Plasma substance P concentrations in patients undergoing general anesthesia: an objective marker associated with postoperative nausea and vomiting

This pilot study, conducted from July through October 2014, was approved by the Human Research Ethics Committee of the Tokushima University registered in a clinical trials database (UMIN000015318). Written informed consent was obtained from all patients. We included 23 patients, ASA grade I-II, who were undergoing elective laparoscopic gynecologic surgical procedures with general anesthesia. Apfel scores were documented on all patients [9].

Anesthesia was induced with remifentanil (0.3 to 0.5 μg/kg/min), propofol (1.0 to 2.0 mg/kg), and rocuronium (0.8 mg/kg) and maintained with sevoflurane (1.0 to 2.0 %) in an oxygen and air mixture and remifentanil (0.1 to 0.5 μg/kg/min); incremental doses of rocuronium were used as necessary for muscle relaxation. Blood was collected from the radial artery at predetermined time points (15–30 min prior anesthesia, 15–30 min after surgery/GA prior to returning to the PACU, and 24 h after surgery). The plasma was immediately separated by centrifugation and stored at -20 °C until extraction. SP concentrations in samples of plasma were measured by ELISA, following the manufacturer protocol (Abcam, Cambridge, MA). All samples were assayed in duplicate.

PONV was determined by modified PONV scale developed by Wengritzky et al. [10] utilization of a nausea score between 0 and 3: 0 = absence of nausea, 1 = mild nausea, 2 = moderate nausea, 3 = severe nausea. A blinded physician who was not involved within the anesthesia visited and asked the patients 24 h after general anesthesia, the number of vomitus and the highest nausea score during the past 24 h. Any nausea score greater than one or any vomitus was considered PONV. Patients were given metoclopramide as a rescue antiemetic as needed.

Given the importance of SP in the pathogenesis of PONV, we hypothesized that SP could be used to identify patients with a high risk of developing PONV induced by general anesthesia. Analysis of data from our present study suggests that SP remains unchanged at the end of anesthesia and then increases over the subsequent 24 h correlating with PONV, whereas SP decreased at the end of anesthesia and recovered after 24 h in patients without PONV. These results suggest that peri and post-operative SP levels may help predict the need of prophylaxis and/or continued monitoring for PONV.

SP concentration as an indicator of pain intensity has been measured in other samples including cerebrospinal fluid (CSF), urine, and wound exudate [11–14]. To date, no studies have investigated plasma SP levels and its relationship to PONV after general anesthesia. However, SP signaling is not a novel mechanism in PONV. Numerous clinical studies have utilized antagonist against SP and have shown improvement over placebo [15] or even ondansetron [16]. Sjostrom et al., [11] demonstrated that CSF concentrations of SP following abdominal surgery and general anesthesia revealed no statistically significant changes following the procedure. However, SP concentrations have been shown to increase following spinal anesthesia in CSF [12] and in wound exudates [13]. Furthermore, urinary SP levels increased and then declined after epidural anesthesia [14]. Although these studies primarily did not investigate PONV, they investigated indirectly the effects of anesthesia on SP. Similarly, CINV investigations also revealed increases in SP following various chemotherapies [6].

Our results suggest that peri-operatively SP is not being expressed in PONV(-) patients as a significant decrease in SP is observed similar to non-cisplatin induced CINV [4], however, patients who expressed PONV continued to express SP peri- and post-operatively. Interestingly, all patients who developed PONV had Apfel scores of greater than or equal to 2, which correlates to a 39 % risk [9], although many with similar scores did not develop PONV. This novel, although preliminary, finding suggests that assessment of SP may result in a relatively accurate predictor of emetic symptoms induced by general anesthesia.

This study has some limitations. Higa et al., [6] measured serum SP levels in patients receiving chemotherapy, baseline SP levels were relatively higher among women and younger patients and are associated with higher risk of developing CINV. As our study had enrolled adult female patients undergoing laparoscopic gynecological surgery, differences may have been detected at peri- and post-operative periods. The results of this study might not be generalizable to other patient populations such as male, children, and other surgical procedures. Additional studies designed to investigate in the SP activity would be useful on this issue. Furthermore, our baseline SP values are higher than previously published values [6]. This is likely a result of different assaying systems and their sensitivities. Finally, nausea is a highly variable, patient-specific, and highly difficult symptom to quantify affecting our results. Utilizing a simple modified PONV scale allowed the incorporation of patients who may have not qualified as PONV in more stringent scales.

Specific receptors including opioid, dopamine, histamine, acetylcholine, serotonin, and SP are known to be associated PONV [2, 3]. In the present study, however, we only focused on the activity of SP levels. Another possible limitation is that after binding to the NK1 receptors, SP regulates many biological functions. These mediators may have affected the activity of SP levels. A larger sample size is required in order to determine the clinical profile of SP.

Predicting whether a patient will have any adverse reactions to general anesthesia is extremely difficult and limited. Our results suggest that SP levels may increase the ability to correctly predict patients with PONV. This preliminary study suggests a role in continued measuring of SP levels post-operatively in order to objectively monitor PONV.