High dose Erythropoietin increases Brain Tissue Oxygen Tension in Severe Vasospasm after Subarachnoid Hemorrhage

Between April 2010 and March 2011 seven consecutive poor grade SAH patients with multimodal neuromonitoring (MM) receiving erythropoietin as compassionate treatment for severe cerebral vasospasm were studied. All patients were admitted to the Neurological Intensive Care Unit at Innsbruck Medical University. The clinical care for SAH patients conforms to guidelines set forth by the American Heart Association [1]. All patients received concomitant statin therapy and were on midazolame, sufentanil and/ or ketamine continuous infusions at the days of intervention. Severe vasospasm was defined by mean transcranial doppler (TCD) velocity >180 cm/sec and a Lindegaard ratio >3 when conventional treatment (continuous intravenous nimodipine application and hemodynamic augmentation with CPP target >80 mmHg) failed. DCI was defined as appearance of new infarction on CT that was judged by an independent radiologist to be attributable to cerebral vasospasm.

EPO (Epoetin alfa, Erypo®, Janssen-Cilag Pharma, Vienna, Austria) 30.000 IU diluted to 50 ml of normal saline was administered as infusion over 30 min every day for 3 consecutive days immediately after severe vasospasm was diagnosed. The decision to start the intervention was made by the neurointensivist in charge (ES, BP, RB, RH). In one patient a single dose was given, another patient received two sets of interventions at intervals of 7 days, leading to 22 interventions analyzed.

Based on the clinical and imaging criteria, the patient underwent monitoring of cerebral metabolism, brain tissue oxygenation (PbtO2), and ICP according to local institutional protocol which is in compliance with the Helsinki Declaration and has been approved by the local ethics committee (UN3898 285/4.8). Written informed consent was obtained according to federal regulations. Through a right frontal burr hole, a triple-lumen bolt was affixed to insert a Licox Clark-type probe (Integra Licox Brain Oxygen Monitoring, Integra NeuroSciences, Ratingen, Germany) to measure PbtO2 and an ICP parenchymal probe (NEUROVENT_P-TEMP, Raumedic, Münchberg, Germany). In addition, a high cut-off brain microdialysis catheter (CMA 71, Dipylon Medical, Solna, Sweden) was tunneled and inserted into the brain parenchyma for hourly assessment of brain metabolism. Isotonic perfusion fluid (Perfusion Fluid CNS, Dipylon Medical) was pumped through the system at a flow rate of 0.3 μl/min. Hourly samples were analyzed with CMA 600 Microdialysis Analyzer (CMA/Microdialysis, Solna, Sweden) for cerebral extracellular glucose, pyruvate, and lactate concentrations. At least 1 h passed after the insertion of the probe and the start of the sampling, to allow for normalization of changes due to probe insertion. The location of the monitoring catheters in the white matter of the right frontal lobe was confirmed by brain CT scan immediately after the procedure. All continuously measured parameters were saved on a 3 min average interval using our patient data management system (Centricity* Critical Care 7.0 SP2, GE Healthcare Information Technologies, Dornstadt, Germany). Transcranial Doppler sonography was performed using the DWL Doppler-Box system (Compumedics, Singen Germany). Data on CPP, ICP and MAP were available during all interventions, P_btO₂ and microdialysis in 14 and 18 observations, respectively.

Continuous variables were assessed for normality. Normally distributed data were reported as mean and standard error of mean, nonparametric data as median and interquartile range (IQR), unless indicated otherwise. Categorical variables were reported as count and proportions in each group. Hourly recorded brain metabolic parameters were averaged for 6 hours episodes, and continuously recorded parameters (P_btO₂, CPP, MAP, ICP) for 2 hours episodes. Baseline values were calculated accordingly and changes from baseline were analyzed: multiple observations per subject were handled by using generalized estimating equations with an autoregressive working correlation matrix. For all tests, significance was set at P < 0.05. All analyses were performed with SPSS V19.0 (SPSS Inc., Chicago, Illinois).

Baseline characteristics are described in the Table 1. Median patient age was 47 years (IQR:32–68) and six of seven were female. None of the patients had a history of malignancy or thrombembolism and no thromboembolic events occurred during hospitalization. All patients developed severe vasospasm in the anterior circulation of the aneurysm site and received Erythropoietin (EPO) at a median of 9 days (IQR:6–12) after ictus. None of the patients died during hospitalization and 3 patients (38 %) developed DCI with evidence of new cerebral infarctions at the site of the ruptured aneurysm distant (>3 cm) to the neuromonitoring probes. In these patients cranial CT scan had been performed after the observation period.

Baseline CPP and MAP were 86 mmHg (IQR:77–95) and 99 mmHg (IQR:85–105), respectively, and ICP was within normal limits (7 mmHg, IQR:4–11). MAP decreased to 92 mmHg (IQR:82–101) 2 hours after intervention (P < 0.04) returning to baseline for the remaining 24 hours without significantly affecting CPP and ICP (Figure 1, Panel A-C).

P_btO₂ (baseline 29 mmHg, IQR:22–32) significantly increased over time by 4 ± 3 mmHg (mean increase compared to baseline) to a maximum of 7 ± 4 mmHg increase 16 hours after start of intervention (P < 0.05) (Figure 1, Panel D). All patients had an increase in P_btO₂ at a certain point during the follow up time of 24 hours. Accounting for the EPO dose given (1^st, 2^nd, 3^rd) per patient did not affect the observed result. Hemoglobin (baseline 9.5 mg/dL, IQR:9–11.5), body temperature (36.8° Celsius, IQR: 36,6-37.1) and SpO2 (96 %, IQR:95–97) remained stable and respirator settings were not changed during the 24 h-observation periods.

Baseline brain metabolic data showed an increased median LPR (32, IQR:29–38) and slightly decreased brain glucose (1.1 mmol/L, IQR:0.8-2.8). Median brain lactate and pyruvate was 4.6 mmol/L (IQR:2.4-6.1) and 131 μmol/L (IQR:88–158), respectively. There was no significant change in brain lactate, pyruvate and brain glucose during the observation periods. (Figure 2, Panel A and B).