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.

Released granulocytic elastase: an indicator of pathobiochemical alterations in septicemia after abdominal surgery.

To discover the role of lysosomal enzyme release from polymorphonuclear (PMN) leukocytes during septicemia, plasma levels of PMN elastase were measured with a newly developed enzyme-linked immunosorbent assay for detection of the PMN elastase-alpha 1-proteinase inhibitor complex (E-alpha 1PI). Plasma samples from 41 patients were assayed continuously before and after major abdominal surgery. The patients were divided into a group without infection (group A) and two septicemia groups (survivors in group B and nonsurvivors in group C). The E-alpha 1PI levels of the 11 patients in group A without any signs of pre- or postoperative infection were in the normal range (a normal value of 86.5 +/- 25.5 ng/ml has been reported in 153 healthy subjects), except for a small increase to 208.8 +/- 25.6 ng/ml 12 hours after surgery. When septicemia was confirmed clinically in patients in groups B and C, the E-alpha 1PI levels rose on average to six times the norm in group B (649.9 +/- 116.3 ng/ml) and to more than 10 times the norm in group C (985.0 +/- 154.6 ng/ml). Peak values greater than 2,200 ng/ml could be measured in both groups. In patients in group B, the E-alpha 1PI levels returned to normal during recovery, while in those in group C they remained significantly elevated (560.5 +/- 174.7 ng/ml) until death. Correlations were demonstrated between the amount of elastase released into the circulation and the decrease in the activities of antithrombin III, coagulation factor XIII, and alpha 2-macroglobulin, as well as the increased C-reactive protein in plasma. We conclude that release of elastase and other lysosomal factors from PMN cells plays a major role in the pathobiochemical alterations during septicemia. In addition, significantly elevated E-alpha 1PI levels in the postoperative course seem to be a suitable indicator for onset and persistance of sepsis as well as of the severity of this disorder in patients after major surgery.

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.

Granulocyte proteinases as mediators of unspecific proteolysis in inflammation: a review.

In severe inflammatory response, various blood and tissue cells, including polymorphonuclear granulocytes, release lysosomal proteinases, extracellularly and into the circulation. Such enzymes, as well as normally intracellular oxidizing agents produced during phagocytosis, enhance the inflammatory response by degrading connective tissue structures, membrane constituents and soluble proteins by proteolysis or oxidation. We first used polymorphonuclear elastase (E) as a marker of such release reactions. The liberated proteinase competes with susceptible substrates, including alpha 1-proteinase inhibitor (alpha 1PI) and alpha 2-macroglobulin, and is eliminated finally as inactive enzyme-inhibitor complexes by the reticulo-endothelial system. Using an enzyme-linked immunosorbent assay, we determined the plasma levels of E-alpha 1PI following major abdominal surgery, multiple trauma and pancreatogenic shock. Whereas the operative trauma was followed by up to 3-fold increase of the E-alpha 1-PI, postoperative septicemia was associated with a 10 to 20 fold increase. The increase of E-alpha 1-PI and a concomitant decrease of plasma factors, such as antithrombin III, clotting factor XIII and alpha 2-macroglobulin, were correlated. Multiple trauma causes a substantial increase of E-alpha 1-PI up to 14 hours after accident. The released elastase seems to correlate with severity of injury, but assessing the relationship to consumption of plasma factors is complicated by concomitant transfusions. In acute pancreatitis, peaks, of E-alpha 1-PI coincide with a massive consumption of antithrombin III and alpha 2-macroglobulin during shock.

Kidney transplantation following treatment with cyclophosphamide and bone marrow grafting.

Canine cyclophosphamide (CY) chimeras permanently accept kidney and skin grafts as do radiation chimeras. Three of five dogs with reversion of chimerism rejected their kidney grafts within 11-16 days, while two of them retained their kidney grafts permanently. These results suggest that the reversion of chimerism in CY chimeras may be due to different mechanisms, either immunologic rejection or a nonimmunologic substitution of the grafted marrow by the host's own hemopoiesis.

[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.

[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.

[Problems of intravenous gammaglobulin therapy (author's transl)]. / Probleme der intravenösen Gammaglobulintherapie.

The presently available i.v. gammaglobulines (GG) can be classified into two groups. Degraded GG are produced by pepsin or plasmin digestion. Intact GG are obtained by beta-propiolactone treatment, acidification at pH or precipitation with polyethylenglycol-hydroxyethylstarch (PEG/HES). The various products have different characteristics with regard to their biological activity (certain functions of complement activation and opsonization are connected with the Fc structure) as well as their elimination (intact GG have longer intra- and extravasal half-life times). While their is no doubt about an effect of GG in animal experiments, little controlled studies have been done for most of the clinical indications. One controlled prospective study showed that in surgical high risk patients the frequency of septic complications can be reduced by prophylactic application of high doses of 7 S-GG. For the future, the development of a broad spectrum of hyperimmunoglobulines seems desirable.

[Immunologic properties, aggregate content and half-life of various human i.v. gamma globulin preparations]. / Immunologische Eigenschaften, Aggregatgehalt und Halbwertszeit verschiedener i.v. Human-Gamma-Globulinpräparate.

Anticomplementary activity, aggregate content, and elimination of i.v. human gamma globulin (HGG). During storage of HGG globulin aggregate formation increases leading to anticomplementary activity. Seventeen patients suffering from postoperative sepsis showed significantly faster elimination rates of HGG than 6 healthy controls, while there was no difference in albumin elimination.

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.

[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.

[What therapeutic possibilities exist in acute antibiotic-resistant and chronic infections]. / Welche Therapiemöpglichkeiten gibt es bei akuten Antibiotika-resistenten und chronischen Infektionen?

Since the rate of mortality in severe sepsis could not be changed in the last years even not by sophisticated antibiotics, and since the mutants of bacteria resistant to antibiotics are permanently increasing, other possibilities must be taken into considerations to prevent or to treat infections. The improvement of the patient's own immune resistance by active or passive immunizations seems to be a cooperative or alternative way to overcome severe and chronic infections. In animal experiments the efficacy of gammaglobulin treatment of a severe infection was tested. The positive result i.e. improvement of the mortality from 75% to 45%, stimulated to a controlled clinical study, in which severe infected patients were additionally treated with gammaglobulin and compared with those without gammaglobulin treatment. Patients with gammaglobulin treatment showed a much better outcome of their infection than control patients. The rate of infections as well as time of hospital stay and other clinical and laboratory parameters were markedly improved in gammaglobulin-treated patients. Also the principle of active immunization was tested in animal experiments. Guinea pigs were orally vaccinated with heat inactivated pathogenic bacteria. In a following challenge infection vaccinated animals survived in a high percentage whereas control animals died. This success in vaccinating animals did lead to a controlled clinical study with patients suffering from chronic bone infection. Patients were treated orally with heat inactivated bacteria over a time of 8 weeks. Not only laboratory data indicating an improved immune response were changed by the treatment but also the clinical findings. These results indicate clearly that infections can be treated not only by attacks against bacteria but also by the improvement of the patient's own bacterial resistance.

[Does i.v. gamma globulin counteract postoperative bacterial infections? (authors's transl)]. / Wirkt i.v. Gammaglobulin (GG) gegen bakterielle Infektionen nach operativen Eingriffen?

A prospective, randomized clinical study investigated the effectiveness of IV gamma-globulin (GG) against bacterial infections after surgical procedures. As a result of 20 g GG IV, given postoperatively, the average concentration decrease for IgG (25% - 30%) could be balanced as soon as the third postoperative day, the local infection rate was decreased in the low-risk group, and, with the occurrence of long-lasting local infections, the number of patients with simultaneous septic complications was lowered.

[Efficacy of intravenous gammaglobulin in bacterial infections in Surgical Patients. Results of a controlled, randomized clinical study (author's transl)]. / Wirksamkeit von i. v. Gammaglobulin gegen bakterielle Infektionen chirurgischer Patienten Ergbnisse einer kontrollierten, randomisierten klinischen Studie.

The efficacy of intravenous gammaglobulin injections against postoperative bacterial infections was investigated in a prospective randomized, controlled clinical trial in 150 patients. It was found that after postoperative administration of 20 g i. v. gammaglobulin (Intraglobin) the preoperative serum levels had already been attained on the third day (without gammaglobulin they were lower than before operation on the 8th postoperative day). By means of this substitution it was possible to reduce the number of local infections (p less than 0.01) where moderate risk existed. With more persistent infections the incidence of septicemic complications were lower (p less than 0.05). On the basis of these results the application for certain indications of high doses of intravenous gammaglobulin discussed.

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.

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.

[Long-term graft survival in the xenogeneic system wolf-dog (author's transl)]. / Langzeitüberleben von Hauttransplantaten im xenogenen System Wolf-Hund

In contrast to the zoological definition that wolf and dog belong to different species, it is shown by this study that in terms of immunology both species appear to be even closer related than DL-A compatible and MLC negative unrelated dogs. However, this close relationship is not expressed in DL-A or MLC tissue typing. Wolf skin-graft survival time in untreated dogs was 12,5, in ALG-treated dogs 85,6 days. The survival time in this system may be less dpendent on DL-A or MLC histocompatibility than on other genetic systems, which are hitherto not sufficiently defined. An accidental, speciesspecific accordance in these systems may explain the obviously weak histocompatbility barrier between wolf and dog. It is concluded that in certain species-combinations xenotransplantation could be more successful than random allotransplantation. The availability of a xenogeneic species related to man similar as wolf to dog would markedly facilitate clinical xenotransplantation.