activity, plasminogen activator inhibitor-1 antigen concentration (PAI-1 antigen), and PAI-1 activity were determined in 63 patients with out-of-hospital cardiopulmonary arrest. In the resuscitated patients, the markedly elevated FPA (194.8 +/- 54.2 ng/ml) at the beginning of cardiopulmonary resuscitation (CPR) significantly decreased to 32.4 +/- 9.1 ng/ml at 24 h after admission (p < 0.01), however, this was still about 20 times that of the normal controls. FPB beta 15-42 and D-dimer increased from the start of CPR to 60 min (189.3 +/- 97.4 ng/ml; p < 0.01 and 7726 +/- 3556 ng/ml; p < 0.001, respectively), and then decreased at 24 h after arrival at the Emergency Department (40.4 +/- 11.1 ng/ml and 5434 +/- 1049 ng/ml, respectively). At 30 min after arrival, FPA and FPB beta 15-42 significantly differed between the resuscitated patients and the patients who died (p < 0.001 and P < 0.05, respectively). Although t-PA antigen and t-PA activity was elevated at the time of arrival, 24 h thereafter, no-t-PA activity was detected. At 24 h after admission, PAI-1 antigen and PAI-1 activity were significantly increased (472.2 +/- 145.5 ng/ml; p < 0.001 and 103.6 +/- 36.1 IU/ml; p < 0.001, respectively). In conclusion, during and after CPR in patients with out-of-hospital cardiac arrest, massive fibrin generation with consecutive impairment of fibrinolysis were observed. These fibrin-mediated events may have some role in the derangement of vital organ function after cardiac arrest.

Platelet activation with massive formation of thromboxane A2 during and after cardiopulmonary resuscitation.

OBJECTIVE: Hypoxia and ischemia cause endothelial cell damage with consequent platelet activation. The hypothesis that human cardiac arrest accelerates platelet activation and the formation of prostanoids was tested. DESIGN: Prospective, observational cohort study. SETTING: Emergency Department and general Intensive Care Unit in a city hospital. INTERVENTIONS: Basic and advanced life support. PATIENTS AND PARTICIPANTS: Forty-seven out-of-hospital cardiac arrest patients. The patients were classified into two groups, those who were resuscitated (n = 18) and those who died (n = 29). MEASUREMENTS AND RESULTS: Serial levels of platelet aggregation, thromboxane B2 (TXB2), 11-dehydro-TXB2 and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were measured. The results of measurements and demographic data were compared between the groups. Platelet counts decreased at the end of cardiopulmonary resuscitation (CPR), the decrease of the platelet counts showed statistical significance especially in the patients who died (p < 0.001). Platelet aggregation induced by adenosine diphosphate, epinephrine and collagen decreased to the lower limits of normal during and after CPR. Although high values of TXB2 and 11-dehydro-TXB2 continued throughout the study period in the resuscitated patients, 6-keto-PGF1 alpha decreased to the normal range (22.7 +/- 3.6 pg.ml-1. p < 0.05 at -24 h after arrival at the Emergency Department. CONCLUSIONS: Platelet activation with the massive formation of thromboxane A2 (TXA2) occurs in patients with out-of-hospital cardiac arrest. Successful resuscitation is not associated with the balanced production of PGI2 against the TXA2 formation.

Ionized hypocalcemia during out-of-hospital cardiac arrest and cardiopulmonary resuscitation is not due to binding by lactate.

OBJECTIVE: To determine the relationship between ionized calcium concentrations and blood lactate levels during cardiac arrest and cardiopulmonary resuscitation (CPR). DESIGN: A prospective cohort study. SETTING: Emergency department (ED) and general intensive care unit in a city hospital (tertiary care center). PATIENTS AND PARTICIPANTS: 32 patients with out-of-hospital cardiac arrest; 14 of the patients had a return of spontaneous circulation (ROSC) and 18 of the patients died. INTERVENTIONS: Basic and advanced life support. MEASUREMENTS AND RESULTS: Concentrations of ionized and total calcium, bicarbonate, lactate, and pyruvate and pH were simultaneously determined immediately upon arrival at the ED, and at 30 and 60 min. Upon arrival at the ED, all patients had ionized hypocalcemia (1.09 +/- 0.02 mmol/l). Ionized and total calcium concentrations progressively decreased during and after CPR, but pH and bicarbonate concentrations did not show any significant changes. In patients who had ROSC, a significant, but perhaps not clinically relevant, relationship was observed between the ionized calcium concentrations and pH (r2 = 0.152, p = 0.0117). In the patients who died, there were significant correlations between ionized calcium and pH (r2 = 0.382, p = 0.0001) and bicarbonate concentrations (r2 = 0.298, p = 0.0006). No definite correlations were demonstrated when comparing ionized calcium concentrations with lactate and pyruvate concentrations. CONCLUSIONS: Ionized hypocalcemia during out-of-hospital cardiac arrest and CPR is not due to binding by both lactate and pyruvate, but may be partly due to complexing by bicarbonate, with some modifications due to variations in pH.

[Two cases of severe cytomegalovirus pneumonitis treated with permissive hypercapnia].

Two patients with severe cytomegalovirus (CMV) pneumonitis were treated with permissive hypercapnia. Case 1 was a 66-year-old male who suffered ventricular septal perforation caused by acute myocardial infarction. Case 2 was a 54-year-old male who sustained a blunt chest injury. In both cases, hypoxia with reduction of lung compliance developed after their operations. They were mechanically ventilated and we limited their peak inspiratory pressure, disregarding hypercapnia (i.e. permissive hypercapnia). During permissive hypercapnia, the maximum arterial partial pressure of carbon dioxide (PaCO2) was 96 mmHg in case 1 and 141 mmHg in case 2. Duration of hypercapnia (PaCO2 > 50mmHg) was 22 days in case 1 and 29 days in case 2. The patients were weaned from the respirator after two months of mechanical ventilation. In conclusion, the permissive hypercapnia was a useful method in the treatment of severe CMV pneumonitis.

Disseminated intravascular coagulation is a frequent complication of systemic inflammatory response syndrome.

To evaluate the role of disseminated intravascular coagulation (DIC) and to determine the influence of antithrombin, protein C, and plasminogen activator inhibitor 1 on multiple organ dysfunction syndrome (MODS) and outcome in patients with systemic inflammatory response syndrome (SIRS), we made a prospective cohort study. The study subjects consisted of thirty-five patients who exhibited two or more of the conditions of SIRS for more than three consecutive days. They were classified into subgroups of survivors (n = 13) and nonsurvivors (n = 22). The global coagulation and fibrinolytic markers, antithrombin, protein C, and plasminogen activator inhibitor 1 were measured on the day of the diagnosis of SIRS, and also on the 1st, 3rd, and 5th days. The results of these measurements, demographic data, criteria of severity, incidence of MODS were compared between the subgroups. For prediction of patient's death, a receiver operating characteristic (ROC) curve analysis was made. DIC was frequently associated with SIRS patients (29/35, 82.9%). A significant decrease in the DIC score was found in the survivors (p = 0.0001). None of them suffered from DIC on the 5th day. In the nonsurvivors, low levels of protein C and antithrombin and markedly high values of plasminogen activator inhibitor 1 continued up to the 5th day, no improvement of the DIC was observed during the study period and the number of the dysfunctioning organs were significantly higher than in the survivors. Plasminogen activator inhibitor 1 on the 5th day had prognostic value for the prediction of death on the SIRS patients. In conclusion, DIC occurs commonly in patients with SIRS and may be the main determinant for the outcome of these patients. Changes in antithrombin, protein C, and plasminogen activator inhibitor 1 are one of the aggravating factors of MODS. Furthermore, plasminogen activator inhibitor 1 is a good predictor of death in these patients.

Cytokines, soluble thrombomodulin and disseminated intravascular coagulation in patients with systemic inflammatory response syndrome.

To investigate the relationships between tumor necrosis factor-alpha (TNF), interleukin-1 beta (IL-1 beta), soluble thrombomodulin (TM), and disseminated intravascular coagulation (DIC) in patients with systemic inflammatory response syndrome (SIRS), twenty-nine SIRS patients were classified into three groups; 4 patients without DIC, 8 DIC patients who recovered, and 17 DIC patients who did not recover. Serum TNF, IL-1 beta, and soluble TM were measured on the day of the diagnosis of SIRS, and also on the 1st, 3rd, 5th days. All of the DIC patients had multiple organ dysfunction syndrome (MODS) and the number of the dysfunctioning organs showed significant differences between the groups (p = .0017). All of the patients who did not recover from DIC died. The serum soluble TM level was higher in the patients without DIC recovery than in either the DIC recovery patients or the non DIC patients throughout the study period. In DIC patients who did not recover, there were significant correlations between soluble TM and TNF (r2 = 0.205, p = .0003) or IL-1 beta (r2 = 0.157, p = .0036). In conclusion, the DIC being associated with endothelial injury is an important pathogenetic factor for MODS and is a main determinant of the outcome of SIRS patients. TNF and IL-1 beta might be involved in the cause of this endothelial injury. The soluble TM is a good predictor of organ dysfunction and also of a poor prognosis.

Soluble thrombomodulin increases in patients with disseminated intravascular coagulation and in those with multiple organ dysfunction syndrome after trauma: role of neutrophil elastase.

OBJECTIVE: Our goal was to investigate the role of soluble thrombomodulin (TM) and neutrophil elastase in patients with trauma. DESIGN: This study is a prospective case-control study. MATERIALS AND METHODS: Forty-seven trauma victims, 14 with disseminated intravascular coagulation (DIC), 5 with multiple organ dysfunction syndrome (MODS), and 28 control patients without DIC or MODS were the participants. Soluble TM and neutrophil elastase (elastase-alpha1-proteinase inhibitor complex) were measured on the day of the injury, and on the first, third, and fifth days after admission. The results of these measurements and demographic data were compared among the groups, and correlations between the soluble TM and the neutrophil elastase were examined. The DIC patients were classified into subgroups of survivors (n = 5) and nonsurvivors (n = 9), and the changes of the soluble TM between the subgroups were then studied. MEASUREMENTS AND MAIN RESULTS: A high incidence of DIC patients encountered MODS complications (12 of 14, 86%). The DIC patients had higher Injury Severity Scores (ISSs) than the other patients. The levels of soluble TM and neutrophil elastase significantly increased on the day of admission in the patients with DIC and also in those with MODS (p < 0.05 vs. control patients) and continued to show markedly high values until the fifth day of admission in the patients with DIC. In the DIC patients, the levels of soluble TM were higher in the nonsurvivors than in the survivors (p < 0.05 on the third and the fifth days of admission). In all patients, there was weak but statistically significant correlation between peak levels of soluble TM and ISS (r2 = 0.125, p < 0.025). Comparison of the levels of soluble TM and neutrophil elastase in the patients with DIC or MODS demonstrated an excellent correlation (r2 = 0.718 and r2 = 0.714, respectively). CONCLUSIONS: Soluble TM as a novel endothelial cell injury marker increases in patients with DIC and also in those with MODS after trauma. Neutrophil elastase may be involved in the pathogenesis of the injury. Soluble TM is a marker of the severity of injury and is a good predictor of MODS.

[A patient with hepatoma and hepatic cirrhosis showing abnormally high blood morphine concentration after periodical suppository administration].

Morphine hydrochloride 10 mg suppository was given every 6 hours in a patient with hepatoma and hepatic cirrhosis. The serum morphine concentration increased continuously until 4 hours after the second administration, and peak level showed 17 ng.ml-1. Morphine-6-glucuronide and morphine-3-glucuronide in the serum persisted at low levels of 32.4 ng.ml-1 and 169 ng.ml-1 respectively. Three days after the administration, morphine suppository had to be discontinued because of severe nausea and vomiting. It should be noticed that a remarkable reduction in morphine metabolism may occur and this may lead to unexpected high serum concentration of morphine in a patient with hepatic dysfunction.

[Anesthetic management of a patient with Chubby Puffer syndrome].

Chubby Puffer syndrome produces symptoms such as sleep apnea, cor pulmonale and upper airway obstruction due to adenotonsillar enlargement. We gave anesthesia for adenotonsillectomy in a 6-year-old boy with this syndrome. The child was massively obese. Anesthesia was induced with thiamylal, nitrous oxide and enflurane by monitoring SaO2. Tracheostomy was performed following orotracheal intubation because of possible difficult postoperative course. At the beginning of operation arterial blood studies showed hypoxemia. Positive end-expiratory pressure ventilation was effective to improve oxygenation. After adenotonsillectomy the symptoms were relieved.

[Three cases of Meige syndrome treated with facial nerve block].

Three cases of Meige syndrome with severe bilateral facial spasm were reported. All patients suffered from abnormal facial movement characterized by blepharospasm and oromandibular dystonia, and had atrophic changes of bilateral basal ganglia which were recognized by brain CT scan. Bilateral facial nerve block at the foramen stylomastoideum was applied to those three patients. Excellent results were obtained by this block technique in all the patients. The technique is not so sophisticated and is recommended for the treatment of the patient with Meige's syndrome.

[The influence of different volatile inhaled anesthetics on the plasma protein binding of lidocaine].

The author investigated the interactions of protein binding of lidocaine by inhaled anesthetics (halothane, enflurane, isoflurane and sevoflurane in vitro and in vivo. In the in vitro study, no significant changes of protein binding ratio were observed between the controls and any concentrations of the inhaled anesthetics even under high concentration (10 MAC). However, the percent of protein binding was inversely related to the total plasma lidocaine concentration. At lidocaine concentrations of 2, 5 and 9 micrograms.ml-1, the binding ratios were 66.37 +/- 5.36 (%), 55.58 +/- 4.38(%) and 51.66 +/- 4.12(%) respectively. By regression analysis (in vivo), the following relationship was obtained. Y = -0.66X +/- 57.4 (Y: % of protein binding fraction, X: lidocaine concentration). In terms of lidocaine protein binding, there seems to be no hazard in using lidocaine with any inhaled anesthetics.