Cerebrospinal fluid cell count variability is a major confounding factor in external ventricular drain-associated infection surveillance diagnostics: a prospective observational study

Abstract

Background External ventricular drain (EVD)-related infections (EVDIs) are feared complications that are difficult to rapidly and correctly diagnose, which can lead to unnecessary treatment with broad-spectrum antibiotics. No readily available diagnostic parameters have been identified to reliably predict or identify EVDIs. Moreover, intraventricular hemorrhage is common and affect cerebrospinal fluid (CSF) cellularity. The relationship between leukocytes and erythrocytes is often used to identify suspected infection and triggers the use of antibiotics pending results of cultures, which may take days. Cell count based surveillance diagnostics assumes a homogeneous distribution of cells in the CSF. Given the intraventricular sedimentation of erythrocytes on computed tomography scans this assumption may be erroneous and could affect diagnostics. Aims To evaluate the consistency of cell counts in serially sampled CSF from EVDs, with and without patient repositioning, to assess the effect on infection diagnostics. Methods We performed a prospective single-center study where routine CSF sampling was followed by a second sample after 10 min, allocated around a standard patient repositioning, or not. Changes in absolute and pairwise cell counts and ratios were analyzed, including mixed regression models. Results Data from 51 patients and 162 paired samples were analyzed. We observed substantial changes in CSF cellularity as the result of both resampling and repositioning, with repositioning found to be an independent predictor of bidirectional cellular change. Glucose and lactate levels were affected, however clinically non-significant. No positive CSF cultures were seen during the study. Thirty percent (30%) of patients changed suspected EVDI status, as defined by the cell component of local and national guidelines, when resampling after repositioning. Conclusions CSF cell counts are not consistent and are affected by patient movement suggesting a heterogeneity in the intraventricular space. The relationship between leukocytes and erythrocytes was less affected than absolute changes. Importantly, cell changes are found to increase with increased cellularity, often leading to changes in suspected EVDI status. Faster and more precise diagnostics are needed, and methods such as emerging next generation sequencing techniques my provide tools to more timely and accurately guide antibiotic treatment. Trial Registration NCT04736407, Clinicaltrials.gov, retrospectively registered 2nd February 2021.

Spatial and temporal variation of routine parameters: pitfalls in the cerebrospinal fluid analysis in central nervous system infections

“…As outlined in the Introduction, even under physiological conditions, the distribution of compounds in the CSF is not homogeneous [ 11 , 27 – 29 ]. Under pathological conditions, obstacles further impeding the distribution of molecules and cells in the CSF are frequent: intraventricular hemorrhage or tumor, obstruction of the foramina of Luschka and Magendie or of the basal cisterns impeding the communication of CSF between the 4th ventricle and the cerebral convexities and the spinal canal, stenoses of the cervical, thoracal or lumbar spinal canal as well as accumulation of pus in the ventricles, over the convexities or in the spinal canal (Fig.…”

“…Here, the quotient of leukocytes to erythrocytes in CSF divided by the quotient of leukocytes to erythrocytes in peripheral blood is calculated. The cell index as an indicator for a CNS infection, however, does not account for the inflammatory stimulus caused by blood in the CSF space leading itself to the migration of leukocytes into the CSF [ 29 ]. Moreover, the cell index assumes that leukocytes and erythrocytes are homogeneously distributed in the CSF space.…”

“…Moreover, the cell index assumes that leukocytes and erythrocytes are homogeneously distributed in the CSF space. Since leukocytes and erythrocytes possess different densities, they separate during gravity sedimentation with leukocytes positioned on top of the erythrocytes [ 29 , 75 ] (Fig. 2 ).…”

“…During these 10 min either a standard clinical re-positioning was performed (the patient was positioned in a lateral side position for 2 h prior to sample 1, then the patient was re-positioned to the contralateral side prior to the collection of the 2nd sample; R-samples), or patients were not moved for 2 h before the 1st sampling and during the 10 min interval between 1st and 2nd sampling (control = C-samples). In 162 pairs of CSF samples from 51 patients, both re-sampling and re-positioning influenced CSF leukocyte and erythrocyte densities: the effect of re-positioning was stronger than the effect of re-sampling with a constant head position, the direction of change was random, variability increased with the leukocyte and erythrocyte count in sample 1, and leukocytes, granulocytes and erythrocytes showed greater variability than lactate or glucose [ 29 ]. When the Stockholm external ventricular drain related infection (EVDI) criteria for suspected EVDI were used, 14 2nd R-samples changed the EVDI diagnostic group, whereas no changes of the diagnostic group were observed with pairs of C-samples [ 29 ].…”

“…In 162 pairs of CSF samples from 51 patients, both re-sampling and re-positioning influenced CSF leukocyte and erythrocyte densities: the effect of re-positioning was stronger than the effect of re-sampling with a constant head position, the direction of change was random, variability increased with the leukocyte and erythrocyte count in sample 1, and leukocytes, granulocytes and erythrocytes showed greater variability than lactate or glucose [ 29 ]. When the Stockholm external ventricular drain related infection (EVDI) criteria for suspected EVDI were used, 14 2nd R-samples changed the EVDI diagnostic group, whereas no changes of the diagnostic group were observed with pairs of C-samples [ 29 ]. The authors concluded that the surveillance of CSF leukocytes and erythrocytes including methods of correction for blood contamination were unreliable for early detection of EVDIs.…”