Effects of the Opioid Analgesic, Sufentanil, on Respiration after Extremity Trauma and Severe Conscious Hemorrhage in Rats
Authors: Calderon Mariam L. , Klemcke Harold G. , Connor Brian S. , Perez Samantha L. , Rodriguez Cassandra M. , Hinojosa-Laborde Carmen 
Published: April 2020

Background: Currently, opioid analgesics such as Sufentanil are not recommended for use on the battlefield for Soldiers with severe hemorrhage and respiratory difficulties, although they are still used during such situations (Schauer et al., Prehosp Emerg Care 21: 744, 2017). Moreover, there have been no controlled, preclinical studies conducted using analgesic doses of Sufentanil to support these guidelines. The current study was conducted to evaluate effects of the opioid analgesic Sufentanil on multiple components of respiration after severe hemorrhage in conscious rats in the absence or presence of extremity trauma. We hypothesized that Sufentanil would negatively impact respiration under such experimental conditions.

Methods

Rats were randomly assigned to receive either 0.9% saline vehicle (VEH), or 1μg/kg Sufentanil (SUF; 0.1μg/100 μl). These treatments were subdivided into rats that were (T) or were not (NT) exposed to trauma (n=9–10 rats/each of the 4 groups). All rats (male; ~ 380grams) were surgically implanted with a carotid catheter. After 24 hours, rats were anesthetized briefly (10 min) to undergo trauma (crushing of the right gastrocnemius and semimembranosus muscles for 30 sec with forceps, T) and fibula fracture. NT rats were anesthetized for 10 min only. Rats were allowed to awaken, and 90 min later underwent a conscious hemorrhage (~55% of blood volume during 25 min) within a whole body plethysmography chamber via the indwelling carotid catheter. At the end of hemorrhage, rats received either VEH or SUFvia the carotid catheter. Respiratory measures were collected and recorded over 1 min intervals and analyzed via Data Sciences International FinePointe software. Primary respiratory measures were respiration rate (RR; breaths/min), tidal volume (TV; ml), and minute volume (MV; ml/min; RR x TV). TV and MV were normalized to the average body weight of all rats used in the study (377 grams). Rats were observed for 1 hr after the start of the hemorrhage. Data were analyzed via multiway analysis of variance (ANOVA) for repeated measures using the Statistical Analysis System.

Results

For RR, there was no effect of trauma (P = 0.43) so data were combined across T and NT groups for each treatment. For a brief period (2–15 min) after SUF injection, RR was lower (P < 0.04) compared with VEH. For TV and MV, there were interactions between treatment and trauma groups. Hence, compared with VEH‐rats, TV in SUF‐rats was intermittently depressed in T‐rats (P < 0.04) but briefly increased in NT‐rats (P < .03) for up to 15 min post injection. In T‐rats only, SUF transiently (12 min) decreased MV (P<0.05) starting 3 min after injection. All respiratory effects induced by SUF were resolved within 15 min.

Conclusions

At the analgesic dose given – previously shown to ameliorate behavioral indices of pain in rats (Xiang, J Trauma Acute care Surg 85: S49, 2018) – and at the times measured, SUF had primarily transient inhibitory effects on respiration that often depended on the presence of previous extremity trauma.

Support or Funding Information

This study was funded by the US Army Medical and Materiel Command, Clinical and Rehabilitative Medicine Research Program.