A case of precipitate in intravenous line when general anesthesia implemented with remimazolam

Abstract

Adverse reactions caused by drug compatibility are more common in clinical practice, including discoloration, precipitation, crystallization, which can be life-threatening in severe cases. We report a 63-year-old man who developed precipitation during maintenance of general anesthesia with remimazolam tosylate for prostate resection. There were many precipitates in the infusion pipeline and the three-way stopcock, and at that time the infusion liquid was Ringer's acetate solution. Then we investigated the possibility of precipitation with different infusion fluids and remimazolam tosylate. In conclusion, precipitates may not form at a lower remimazolam tosylate concentration and a faster liquid infusion rate and require appropriate attention.

Precipitate; Remimazolam tosylate; Anesthesia.

1. Introduction

In recent years, with the emergence of new drugs and the increasing number of drug combinations, there have been some changes and problems in drug compatibility and application. In clinical practice, it is likely to identify through a short-time backtracking when drug precipitation occurs. Currently, the known drug precipitation is more common during the infusion of antitumor drugs.

Remimazolam tosylate (Hengruipharma Co, Lianyungang, China) is a new type of ultra-short-acting benzodiazepine drug which has a rapid onset of action and a short duration of action. It is metabolized by plasma esterase rather than relying on liver and kidney function. Remimazolam tosylate has no obvious effect on hemodynamics, and there is specific antagonist flumazenil. Now it is mainly used clinically for induction, maintenance of general anesthesia [1], and long-term sedation for critically ill patients in ICU.

So far, there are no report on the precipitation of remimazolam tosylate. In this study, we report a man who developed precipitation during maintenance of general anesthesia with remimazolam tosylate for prostate resection.

2. Case presentation

The patient was a 63-year-old man who underwent transurethral resection of the prostate under general anesthesia. The patient had no history of surgery and no known history of drug allergies. When the patient entered the operating room, vital signs were monitored, including ECG, blood pressure, pulse oxygen, and BIS. A 22G venous indwelling needle was inserted into the superficial vein of the right hand for infusion of Ringer's acetate solution. In compliance with the package insert, we formulated remimazolam tosylate with normal saline. There was no unified standard for the concentration of remimazolam tosylate used in the induction and maintenance of general anesthesia. Due to the product specification of 36 mg (Hengrui medicine, Lianyungang, China) and the induction dosage, for the convenience of calculation, we diluted remimazolam tosylate to 2 mg/ml so that the number of milliliters for the bolus is equal to one-tenth of the body weight. The induction dose of remimazolam tosylate was 0.2 mg/kg and the maintenance infusion rate was 1 mg kg⁻¹·h⁻¹. After adequate pre-oxygenation, sufentanil, remimazolam tosylate, and rocuronium were administered in sequence through a three-way stopcock, and mechanical ventilation was administered after tracheal intubation. Intravenous maintenance drugs remimazolam tosylate and remifentanil were connected to the three way stopcock, and the drug dosage was adjusted according to blood pressure, heart rate, and BIS value during the operation. One hour later, we found that the drip pot of the infusion set was full, and there were many white precipitations in the venous tube. The patient's BIS value at that time was 53, a normal BIS value of anesthesia status. The nurse urgently reopened the vein in the left hand, and then anesthesiologist replaced remimazolam tosylate with propofol for intravenous maintenance. Anesthesia time was 100 min, and operation time was 79 minutes. Intraoperative fluid volume was 1500 ml, of which Ringer's acetate and normal saline were 500 ml and 1000 ml, respectively. There was no abnormality and intraoperative awareness during postoperative follow-up.

3. Discussion

The instructions recommend that remimazolam tosylate be dissolved in normal saline at 1 mg/ml. However, there are few studies on the compatibility of remimazolam tosylate and infusion solutions and the compatibility mechanism is still unclear. In addition to the presence of white precipitations in the venous pipeline, a white membrane-like substance can be seen at the connection of the three-way stopcock in this case (Figure 1a). On the background of the Sterile Surgical Ruler (Figure 1b), the maximum length of precipitation was close to 1.5 cm (Figure 1c). This finding is consistent with Sasaki [2]whose finding encountered complete occlusion of i.v. line. It possibly attributed to the slower intravenous Ringer's acetate solution infusion rate and high remimazolam concentration. We tested whether precipitation occurred by pairing different remimazolam tosylate concentrations with different infusion fluid types in vitro. We found that lower concentrations of remimazolam tosylate (1 mg/ml) did not form precipitates at any infusion rate of Ringer's lactate solution and Ringer's acetate solution. With remimazolam tosylate 2 mg/ml we observed precipitation in the i.v. catheter at slower infusion rates (100 ml/h) of Ringer's acetate solution. Sasaki [3]also tested whether remimazolam concentration and infusion rate of Ringers's acetate solution contributed to the precipitates and found that when the concentration of remimazolam is as high as 5 mg/ml, even if the infusion rate of Ringer's acetate reaches 300 ml/h, there will be precipitation in the intravenous line and the three-way stopcock. Remimzolam tosylate is unstable in alkaline environments, even though the pH of Ringer's acetate is lower than that of Ringer's actate, precipitate formation still occurs with the combined use of Ringer's acetate and remimazolam tosylate. When we removed the precipitation and placed it in Ringer's acetate solution, we can see the precipitation redissolving. Precipitation in the venous line disappeared after more than 2 months, and there was a gap between fluid and air in the line (Figure 1d). Remimazolam tosylate has low thermal stability and requires storage at 2–8 in the dark to maintain product quality. Compared to remimazolam besylate, the excipient of remimazolam tosylate contains β-cyclodextrin derivatives, which have low water solubility and may be related to the occurrence of precipitation. Yamazaki [4] washed the precipitate with distilled water and dried it in the open air. The precipitate was analyzed by proton nuclear magnetic resonance spectra to be remimazolam. Their findings indicated that the solution of remimazolam in saline mixed with Physio 140 would be saturated when the concentration was above 0.75 mg/ml. Lower saturated concentrations of remimazolam were observed as the pH of the mixture was increased.

Figure 1.

(a) Many white precipitates in the i.v. line of the patient (b) White precipitates on the background of Sterile Surgical Ruler (c) The maximum length of precipitation was close to 1.5cm (d)The precipitate in the i.v. line disappeared after about two months, indicating that the remimazolam precipitates were redissolved.

Compared with traditional anesthesia and sedation drugs, remimazolam tosylate has smaller hemodynamic fluctuations, and the depth of sedation can favorably meet the needs of surgery. The future application prospects are bright. Up to now, there are no relevant statistics on the incidence of remimazolam with different infusion liquids, and the related incidence should be very low. Although the incidence of precipitation is low and intraoperative related hemodynamic parameters are stable, anesthesiologists should still strengthen monitoring to avoid the occurrence of body movement and intraoperative awareness.

Consent

Written informed consent was obtained from the patient to publish this case report and accompanying images. Permission was also obtained from local administrators. A copy of the written consent is available on request.

Declarations

Author contribution statement

All authors listed have significantly contributed to the investigation, development and writing of this article.

Funding statement

This work was supported by Clinical Research Fund of Lianyungang Clinical College of Nanjing Medical University (LC13).

Data availability statement

Data included in article/supp. material/referenced in article.

Declaration of interests statement

The authors declare no competing interests.

Additional information

No additional information is available for this paper.