Double Blind, Randomised Controlled Trial

Purpose Surgical patients are at high risk for developing infectious complications and postoperative delirium. Prolonged infections and delirium result in worse outcome. Granulocyte-macrophage colony-stimulating factor (GM- CSF) and influenza vaccination are known to increase HLA-DR on monocytes and improve immune reactivity. This study aimed to investigate whether GM-CSF or vaccination reverses monocyte deactivation. Secondary aims were whether it decreases infection and delirium days after esophageal or pancreatic resection over time. Methods In this prospective, randomized, placebo-controlled, double-blind, double dummy trial setting on an interdisciplinary ICU of a university hospital 61 patients with immunosuppression (monocytic HLA-DR [mHLA-DR] <10,000 monoclonal antibodies [mAb] per cell) on the first day after esophageal or pancreatic resection were treated with either GM-CSF (250 μg/m2/d), influenza vaccination (Mutagrip 0.5 ml/d) or placebo for a maximum of 3 consecutive days if mHLA-DR remained below 10,000 mAb per cell. HLA-DR on monocytes was measured daily until day 5 after surgery. Infections and delirium were followed up for 9 days after surgery. Primary outcome was HLA-DR on monocytes, and secondary outcomes were duration of infection and delirium. Results mHLA-DR was significantly increased compared to placebo (p < 0.001) and influenza vaccination (p < 0.001) on the second postoperative day. Compared with placebo, GM-CSF-treated patients revealed shorter duration of infection (p < 0.001); the duration of delirium was increased after vaccination (p = 0.003). Conclusion Treatment with GM-CSF in patients with postoperative immune suppression was safe and effective in restoring monocytic immune competence. Furthermore, therapy with GM-CSF reduced duration of infection in immune compromised patients. However, influenza vaccination increased duration of delirium after major surgery

Leukocytes over time.

<p>From day of surgery (dOs) until day 5 after surgery (<i>pod5</i>) between groups. Leukocytes significantly increased on pod2 (p = 0.003) after stimulation with GM-CSF.</p

Number of infection days.

<p>From day 1 (<i>pod1</i>, before intervention) until day 9 after surgery (<i>pod9</i>). Between all three groups: p = 0.001. Placebo vs. GM-CSF: p < 0.001. Placebo vs. vaccination: p = 0.068. Vaccination vs. GM-CSF: p = 0.044.</p

Post-interventional course and outcome parameters.

<p>Continuous quantities in median (25%-75% percentiles), frequencies with n; APACHE, Acute Physiology and Chronic Health Evaluation; SAPS, Simplified Acute Physiology Score; SOFA, Sequential Organ Failure Assessment; TISS, Therapeutic Intervention Scoring System; ICU, Intensive Care Unit.</p

Number of delirium days (DDS > 3).

<p>From day 1 (<i>pod1</i>, before intervention) until day 9 after surgery (<i>pod9</i>). Between all three groups: p = 0.004. Placebo vs. GM-CSF: p = 0.737. Placebo vs. vaccination: p = 0.003. Vaccination vs. GM-CSF: p = 0.007.</p

Consort diagram.

<p><i>dBs</i>, day before surgery. <i>dOs</i>, day of surgery. <i>pod</i>, postoperative day.</p

Influence of Granulocyte-Macrophage Colony-Stimulating Factor or Influenza Vaccination on HLA-DR, Infection and Delirium Days in Immunosuppressed Surgical Patients: Double Blind, Randomised Controlled Trial

<div><p>Purpose</p><p>Surgical patients are at high risk for developing infectious complications and postoperative delirium. Prolonged infections and delirium result in worse outcome. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and influenza vaccination are known to increase HLA-DR on monocytes and improve immune reactivity. This study aimed to investigate whether GM-CSF or vaccination reverses monocyte deactivation. Secondary aims were whether it decreases infection and delirium days after esophageal or pancreatic resection over time.</p><p>Methods</p><p>In this prospective, randomized, placebo-controlled, double-blind, double dummy trial setting on an interdisciplinary ICU of a university hospital 61 patients with immunosuppression (monocytic HLA-DR [mHLA-DR] <10,000 monoclonal antibodies [mAb] per cell) on the first day after esophageal or pancreatic resection were treated with either GM-CSF (250 μg/m²/d), influenza vaccination (Mutagrip 0.5 ml/d) or placebo for a maximum of 3 consecutive days if mHLA-DR remained below 10,000 mAb per cell. HLA-DR on monocytes was measured daily until day 5 after surgery. Infections and delirium were followed up for 9 days after surgery. Primary outcome was HLA-DR on monocytes, and secondary outcomes were duration of infection and delirium.</p><p>Results</p><p>mHLA-DR was significantly increased compared to placebo (p < 0.001) and influenza vaccination (p < 0.001) on the second postoperative day. Compared with placebo, GM-CSF-treated patients revealed shorter duration of infection (p < 0.001); the duration of delirium was increased after vaccination (p = 0.003).</p><p>Conclusion</p><p>Treatment with GM-CSF in patients with postoperative immune suppression was safe and effective in restoring monocytic immune competence. Furthermore, therapy with GM-CSF reduced duration of infection in immune compromised patients. However, influenza vaccination increased duration of delirium after major surgery.</p><p>Trial Registration</p><p><a href="http://www.controlled-trials.com" target="_blank">www.controlled-trials.com</a><a href="http://www.controlled-trials.com/ISRCTN27114642?q=ISRCTN27114642%20&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10&searchType=basic-search" target="_blank">ISRCTN27114642</a></p></div

Infection and delirium days (DDS > 3).

<p>Overall (Kruskal-Wallis): <b>Infection days</b>: p = 0.001; <b>Delirium days (DDS > 3)</b>: p = 0.004; IQR: Interquartile Range.</p

Monocytic HLA-DR (mHLA-DR) on day 1 (<i>pod1)</i> and day 2 <i>(pod2)</i> after surgery.

<p>Paired Wilcoxon Test (<b><i>pod1 versus pod2</i></b>): Placebo: p = 0.0027; Vaccination: p = 0.013; GM-CSF: p < 0.001; Overall (Kruskal-Wallis): <b><i>pod1</i></b>: p = 0.667; <b><i>pod2</i></b>: p < 0.001; <b><i>pod1 –pod2</i></b>: p < 0.001; IQR: Interquartile Range.</p

Basic patient characteristics and pre-interventional course.

<p>Continuous quantities in median (25%-75% percentiles), frequencies with n (%); NRS, Numeric Rating Scale; <i>dBs</i>, day before surgery; <i>pod1</i>, day 1 after surgery; ASA, American Society of Anesthesiologists; AUDIT score, Alcohol Use Disorders Identification Test; PONV, postoperative nausea and vomiting; APACHE, Acute Physiology and Chronic Health Evaluation; SAPS, Simplified Acute Physiology Score; SOFA, Sequential Organ Failure Assessment; TISS, Therapeutic Intervention Scoring System; ICU, Intensive Care Unit.</p