Treatment of severe Candida infections in high-risk patients in Germany: consensus formed by a panel of interdisciplinary investigators.

Now that modern medicine can provide increasing chances of cure to patients with formerly incurable disorders, therapy-related complications play the key role in outcome. Thus, among opportunistic infections, severe candidiasis remains a challenge. A multidisciplinary panel of 20 investigators was formed to find a consensus on antifungal strategies for various underlying conditions in neutropenic and non-neutropenic patients. To record their preferences, the investigators used an anonymous voting system. Among antifungal agents, fluconazole emerged as the major alternative to the classic amphotericin B, being therapeutically at least equivalent but clearly less toxic. Factors that restrict the use of fluconazole include pretreatment with azoles, involvement of resistant species like Candida krusei, and an inability to exclude aspergillosis. Flucytosine can be reasonably combined with both amphotericin B and fluconazole. Within the limited antifungal armamentarium, amphotericin B lipid formulations and itraconazole also appear useful and require further investigation. The general consensus of the group is that antifungal agents should be administered at sufficient dosages, rather early, and often empirically.

Nonsurgical treatment of a severe tracheal rupture after endotracheal intubation.

OBJECTIVE: We report the case of an 82-yr-old woman with a large complete longitudinal tracheal rupture, following endotracheal intubation. The patient was treated nonoperatively with excellent outcome. The diagnostic and therapeutic course as well as other therapeutic options are discussed.

[Value of high dosage fluconazole in therapy of candida infections in intensive care medicine]. / Stellenwert von hochdosiertem Fluconazol zur Therapie von Candida-Infektionen in der Intensivmedizin.

The administration of fluconazole in the ICU setting in dosages of > or = 800 mg/day or > or = 10 mg/kg/day has been reported in about 400 patients with candidiasis of different localisation including candidemia, with a rapidly increasing incidence of serious candidal infections. In Germany, fluconazole is approved for therapy of life-threatening infections caused by Candida spp. and Cryptococcus neoformans in a dosage of up to 800 mg/day. Especially in non-neutropenic patients with life-threatening infections caused by Candida spp., Cryptococcus neoformans and Coccidioides immitis, the results of a limited number of dose-finding trials show dose-dependent response rates. These findings strongly advocate the application of high-dose fluconazole; their evaluation, however, still awaits final clarification. The good safety profile even for maximum dosages of up to 2000 mg/day and the linear, predictable pharmacokinetics up to 1600 mg/day indicate the excellent tolerability of fluconazole in the clinical situation, which justifies prospective, randomized clinical trials with treatment groups as homogeneous as possible for further evaluation of the optimum dosage and duration of treatment in the various types of candidal infection.

[Effect of kinetic therapy on the treatment outcome in patients with post-traumatic lung failure]. / Einfluss der kinetischen Therapie auf den Behandlungsverlauf bei Patienten mit posttraumatischem Lungenversagen.

Intermittent prone positioning (PP) is a promising therapy of patients with severe respiratory failure. Evaluations of patient outcomes can not, to dare, be found in the literature. This study was conducted to investigate the effects of intermittent PP on patients with posttraumatic respiratory failure (PaO2/FiO2 < 280 mmHg) in comparison with conventional therapy in suspine position. The collected data is part of our prospective polytrauma study. 136 polytraumized patients (mean ISS 23.4) were included and evaluated. 77 patients had a severe chest trauma with an AIS > or = 3. Of these, 47 patients developed a respiratory failure. 19 of these patients were treated conventionally in suspine position, 28 patients were intermittently turned prone. Having similar AIS (3.6 vs. 33), the PP-patients had a significantly severer trauma (ISS 35.8 vs. 24.5). Though the injury severity of the PP-patients was much higher, the time of ventilation (32 vs. 31 d) and the ICU stay (39 vs. 36 d) was similar to the patients treated in suspine position. The mortility of PP-patients was 0%, of suspine positioned patients 26%. After the first PP the PaO2/FiO2 ratio increased with an average of 82 mmHg (26-151 mmHg). The FiO2 was reduced from 0.45 (0.35-1.0) to 0.26 (0.21-0.35). Beside the beneficial effect of PP on the oxygenation we have, for the first time evidence that PP improves the outcome of patients with posttraumatic respiratory failure.

[Effect of kinetic therapy on the course of treatment of patients with post-traumatic lung failure]. / Einfluss der kinetischen Therapie auf den Behandlungsverlauf bei Patienten mit posttraumatischem Lungenversagen.

This study was conducted to investigate the effects of intermittent prone positioning of patients with post-traumatic respiratory failure (paO2/FiO2 < 280 mm Hg) in comparison with conventional therapy in a supine position. Although the severity of injury of the prone-positioned patients was much higher (ISS 35.8 vs 24.5), the ventilation time (32 vs 31 days) and ICU stay (39 vs 36 days) were similar to patients treated in the supine position. Besides the beneficial effect of prone positioning on oxygenation, for the first time we have evidence that prone positioning improves the outcome of patients with post-traumatic respiratory failure.

High-dose therapy with fluconazole > or = 800 mg day-1.

Fluconazole dosages greater than 800 mg day-1 have been reported in about 900 patients treated for candidemia, oropharyngeal candidiasis and cryptococcal meningitis in HIV-infected patients, and for initial therapy of endemic mycoses. In patients with life-threatening infections caused by Candida spp., Cryptococcus neoformans and Coccidioides immitis, results of a limited number of dose-finding trials with non-neutropenic and HIV-infected patients show dose-dependent responses. These study results indicate that higher daily doses of fluconazole than are currently approved for these indications are well tolerated and tend to provide better clinical efficacy in selected patient populations. An excellent safety profile of dosages up to 2000 mg day-1 and linear predictable pharmacokinetics up to 1600 mg day-1 appear to justify further clinical investigations to better determine the optimum dosage and duration of treatment.

Deterioration of respiratory function after intra-hospital transport of critically ill surgical patients.

OBJECTIVE: To evaluate the impact of intra-hospital transport of artificially ventilated patients on respiratory function, and to define predictors that may allow estimation of the risk of post-transport pulmonary deterioration. DESIGN: Prospective observation study. SETTING: Surgical ICU, University Hospital. PATIENTS: 49 intra-hospital transports (median Apache-score before transport 21, of 28 consecutive patients (all intubated and mechanically ventilated) were studied. INTERVENTIONS: 32 transports were destined to the radiology department and 17 to the operating theatre. Patients were ventilated during transportation with a transport ventilator. MEASUREMENTS AND RESULTS: The base-line condition of the patients and any changes of hemodynamic function were noted. Arterial blood gases were determined before transport as well as 0.25, 1, 6, 12, and 24 h after return of the patient to the ICU. Of the transports 41 (83.7%) resulted in a decrease of PO2/FIO2-ratio with a deterioration of more than 20% from baseline in 21 cases (42.8%). The impairment of respiratory function lasted longer than 24 h in 10 subjects (20.4%). Ventilation with positive end-expiratory pressure correlated significantly (r = -0.4) with post-transport change of PO2/FIO2-ratio, whereas initial FIO2, initial PO2/FIO2-ratio, Apache II-score, patients' age or transport time did not distinguish between patients with and without a consecutive decrease of pulmonary function. CONCLUSION: Intra-hospital transport of ventilated critically ill patients may result in a considerable and long-standing deterioration of respiratory function. Patients ventilated with positive end-expiratory pressure are at an increased risk and the indication for procedures away from the ICU has to be weighted carefully in these subjects.

[The role of an abdominal injury in follow-up of polytrauma patients]. / Stellenwert der Abdominalverletzung für den Verlauf des Polytraumatisierten.

Patients with multiple injuries were studied retrospectively (n = 483, ISS = 28 pts) and prospectively (n = 133, ISS = 42 pts) to determine the significance of concomitant intraabdominal lesions in the management and outcome of these subjects. In the retrospective part of the investigation 134 patients with intra-abdominal trauma presented with significantly more severe injuries (ISS = 38) as compared to 349 subjects with bland abdomen (ISS = 25). This resulted in a significantly different mortality rate (27 vs 11%). 119 patients with abdominal trauma were managed operatively, with surgery instituted within 4 hrs after the accident in 104 cases. Delayed abdominal surgery was performed in 18 patients due to complications from the initial laparotomy and in 15 cases because of delayed diagnosis. Delayed operations resulted in an increased rate of local complications (33 vs. 6%). In the prospective part of the study 33 out of 133 patients succumbed during resuscitation. In 14 of these, intractable bleeding from abdominal lesions was identified as the cause. In the 100 primary survivors, there was found no difference between 41 patients with and 59 patients without abdominal pathology with respect to injury severity, mortality, complications, initial hemodynamic parameters or the secondary release of inflammatory mediators. However, the initial requirement for red blood cell substitution was significantly higher in subjects with intra-abdominal trauma. Our results demonstrate that massive intra-abdominal hemorrhage may cause early mortality. In primary survivors, abdominal lesions have not shown to be of prognostic relevance, provided that early resuscitation, early diagnosis and early operative therapy can be instituted.

Increased serum concentrations of procollagen type III peptide in severely injured patients: an indicator of fibrosing activity?

OBJECTIVES: To determine the serum concentrations of procollagen type III peptide in severely injured patients with different outcomes and to evaluate the relationship between serum procollagen type III peptide concentrations, sources of increased posttraumatic fibrotic activity (wounds, lung, liver, kidney), and decreased elimination of procollagen type III peptide (liver). DESIGN: Prospective study. SETTING: Surgical ICU, university hospital. PATIENTS: Fifty-seven patients (mean injury severity score: 38.5 points, range 13 to 75 points), between 16 and 70 yrs of age, treated in our institution within 6 hrs after the accident. MEASUREMENTS: Serial measurements were started on admission and continued on a 6-hr basis. After 48 hrs, the monitoring interval was extended to 24 hrs until recovery (but at least until day 14) or death. At each point of evaluation, pulmonary and circulatory function parameters and chest radiographs (once a day) were evaluated, the results were recorded, and blood samples were drawn to determine procollagen type III peptide, total bilirubin, creatinine, gamma-glutamyl transferase, polymorphonuclear elastase, and other parameters. Statistic evaluation was done with the Wilcoxon test, Spearman rank correlation, and a multiple regression model. RESULTS: Mean procollagen type III peptide serum concentrations (+/- SD) were significantly different in patients who died (8.0 +/- 3.8 U/mL) compared with those patients who survived with organ failure (2.7 +/- 1.3 U/mL) or without complications (1.4 +/- 0.5 U/mL), respectively. Significant correlations of procollagen type III peptide concentrations with the serum bilirubin concentrations (r = .7), days with need of mechanical ventilation (r = .64), PaO2/FIO2 ratio (r = -.6), polymorphonuclear elastase (r = .6), serum creatinine concentrations (r = .55), and injury severity score (r = .33) were observed. There was a tendency toward higher serum procollagen type III peptide concentrations in patients with severe skeletal injuries. CONCLUSIONS: Serum procollagen type III peptide concentrations in severely injured patients may be considerably increased in correlation with injury severity and outcome. Procollagen type III peptide serum concentrations seem to reflect the sum of increased collagen formation from wound healing and fibrogenesis of mediator-related organ damage (especially lung) and decreased procollagen type III peptide excretion due to impaired liver function. Further data are necessary to evaluate the role of hepatic elimination in these patients.

Inflammatory mediators, infection, sepsis, and multiple organ failure after severe trauma.

The relation of (multiple) organ failure (OF) to the release of inflammatory mediators and the incidence of infection and sepsis was studied prospectively in 100 patients with multiple trauma (injury severity score = 37). Sixteen patients died of OF, 47 patients survived OF, and 37 patients had no OF. Fifteen (24%) of the patients with OF showed no signs of infection. In patients with early onset of OF (n=45), infection followed with a lag of 2 or more days. In 16 (44%) of these patients, infection led to a deterioration in organ function. With late onset of OF (n=18), infection preceded OF in nine patients. Polymorphonuclear leukocyte-elastase, neopterin, C-reactive protein, lactate, antithrombin III, and phospholipase A discriminated significantly among the three outcome groups. Of all factors, only polymorphonuclear leukocyte-elastase showed a difference between patients with and without infection or sepsis, respectively. These data indicate that infection might not play a crucial role in the pathogenesis of posttraumatic OF in a substantial portion of patients with trauma. Early OF, especially, seems to be mainly influenced by the direct sequelae of tissue damage and shock (eg, the release of inflammatory mediators). Since infection and sepsis did not lead to an augmented release of mediators in patients with trauma, the role of both entities remains unclear.

[Biochemical factors as objective parameters for assessing the prognosis in polytrauma]. / Biochemische Faktoren als objektive Parameter zur Prognoseabschätzung beim Polytrauma.

One hundred patients with multiple injuries (mean ISS 37 patients) were prospectively evaluated over a period of 14 days following trauma. Significant differences in the blood levels of PMN elastase, cathepsin B, lactate, neopterin, C-reactive protein (CRP) and antithrombin III (ATIII) were found in non-survivors and in survivors with and without organ failure. On admission, a prediction of organ failure was possible with an accuracy of 63% to 69% (PMN elastase, cathepsin B, ATIII). Death was predictable with an 80% to 90% accuracy within the first 4 days (PMN elastase, lactate, CRP, neopterin). The prognostic value of these factors was comparable to trauma scores regarding organ failure and better with respect to death. Biochemical parameters may be helpful in estimating the severity of the injury and prognosis and in monitoring the ICU course of such patients.

[Is there a favorable time for the management of femoral shaft fractures in polytrauma?]. / Günstigster Operationszeitpunkt für die Versorgung von Femurschaftfrakturen beim Polytrauma?

Despite the wide-spread opinion, that early stabilisation of femur fractures in multiply injured patients is of advantage, there are no publications that unambiguously prove this statement. In contrast, primary fracture stabilisation of the femur with concomitant thoracic trauma seems to increase the rate of complications. The biochemical data of the prospective study presented here suggest, that operative stabilisation of femoral fractures imposes an additional trauma on the already compromised organism. The period between days 2 to 4, when the primary activation of humoral and cellular mediators has returned to normal levels, seems to be the best time for osteosyntheses of these fractures. The operation in this period allows intramedullary fixation--the biologically and biomechanically best fixation procedure--with low risk.

Prognostic value of serum phospholipase A in the multitraumatized patient.

Phospholipase A serum activity was prospectively studied in 39 patients with multiple trauma. There was no correlation of phospholipase A activity with type or severity of injury. With increasing phospholipase A levels, a rise in mortality was found. A prediction of fatal outcome on an individual basis was not possible. The sensitivity for complications was 90%, whereas the predictive value of the positive test (64%) and specificity (47%) were low. When the behavior of phospholipase A and elastase release were compared, no correlation between these two parameters could be detected. Therefore, PMN leukocytes do not seem to be a major source of phospholipase A in serum.

Pathobiochemistry of sepsis: role of proteinases, proteinase inhibitors and oxidizing agents.

Degradation of structural elements and excessive consumption of humoral factors, especially of plasma proteinase inhibitors, by proteolysis and/or oxidation is a major cause of multiple organ failure in sepsis or septic shock. Such pathobiochemical reactions seem to be induced primarily by extracellularly liberated lysosomal proteins from PMN granulocytes (e.g. elastase, cathepsin G, myeloperoxidase, lactoferrin) as well as oxygen radicals produced during extensive phagocytosis. In clinical studies on septicemia and septic shock the consumption of plasma proteins including proteinase inhibitors was inversely correlated to the liberation of lysosomal factors, especially the granulocytic elastase. Administration of relatively specific elastase-cathepsin G-inhibitors (Bowman-Birk inhibitor, eglin) in experimental septicemia proved to be a promising therapeutic approach to reduce consumption of plasma proteinase inhibitors and development of interstitial lung edema in severe inflammation.