Effect of extended intravenous diclofenac infusions on brain tissue oxygenation in patients with acute brain injury

Abstract

Background: Fever is associated with worse outcomes in patients with acute brain injury. Diclofenac, a non-steroidal anti-inflammatory drug, is commonly used as antipyretic therapy. As evidence emerged that short diclofenac infusions (< 1 h) decrease brain tissue oxygen (PtO2) and cerebral perfusion pressure (CPP), clinical practice has shifted to extended infusions (12 h). The purpose of this study was to investigate the effects of extended diclofenac infusion for the treatment of fever on cerebral perfusion and tissue oxygenation after acute brain injury.

Results: We conducted a retrospective study of prospectively collected data from a cohort of 18 patients with acute brain injury and PtO2 monitoring admitted between November 2018 and April 2024. The hour before and the 12 h during an extended diclofenac infusion were compared. Additionally, we compared the 12 h prior and 12 h during the diclofenac infusion. Cerebral autoregulation and metabolites obtained by microdialysis were assessed in a subgroup of patients. Thirty-nine interventions were analyzed. Core temperature decreased from 38.1°C in the hour before to 37.4 °C during an extended diclofenac infusion (p < 0.0001). ICP (11.0 vs 10.0 mmHg, p < 0.0001) and heart rate (84 vs. 77 bpm, p < 0.0001) decreased. CPP and PaCO2 did not vary significantly. PtO2 decreased from 23.1 mmHg (IQR 19.0-31.4) during fever peak to 21.7 mmHg (IQR 17.8-27.2) (p < 0.0001). Median PtO2 during the 12 h before diclofenac was 23.3 mmHg (IQR 18.9-30.5). In a multivariable analysis the effect of treatment was significantly influenced by heart rate and temperature (p < 0.0001).

Conclusions: Extended diclofenac infusions for the treatment of fever in patients with acute brain injury achieve a clinically significant reduction in temperature but are associated with a small decrease in PtO2, even in the setting of maintained CPP.

Keywords: Brain tissue oxygen; Diclofenac; Fever; Subarachnoid hemorrhage; Temperature control; Traumatic brain injury.

Fig. 1

Systemic and intra-cerebral hemodynamic indices before and after the initiation of an extended diclofenac infusion. Temperature (green), PtO2 (blue), CPP (magenta) and heart rate (red) during the 12 h before and after the start of an extended diclofenac infusion (75 mg over 12 h, grey bar). The relative time to the start of the diclofenac infusion is represented on the x-axis (hours). Temperature (°C), PtO₂ (mmHg), CPP (mmHg) and heart rate (bpm) are represented on the 4 separate y-axes. Lines represent the mean value in time bins of 6 min (t = 241) for all patients (n = 18). Shaded areas represent the 95% confidence intervals of the mean obtained through bootstrapping (n = 1000). After the start of the infusion, temperature, heart rate and PtO2 decrease concomitantly. CPP decreases minimally. PtO2: cerebral tissue oxygen pressure, CPP: cerebral perfusion pressure, bpm: beats per minute

Fig. 2

Brain tissue oxygen tension, arterial and end-tidal CO₂ before and after the initiation of an extended diclofenac infusion. PtO2 (blue), PaCO2 (red) and EtCO₂ (orange) during the 12 h before and after the start of an extended diclofenac infusion (75 mg over 12 h). The relative time to the start of the diclofenac infusion is represented on the x-axis (hours). PtO₂ (mmHg), PaCO₂ (mmHg) and EtCO₂ (mmHg) are represented on the 3 separate y-axes. Lines represent the mean value in time bins of 6 min (PtO₂) (t = 241) or 30 min (PaCO₂ & EtCO₂) (t = 49) for all patients (n = 18). Shaded areas represent the 95% confidence intervals of the mean obtained through bootstrapping (n = 1000). After the start of the infusion, PaCO2 remains constant (p = 0.5703), whereas EtCO₂ slightly decreases (p < 0.0001). PtO₂: cerebral tissue oxygen pressure, PaCO2: partial arterial pressure of carbon dioxide, EtCO₂: end-tidal partial pressure of carbon dioxide

Fig. 3

Time spent under an ischemic threshold of PtO2 before and after the initiation of an extended diclofenac infusion. Boxplot representing time spent under a threshold of PtO2 < 20 mmHg in hours during the 12 h before (light blue) and after (dark blue) the initiation of an extended diclofenac infusion for all patients (n = 18). The box spans from the lower to the upper quartile and a horizontal line represents the median. Whiskers indicate full range of data. The difference of time spent under an ischemic threshold is not statistically different before and after the onset of a diclofenac infusion (p = 0.7903)

Fig. 4

Brain tissue oxygen tension and lactate–pyruvate ratio before and after the initiation of an extended diclofenac infusion. PtO2 (blue) and LPR (dark red) in a subset of patients (n = 8) with cerebral microdialysis monitoring during the 12 h before and after the start of an extended diclofenac infusion (75 mg over 12 h). The relative time to the start of the diclofenac infusion is represented on the x-axis (hours). PtO2 (mmHg), and LPR are represented on the 2 separate y-axes. Lines represent the mean value in time bins of 6 min (t = 241). Shaded areas represent the 95% confidence intervals of the mean obtained through bootstrapping (n = 1000). After the start of the infusion, both PtO2 and LPR decrease (p = 0.0003). Although LPR is globally elevated, the decrease In PtO2 is not accompanied by metabolic ischemia. PtO2: cerebral tissue oxygen pressure, LPR: lactate–pyruvate ratio

Fig. 5

Brain tissue oxygen tension and pressure reactivity index before and after the initiation of an extended diclofenac infusion. PtO2 (blue) and PRx (red) in a subset of patients (n = 15) with autoregulation monitoring during the 12 h before and after the start of an extended diclofenac infusion (75 mg over 12 h). The relative time to the start of the diclofenac infusion is represented on the x-axis (hours). PtO2 (mmHg), and PRx are represented on the 2 separate y-axes. Lines represent the mean value in time bins of 6 min (t = 241). Shaded areas represent the 95% confidence intervals of the mean obtained through bootstrapping (n = 1000). After the start of the infusion, PRx increases minimally (p = 0.0186), within the normal range. PtO2 cerebral tissue oxygen pressure, PRx: pressure reactivity index