Acid Sphingomyelinase Serum Activity Predicts Mortality in Intensive Care Unit Patients after Systemic Inflammation: A Prospective Cohort Study

<div><p>Introduction</p><p>Acid sphingomyelinase is involved in lipid signalling pathways and regulation of apoptosis by the generation of ceramide and plays an important role during the host response to infectious stimuli. It thus has the potential to be used as a novel diagnostic marker in the management of critically ill patients. The objective of our study was to evaluate acid sphingomyelinase serum activity (ASM) as a diagnostic and prognostic marker in a mixed intensive care unit population before, during, and after systemic inflammation.</p><p>Methods</p><p>40 patients admitted to the intensive care unit at risk for developing systemic inflammation (defined as systemic inflammatory response syndrome <i>plus</i> a significant procalcitonin [PCT] increase) were included. ASM was analysed on ICU admission, before (<i>PCT_before)</i>, during (<i>PCT_peak</i>) and after (<i>PCT_low)</i> onset of SIRS. Patients undergoing elective surgery served as control (N = 8). Receiver-operating characteristics curves were computed.</p><p>Results</p><p>ASM significantly increased after surgery in the eight control patients. Patients from the intensive care unit had significantly higher ASM on admission than control patients after surgery. 19 out of 40 patients admitted to the intensive care unit developed systemic inflammation and 21 did not, with no differences in ASM between these two groups on admission. In patients with SIRS and PCT peak, ASM between admission and <i>PCT_before</i> was not different, but further increased at <i>PCT_peak</i> in non-survivors and was significantly higher at <i>PCT_low</i> compared to survivors. Survivors exhibited decreased ASM at <i>PCT_peak</i> and <i>PCT_low</i>. Receiver operating curve analysis on discrimination of ICU mortality showed an area under the curve of 0.79 for ASM at <i>PCT_low</i>.</p><p>Conclusions</p><p>In summary, ASM was generally higher in patients admitted to the intensive care unit compared to patients undergoing uncomplicated surgery. ASM did not indicate onset of systemic inflammation. In contrast to PCT however, it remained high in non-surviving ICU patients after systemic inflammation.</p></div

Receiver operating characteristics curve analysis for patients with systemic inflammation at <i>PCT_low</i> (N = 19).

<p>At the two other time points, receiver operating characteristics curves were not significantly different from 0.5. Systemic inflammation was defined as new onset of systemic inflammatory response syndrome plus a two-fold increase in PCT concentration compared to the value of the preceding day or exceeding a minimum of >2 ng/ml. ASM: acid sphingomyelinase serum activity; AUC: area under the curve; LR: likelihood ratio; CRP: C-reactive protein; PCT: procalcitonin.</p><p>Receiver operating characteristics curve analysis for patients with systemic inflammation at <i>PCT_low</i> (N = 19).</p

Kinetics of acid sphingomyelinase serum activity in the control group.

<p>The box plots display the minima/maxima (whiskers), 25%/75% percentile (box), median (−) and mean (+) values. Statistically significant differences (<i>P</i><0.05) between baseline (BL) and post-operative values are marked with an asterisk (*). ASM: acid sphingomyelinase activity; BL: baseline (before surgery); d: days.</p

Acid sphingomyelinase serum activity in control and ICU patients.

<p>This figure indicates median pre- and post-operative acid sphingomyelinase serum activity of the control group and median acid sphingomyelinase serum activity of the ICU group on admission. Statistical significant differences between groups (<i>P</i><0.05) are marked with an asterisk (*). The box plots display the minima/maxima (whiskers), 25%/75% percentile (box), and median (−) values. ASM: acid sphingomyelinase serum activity.</p

Biomarker level and severity of illness measures in patients with systemic inflammation (N = 19) according to PCT time points.

<p>Time points were the day before the PCT peak (<i>PCT_before</i>), the day of the PCT peak (<i>PCT_peak</i>) and again lowered PCT (<i>PCT_low</i>).</p><p>*<i>P</i> value for comparison of survivors vs. non-survivors. Systemic inflammation was defined as new onset of systemic inflammatory response syndrome plus a two-fold increase in PCT concentration compared to the value of the preceding day or exceeding a minimum of >2 ng/ml. ASM: acid sphingomyelinase serum activity, CRP: C-reactive protein concentration, mSOFA: modified Sequential Organ Failure Assessment Score (excluding central nervous system); PCT: procalcitonin; SAPS II: Simplified Acute and Physiology Score II; TISS: Therapeutic Intervention Scoring System.</p><p>Biomarker level and severity of illness measures in patients with systemic inflammation (N = 19) according to PCT time points.</p

Acid sphingomyelinase serum activity in ICU patients with SIRS.

<p>Clear boxes represent survivors (n = 9) and grey boxes non-survivors (N = 10). Statistically significant difference (<i>P</i><0.05) between survivors and non-survivors at <i>PCT_low</i> (*) for acid sphingomyelinase serum. The box plots show the minima/maxima (whiskers), 25%/75% percentile (box), and median (−) values. ASM: acid sphingomyelinase serum activity.</p

Baseline patient characteristics and outcomes.

<p>Systemic inflammation was defined as new onset of systemic inflammatory response syndrome plus a two-fold increase in PCT concentration compared to the value of the preceding day or exceeding a minimum of >2 ng/ml. PCT: procalcitonin, ICU: intensive care unit; SI: systemic inflammation.</p><p>Baseline patient characteristics and outcomes.</p

Study flow chart.

<p>Study flow chart.</p

Biomarker level and severity of illness measures of all study patients.

<p>In the ICU group, biomarker levels were measured in all patients at intensive care unit admission. For the control group, the pre-operative biomarker levels are displayed. Data are shown as median with interquartile ranges. Systemic inflammation was defined as new onset of systemic inflammatory response syndrome plus a two-fold increase in PCT concentration compared to the value of the preceding day or exceeding a minimum of >2 ng/ml. ASM: acid sphingomyelinase serum activity; CRP: C-reactive protein; mSOFA: modified Sequential Organ Failure Assessment score (excluding central nervous system); PCT: procalcitonin; SAPS II: Simplified Acute and Physiology Score II; SI: systemic inflammation; TISS: Therapeutic Intervention Scoring System.</p><p>Biomarker level and severity of illness measures of all study patients.</p

Receiver operating characteristics curve (ROC) analysis of acid sphingomyelinase serum activity.

<p>ROC analyses were performed at all three time points: <i>PCT_before</i> (fine dashed line), <i>PCT_peak</i> (dashed line), and <i>PCT_low</i> (solid line). ROC curves statistically significant different from 0.5 are marked with an asterisk (*). ASM: acid sphingomyelinase serum activity.</p