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  • 1
    ISSN: 1432-055X
    Keywords: Schlüsselwörter SIRS ; Sepsis ; MODS ; Hämodynamik ; Interleukin-2 ; Interferon-α ; Key words SIRS ; Sepsis ; MODS ; Haemodynamics ; Interleukin-2 ; Interferon-alpha
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Abstract Human recombinant interleukin 2 (IL-2), alone or in combination with other cytokines, is currently under investigation for the immunotherapy of metastatic tumours. Objective responses of 20%–35% have been reported in patients with disseminated melanoma and renal cell carcinoma who received high-dose intravenous IL-2 in combination with interferon-α (IFNα). However, treatment with IL-2 is complicated by a syndrome of life-threatening adverse reactions such as disseminated vascular leakage, fluid retention, severe hypotension, and (reversible) multiple organ dysfunction (MODS). A systemic inflammatory reaction (SIRS)/sepsis sepsis-like haemodynamic pattern has been described in patients after IL-2 bolus application alone. Our purpose was to study the haemodynamic changes in patients treated with high-dose IL-2 administered as a constant infusion and in combination with IFNα. Patients and Methods. Haemodynamic variables were obtained during therapy courses of 11 patients (aged 48 to 71 years, median 61) with metastatic renal cell carcinoma receiving immunotherapy with IL-2/IFNα. Therapy consisted in (Fig. 1): IFNα 10·1010 IU/m2 body surface area (BSA) once daily on days 1–5 i.m. on a regular ward, followed by IL-2 as a constant infusion of 18·106 IU/m2 BSA on days 6–11 in an intensive care unit (ICU). Haemodynamics were first measured after 5 days of IFNα application and transfer to the ICU on day 6, a further 24 h after the beginning of IL-2 infusion (day 7), and at the end of the therapy course (days 10 and 11). Mean arterial pressure (MAP) was measured noninvasively using an oscillometric device (Dinamap®, Critikon). Mixed-venous oxygen saturation (sv¯¯ O2) was measured using an CO-oxymeter (OSM 3®, Radiometer) and peripheral arterial oxygen saturation (psaO2) was recorded continuously with a pulse oximeter (Oxyshuttle®, Critikon). In case of haemodynamic instability, stabilisation had priority over invasive haemodynamic measurements, so that nadir values of blood pressure (BP) did not influence mean MAP and are reported separately. Lactate values and criteria for SIRS were obtained before and during IL-2 infusion. Lactate measurements were performed using an enzymatic essay (Abbot FLx®). The mean effect size of the haemodynamic values, SIRS criteria, and lactate concentrations during IL-2 infusion (days 6–11) were calculated, and 95% confidence intervals for the effect sizes are indicated in Table 1. Results. After their daily i.m. injections of IFNα, patients had short episodes of fever and tachycardia without significant drops in BP. A few hours after transfer to the ICU and continuous infusion of IL-2, they developed a syndrome of fever, tachycardia and tachypnoea. The haemodynamic values after 5 days of IFNα therapy remained in the normal range, whereas those during IL-2 infusion strongly resembled SIRS and sepsis, with a decrease in MAP (98 to 82 mm Hg) and systemic vascular resistance (SVR, 1477 to 805 dyn·s·cm−5) and an increase in cardiac output (cardiac index 2.8 to 4.3 l·min−1·m−2) (Fig. 2, Table 1). MAP often had to be stabilised with colloids during the last 48 h of therapy; 5 patients had nadir values below 60 mm Hg, or 30% below basic values in hypertensive patients. Catecholamine therapy became mandatory in 1 patient and therapy had to be discontinued. Surprisingly, some patients already had elevated plasma lactate concentrations after IFNα therapy. During IL-2 infusion mean plasma lactate levels increased from 2.3 to 3.2 mmol·l−1 and all patients had lactate concentrations above 2.0 mmol·l−1 at the end of therapy (Fig. 3, Table 1). During the last 48 to 72 h of IL-2 infusion, patients suffered from MODS with altered mental state (7 patients), oligoanuria (all patients), cardiac dysrhythmias (4 patients), congestive heart failure (1 patient, which led to a second case of therapy interruption), elevated bilirubin (4 patients), and pulmonary dysfunction. In 9 patients supplementary oxygen was necessary when psaO2 fell below 92%. Chest X-rays showed signs of pulmonary interstitial oedema. All patients developed significant generalised oedema due to a vascular leak syndrome, with fluid retention and weight gains of 6.3% during IL-2 infusion (Tables 1 and 2). Leukocyte counts dropped to 3670 μl−1 after 5 days of IFNα injection and rose to 9970 μl−1 at the and of IL-2 infusion. After discontinuation of IL-2 (day 11) the body temperature, heart rate, BP, and criteria of impaired organ function rapidly returned to the normal range, but leukocyte counts rose to 15360-μl−1 on day 12 (Table 1). Conclusion. High-dose IL-2 administered as a constant infusion and in combination with IFNα results in similar haemodynamic changes to those seen during high-dose IL-2 bolus application alone. The observed haemodynamic pattern strongly resembles SIRS and sepsis. MODS, fluid retention, and increases in plasma lactate indicate microcircular disorders. Elevated levels of sepsis mediators such as tumor necrosis factor and interleukin-1, activation of the complement cascade, activated neutrophil granulocytes and endothelial cells have been reported in patients receiving high-dose IL-2 bolus treatment. Our results and data of other investigators lead us to conclude that not only the (macro)haemodynamic pattern of IL-2/IFNα therapy, but also its pathogenetic pathways parallel SIRS and sepsis. IL-2/IFNα immunotherapy may therefore be used as a clinical “model” for sepsis research.
    Notes: Zusammenfassung Die Zytokine Interleukin-2 (IL-2) und Interferon-α (IFNα) werden zur Immuntherapie metastasierender Malignome eingesetzt. In der vorliegenden Studie wurde bei 11 Patienten mit Nierenzellkarzinom die Hämodynamik während einer fünftägigen, hochdosierten, kontinuierlichen IL-2 Infusion in Kombination mit der i.m.-Applikation von IFNα mit einem Pulmonalarterienkatheter invasiv überwacht. Die Patienten entwickelten wenige Stunden nach Beginn der kontinuierlichen IL-2 Infusion ein Syndrom aus Fieber, Tachykardie, Tachypnoe und im weiteren Verlauf Leukozytose (SIRS). Die Hämodynamik ähnelte den hyperdynamen Kreislaufverhältnissen bei SIRS und Sepsis. Hinweise auf eine Mikrozirkulationsstörung ergaben sich aus einem Anstieg der Plasma-Laktatkonzentrationen, muliplen Organfunktionsstörungen und einer erheblichen interstitiellen Flüssigkeitsretention aufgrund eines „vascular leak“-Syndroms. Hieraus und aus der von anderen Autoren beschriebenen Aktivierung von Sepsis-typischen Mediatoren unter IL-2-Applikation schließen wir auf eine weitgehende Parallelität in der Pathogenese von hochdosierter IL-2-/IFNα Therapie und SIRS bzw. Sepsis. Die IL-2-/IFNα Therapie bietet sich daher als klinisches Modell der Sepsis an.
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  • 2
    ISSN: 0942-0940
    Keywords: Cervical spondylosis ; cervical disc ; Cloward procedure ; anterior fusion ; late myelography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary During a 13 year period, 286 patients with cervical disc herniation and/or spondylotic spurs, were subjected to anterior decompression and vertebral interbody fusion with autologous bone. Twenty patients were re-admitted in the late postoperative period due to recurrent radicular symptoms and/or signs of myelopathy. In these patients myelography was performed again. In 14 patients spinal cord compression and/or nerve root involvement at a new level was visualized. At the operated level, however, the myelograms demonstrated a smooth anterior wall in the spinal canal. The series confirms the safety, effectiveness and reliability of the Cloward procedure in achieving long term spinal cord and nerve root decompression, and a solid vertebral interbody fusion.
    Type of Medium: Electronic Resource
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