Trial registration: The study is registered in the German Clinical Trials Register (DRKS00031942)

Hypoxia is a risk factor for non-union and appears to be one of the causes of the higher incidence of non-union in patients with multiple injuries [1]. Norepinephrine (NE) decreased bone perfusion in animal studies [2]. While the intramedullary bone-marrow pressure usually correlates with the systemic blood pressure, the contrary was observed under NE treatment: the systemic blood pressure increased, and simultaneously, the intramedullary bone-marrow pressure dropped [2]. This effect was independent of the systemic blood pressure and is probably caused by α-receptor-transmitted vasoconstriction of the nutrient vessels. Patients in a more severe state receive NE to increase their systemic blood pressure. The target systolic blood pressure, according to current guidelines, is 80–90 mmHg [3]. NE is currently the most frequently used and recommended catecholamine for polytraumatized patients in intensive care units [3, 4]. In human patients, the effect of i.v.-NE administration on the blood perfusion in fractures and the correlation with the systemic arterial blood pressure have not yet been investigated. We hypothesized lower oxygen saturation (SO2) in the fracture gap with higher doses of NE, independent of MAP.

In a pilot trial, we used the laser-Doppler device ‘Oxygen to see’ (O2C, LEA Medizintechnik, Winchesterstr. 2, D-35394 Gießen, Germany) to measure SO2, haemoglobin (Hb), and blood flow (BF) in 3, 10, and 14/16 mm depth in four tibial and clavicle fractures of three patients with multiple injuries who received NE. The O2C operates with a laser (wavelength 820 nm) and a detector in the white-light spectrum range (wavelength 500–800 nm) [5]. Probes were covered in single-use ‘Ultracover for TEE Endocavity Probe Cover’ (ECOLAB, Microtek Medical B.V., Hekkehorst 24, 7207 NL-Zutphen, The Netherlands), 25 × 11 × 1000 mm, made of polyurethane. The non-invasive probe was fixed on the skin with black kinesiology tape to avoid measurement error by the ambient light and to standardize the contact pressure. In each of the fractures, multiple measurements were conducted throughout the time course of treatment with varying NE rates. During each measurement, three recordings of 10 s each were taken in slightly different spots over each fracture gap and averaged. MAP was measured by an arterial probe as part of regular patient monitoring and recorded for each measurement. Of note, the present study was purely observational and did not interfere with the NE administration rate. NE was administered through injection pumps solely operated by the intensive care unit staff independent of the study. Multiple linear regression statistics were conducted with forced entry for each of the perfusion parameters and each depth separate as the dependent variable. The relationships of each of these parameters with the NE rate and the MAP as independent variables were explored.

Three male patients with three tibial fractures and a clavicle fracture were included (age 57.3 ± 33.1 years, weight 77.7 ± 6.8 kg, height 177.7 ± 4.0 cm, BMI 24.7 ± 3.1 kg/cm2). A total of 125 measurements were taken, all within the first week after fracture. Significantly higher NE rates were associated with lower SO2 in 10 mm (p = 0.018) and 14/16 mm depth (p = 0.006) of fractures (Fig. 1A–C). Significant correlations between the MAP and SO2 were found in 3 (p = 0.007) and 10 mm depth (p = 0.030) (Fig. 1D–F). Higher NE administration rates and lower MAP were associated with lower SO2. Hb and BF in the fracture gap were neither affected by the NE rate nor the MAP. In 10 mm depth, up to 16.2% (adjusted R2) of the variability of SO2 could be explained by NE and MAP. In 3 mm, up to 14.7% of the variability could be explained by MAP alone, and in 14/16 mm, up to 13.5% by NE alone. Thus, only NE and not MAP had an effect on SO2 in 14/16 mm depth inside the fractures.

Fig. 1
figure 1

Relationships of the NE rate (A–C) and the MAP (D–F) with the measured SO2 values. P values from the multiple linear regression analysis are shown only, if significant

Full size image

The present pilot study is the first to measure fracture perfusion in patients with NE. The presented findings need to be confirmed in larger cohorts. The reported data indicate an association of NE administration rates with decreases in bone fracture oxygenation that may be caused by the NE, but could also be related to other mechanisms associated with the more severe state of the patients that require NE treatment. As lower SO2 in fractures may lead to delayed bone healing and non-union, it might be of interest to study the effects of alternative drugs for blood pressure elevation on bone perfusion that do not show a vasoconstrictive effect on bone. Among the catecholamines, dobutamine mainly has an effect on β1 receptors, but shows almost no α-receptor-mediated vasoconstriction. If it can be confirmed that NE decreases bone blood supply, NE might be used to decrease blood loss from fractures. Laser-Doppler-based devices and other instruments should be validated for perfusion measurements and SO2-monitoring in bone fractures of patients.