Extracorporeal cell therapy of septic shock patients with donor granulocytes: a pilot study

Jens Altrichter, Martin Sauer, Katharina Kaftan, Thomas Birken, Doris Gloger, Martin Gloger, Jörg Henschel, Heiko Hickstein, Ernst Klar, Sebastian Koball, Annette Pertschy, Gabriele Nöldge-Schomburg, Dierk A Vagts, Steffen R Mitzner, Jens Altrichter, Martin Sauer, Katharina Kaftan, Thomas Birken, Doris Gloger, Martin Gloger, Jörg Henschel, Heiko Hickstein, Ernst Klar, Sebastian Koball, Annette Pertschy, Gabriele Nöldge-Schomburg, Dierk A Vagts, Steffen R Mitzner

Abstract

Introduction: Neutrophil granulocytes are the first defense line in bacterial infections. However, granulocytes are also responsible for severe local tissue impairment. In order to use donor granulocytes, but at the same time to avoid local side effects, we developed an extracorporeal immune support system. This first-in-man study investigated whether an extracorporeal plasma treatment with a granulocyte bioreactor is tolerable in patients with septic shock. A further intention was to find suitable efficacy end-points for subsequent controlled trials.

Methods: The trial was conducted as a prospective uncontrolled clinical phase I/II study with 28-day follow-up at three university hospital intensive care units. Ten consecutive patients (five men, five women, mean age 60.3 ± 13.9 standard deviation (SD) years) with septic shock with mean ICU entrance scores of Acute Physiology and Chronic Health Evaluation (APACHE) II of 29.9 ± 7.2 and of Simplified Acute Physiology Score (SAPS) II of 66.2 ± 19.5 were treated twice within 72 hours for a mean of 342 ± 64 minutes/treatment with an extracorporeal bioreactor containing 1.41 ± 0.43 × 10E10 granulocytes from healthy donors. On average, 9.8 ± 2.3 liters separated plasma were treated by the therapeutic donor cells. Patients were followed up for 28 days.

Results: Tolerance and technical safety during treatment, single organ functions pre/post treatment, and hospital survival were monitored. The extracorporeal treatments were well tolerated. During the treatments, the bacterial endotoxin concentration showed significant reduction. Furthermore, noradrenaline dosage could be significantly reduced while mean arterial pressure was stable. Also, C-reactive protein, procalcitonin, and human leukocyte antigen DR (HLA-DR) showed significant improvement. Four patients died in the hospital on days 6, 9, 18 and 40. Six patients could be discharged.

Conclusions: The extracorporeal treatment with donor granulocytes appeared to be well tolerated and showed promising efficacy results, encouraging further studies.

Trial registration: ClinicalTrials.gov Identifier: NCT00818597.

Figures

Figure 1
Figure 1
Schematic view of the study flow.
Figure 2
Figure 2
Schematic drawing of the extracorporeal treatment. Plasma is separated from blood, transferred to the cell-compartment, and then returned to the patient.
Figure 3
Figure 3
Box plots of data describing the time course of C-reactive protein. Significant changes (P < 0.05) vs. inclusion day (indicated by *) and vs. Day 1 (§) were observed.
Figure 4
Figure 4
Box plots of data describing the time course of procalcitonin. Significant changes (P < 0.05) vs. inclusion day (indicated by *) and vs. Day 1 (§) were observed.
Figure 5
Figure 5
Box plots of data describing the time course of HLA-DR expression on CD14 positive monocytes. Significant changes (P < 0.05) vs. inclusion day (indicated by *) and vs. Day 1 (§) were observed.
Figure 6
Figure 6
Box plots of data describing the time course of total daily noradrenaline dosage. Significant changes (P < 0.05) vs. inclusion day (indicated by *) and vs. Day 1 (§) were observed.

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