Healthcare Utilization and Costs in Sepsis Survivors in Germany-Secondary Analysis of a Prospective Cohort Study

Background: Survivors of sepsis often face long-term sequelae after intensive care treatment. Compared to the period of hospitalization, little is known about the ambulatory healthcare utilization in sepsis patients. The study evaluated healthcare utilization and associated costs of sepsis care including allied health professions after initial hospitalization. Methods: Secondary analysis was performed on data in 210 sepsis patients prospectively enrolled from nine intensive care study centers across Germany. Data was collected via structured surveys among their Primary care (Family-) physicians (PCPs) within the first month after discharge from ICU (baseline) and again at 6, 12 and 24 months after discharge, each relating to the period following the last survey. Costs were assessed by standardized cost unit rates from a health care system’s perspective. Changes in healthcare utilization and costs over time were calculated using the Wilcoxon rank-sum test. Results: Of the 210 patients enrolled, 146 (69.5%) patients completed the 24 months follow-up. In total, 109 patients were hospitalized within the first 6 months post-intensive care. Mean total direct costs per patient at 0–6 months were €17,531 (median: €6047), at 7–12 months €9029 (median: €3312), and at 13–24 months €18,703 (median: €12,828). The largest contributor to the total direct costs within the first 6 months was re-hospitalizations (€13,787 (median: €2965). After this first half year, we observed a significant decline in inpatient care costs for re-hospitalizations (p ≤ 0.001). PCPs were visited by more than 95% of patients over 24 months. Conclusions: Sepsis survivors have high health care utilization. Hospital readmissions are frequent and costly. Highest costs and hospitalizations were observed in more than half of patients within the first six months post-intensive care. Among all outpatient care providers, PCPs were consulted most frequently. Clinical impact: Sepsis survivors have a high healthcare utilization and related costs which persist after discharge from hospital. Within outpatient care, possible needs of sepsis survivors as physiotherapy or psychotherapy seem not to be met appropriately. Development of sepsis aftercare programs for early detection and treatment of complications should be prioritized

Peripheral mechanisms of electroacupuncture in inflammatory pain

Die Grundlage für diese Arbeit bildete ein Modell mit CFA-(komplettes Freundsches Adjuvant) induziertem Entzündungsschmerz in Ratten, bei denen eine zweimalige Behandlung mit Elektroakupunktur zu einer langanhaltenden Antinozizeption führte, welche abhängig von peripheren Opioiden war. In einem nächsten Schritt sollten nun die durch Akupunktur vermittelten Zytokin- und Chemokinveränderungen untersucht und deren Beitrag zu den antinozizeptiven und anttiinflammatorischen Mechanismen geklärt werden. Mittels ELISA und PCR wurden die Protein- und mRNA-Level der klassischen Zytokine und des Chemokins CXCL10 bestimmt. CXCL10, welches durch Elektroakupunktur sowohl auf Transkriptions- als auch auf Translationsebene hochreguliert wurde, ist notwendig für die Rekrutierung β-Endorphin haltiger Makrophagen in das entzündete Gewebe und für die antinozizeptive Wirkung der Akupunkturbehandlung. Ein antiinflammatorischer Effekt der Akupunkturbehandlung äußerte sich durch die Reduktion von TNF-α und IL-1β und ein erhöhtes IL-13. Das einzige hochregulierte proinflammatorische Zytokin war IFN-γ. Ein Teil der entzündungshemmenden Wirkung, die Reduktion der proinflammatorischen Zytokine TNF-α und IL-1β, wird durch Adenosin-2B-Rezeptoren vermittelt, welche bekannt sind für ihre Rolle in der „Deaktivierung“ IFN-γ-stimulierter Makrophagen. Diese Ergebnisse verweisen auf die bisher unbekannte Verbindung zwischen chemokinvermittelter peripherer, opioidabhängiger Antinozizeption durch Elektroakupunktur. Sie erweitern das Verständnis für das Zusammenspiel von Immunzellen, Adenosin und Akupunktur. Weitere Untersuchungen sind notwendig, um neuroimmunologische Verbindungen zu klären und die Wirkungen durch die Nadelinsertion mit Effekten in der entfernten Rattenpfote besser zu verstehen.This work is based on a rat model with complete Freund's adjuvant (CFA)-induced hind paw inflammation. Animals were treated twice with electroacupuncture eliciting long-term antinociception, which depended on peripheral opioids. In a next step we wanted to study acupuncture mediated changes in cytokine and chemokine profiles and their contribution to antinociceptive and anti-inflammatory mechanisms. For the measurement of protein and mRNA levels of classical cytokines and the chemokine CXCL10 ELISA and real-time PCR were used. CXCL10, which was upregulated on transcriptional and translational level, increased infiltrating β-endorphin containing macrophages within the inflamed tissue and was necessary for the antinociceptive effect of acupuncture treatment. Anti-inflammatory effects were seen in changed cytokine profiles with decreased TNF-α and IL-1β and increased IL-13. The only pro-inflammatory cytokine which was upregulated was IFN-γ. The anti-inflammatory effect caused by the changed cytokines may partly be mediated by Adenosine-2B Receptors, known for their deactivation of IFN-γ stimulated macrophages. In summary these results show a novel connection of chemokine-mediated, peripheral, opoid-dependent antinociception in electroacupuncture. They expand our understanding of the interaction of immune cells, adenosine and acupuncture. More research is needed to examine neuroimmunological mechanisms and the connection between needle insertion and detected effects in the rat paw

CXCL10 Controls Inflammatory Pain via Opioid Peptide- Containing Macrophages in Electroacupuncture

Acupuncture is widely used for pain treatment in patients with osteoarthritis or low back pain, but molecular mechanisms remain largely enigmatic. In the early phase of inflammation neutrophilic chemokines direct opioid-containing neutrophils in the inflamed tissue and stimulate opioid peptide release and antinociception. In this study the molecular pathway and neuroimmune connections in complete Freund's adjuvant (CFA)-induced hind paw inflammation and electroacupuncture for peripheral pain control were analyzed. Free moving Wistar rats with hind paw inflammation were treated twice with electroacupuncture at GB30 (Huan Tiao - gall bladder meridian) (day 0 and 1) and analyzed for mechanical and thermal nociceptive thresholds. The cytokine profiles as well as the expression of opioid peptides were quantified in the inflamed paw. Electroacupuncture elicited long-term antinociception blocked by local injection of anti-opioid peptide antibodies (beta-endorphin, met-enkephalin, dynorphin A). The treatment altered the cytokine profile towards an anti-inflammatory pattern but augmented interferon (IFN)-gamma and the chemokine CXCL10 (IP-10: interferon gamma-inducible protein) protein and mRNA expression with concomitant increased numbers of opioid peptide-containing CXCR3+ macrophages. In rats with CFA hind paw inflammation without acupuncture repeated injection of CXCL10 triggered opioid-mediated antinociception and increase opioid-containing macrophages. Conversely, neutralization of CXCL10 time-dependently decreased electroacupuncture-induced antinociception and the number of infiltrating opioid peptide-expressing CXCR3+ macrophages. In summary, we describe a novel function of the chemokine CXCL10 - as a regulator for an increase of opioid-containing macrophages and antinociceptive mediator in inflammatory pain and as a key chemokine regulated by electroacupuncture

Opioid peptide–dependent sustained antinociception and increase opioid peptide expressed macrophages by repeated CXCL10 injection.

<p>Rats were i.pl. injected with CFA and daily with CXCL10 (0.2 ng) or solvent control. [A] Mechanical nociceptive thresholds were determined daily before each injection. Data were presented as mean ± SEM (n = 6 per group, *p<0.05, **p<0.01, CFA+CXCL10 versus CFA+solvent; Two-way RM ANOVA, Student-Newman-Keuls). [B] Anti-END (2 µg, anti-ENK (1.25 µg) or anti-DYN (1 µg) was locally injected (i.pl.) at 4 d post CFA on rats with repeated injection of CXCL10 (0.2 ng). Identical doses of anti-rabbit IgG were used as control. Data were presented as mean ± SEM (n = 6 per group, *p<0.05, **p<0.01, CFA+CXCL10+IgG versus CFA+CXCL10+anti-END/ENK/DYN; Two-way RM ANOVA, Student-Newman-Keuls). [C] Immunohistochemical staining of paw tissue was performed at 96 h with a mouse anti-ED1 (CD68) macrophage antibody (green) and with rabbit anti-END, anti-ENK or anti-DYN antibodies (all was marked red) as well as DAPI. Representative sections are shown. Arrows pointing at double positive cells. (scale bar: 50 µm). [D] The percentage of END/ENK/DYN+ and ED1+ was quantified. All the data are presented as mean ± SEM (n = 3 per group, *p<0.05, CFA+ solvent versus CFA+CXCL10; t-test).</p

Neutralization of CXCL10 fully reversed electroacupuncture (EA)-induced antinociception and increase of opioid-containing monocytes/macrophages.

<p>[A] Rats with CFA inflammation and EA treatment were daily i.pl. injected with an antibody against CXCL10. Controls were injected with anti-rabbit IgG antibody. Mechanical nociceptive thresholds were determined before (BL) and after injections. Data are presented as mean ± SEM (n = 6 per group, *p<0.05, **p<0.01, CFA+EA+IgG versus CFA+EA+anti-CXCL10; Two-way RM ANOVA, Student-Newman-Keuls). [B–D] Immunohistochemical staining was performed for mouse anti-ED1 monocytes/macrophages (green) and rabbit anti-END, anti-ENK or anti-DYN antibodies respectively (red). DAPI (blue) was used to recognize cell nuclei. Representative sections are shown, arrows pointing at double positive cells (scale bar: 50 µm). [E] Quantification for immunohistochemical staining showed the percentage of double positive ED1 and END/ENK/DYN cells. All the data are presented as mean ± SEM (n = 3 per group, *p<0.05, CFA+EA+IgG versus CFA+EA+anti-CXCL10; t-test).</p

The antinociceptive effect of electroacupuncture (EA) via opioid peptides at the site of inflammation.

<p>Wistar rats were injected with CFA i.pl. for 48–96 h and treated with CFA and electroacupuncture (EA) at GB30 at 0 and 24 h (day 0 and 1, 100 Hz, 20 min, 2–3 mA) (CFA+EA). [<b>A, E</b>] In previous studies, sham-EA rats did not show significant difference in both mechanical and thermal nociceptive thresholds measurements at 0, 48, 72 and 96 h. Data were presented as mean ± SEM (*p<0.05, CFA+EA versus CFA; ^$p<0.05, CFA+EA versus CFA+ sham; ^#p<0.05, CFA+ sham versus CFA; Two-way RM ANOVA, Student-Newman-Keuls). We therefore omitted sham-EA treatment in following studies. Anti-END (2 µg [<b>B, F</b>], anti-ENK (1.25 µg [<b>C, G</b>]) or anti-DYN (1 µg [<b>D, H</b>]) was locally injected (i.pl.) at 4 d post CFA and concomitant twice EA treatment (black circles). Two control groups were added: injection with identical doses of nonspecific anti-rabbit IgG (white circle) or for comparison CFA without EA (black triangle). Paw withdrawal latency (thermal nociceptive thresholds [<b>A–D</b>]) or paw pressure thresholds (mechanical nociceptive thresholds [<b>E–H</b>]) were determined before (BL: baseline) and 5 min after injection (treated). All the data are presented as mean ± SEM (n = 6 per group, *p<0.05, **p<0.01, CFA+EA+IgG versus CFA+EA+anti-END/ENK/DYN; Two-way RM ANOVA, Student-Newman-Keuls).</p

Differential alterations in pro- and anti-inflammatory cytokines in inflamed paw tissue by electroacupuncture (EA).

<p>Rats were injected with CFA treated with (CFA+EA) or without (CFA) EA. Based on the results from pilot experiments for immune array of 29 cytokines (data not shown), [<b>A–F</b>] <i>pro- and anti-inflammatory</i> cytokines including TNF-alpha, IL-1alpha, IL-1beta, IFN-gamma, IL-4 and IL-13 in the paws were selectively quantified by ELISA after 96 h CFA. Data are presented as mean ± SEM (n = 5–10 per group, *p<0.05, CFA+EA versus CFA; t-test).</p

EA enhanced the recruitment of opioid-containing macrophages.

<p>Rats were injected with CFA with (CFA+EA), (CFA + sham) or without (CFA) EA treatment for 4 days. Immunohistochemical staining was performed for mouse anti-CD68 macrophages (green) and rabbit [<b>A</b>] anti-END, [<b>B</b>] anti-ENK or [<b>C</b>] anti-DYN antibodies respectively (red). DAPI (blue) was used to recognize cell nuclei (Representative sections are shown by arrows, scale bars: 50 µm). [<b>D</b>] The percentage of ED1 and opioid positive cells was quantified. All the data are presented as mean ± SEM (n = 3 per group, *p<0.05, one way ANOVA, Holm-Sidak method).</p

Upregulation of CXCL10 and an increase of CXCR3⁺macrophages in inflamed paw tissue by electroacupuncture (EA).

<p>Rats were injected with CFA and treated with (CFA+EA), (CFA+sham) or CFA only. On day 4 (96 h), CXCL10 was quantified by ELISA [<b>A</b>] and semi-quantitative RT-PCR (72 and 96 h) in subcutaneous paw tissue ([<b>B</b>] noninflamed contralateral paw (contra.) is only shown as a negative control). Data are presented as mean ± SEM (For ELISA: n = 6 per group, *p<0.05, one way ANOVA, Holm-Sidak method; For RT-PCR: n = 6 per group, *p<0.05, CFA+EA versus CFA; t-test). [<b>C</b>] Tissue sections were stained with rabbit anti-rat macrophage serum (red), mouse anti-rat CXCR3 antibody (green) and DAPI. The arrows are pointing at CXCR3 expressed macrophages. Representative sections are shown, arrows pointing on double positive cells (scale bar: 50 µm). [<b>D</b>] The percentage of macrophages and opioid positive cells was analyzed. All data are presented as mean ± SEM (n = 3 per group, *p<0.05, CFA+EA versus CFA; t-test).</p