Two fatal and four surviving cases after accidental infusion of ropivacaine

Optimal peri- and postoperative pain management operates on a multidisciplinary basis, combining individual patient-related variables with current management guidelines. In this context, the application of amide-type local anaesthetics through epidural or perineural catheters plays an important role [1, 2]. The amide-type local anaesthetics lidocaine, bupivacaine and ropivacaine are commonly used for pain control. These substances reversibly inhibit regional sensory nerve impulse conduction without affecting consciousness. As one possible and in some cases even severe side-effect, cardiotoxicity has been described in the medical literature [3, 4].

Because of several deaths after the use of bupivacaine and etidocaine, the development and search for drugs with less cardiotoxicity was necessary. Thus, ropivacaine was developed and introduced to the market as an alternative to bupivacaine [5]. It is a newer long-acting amide-local anaesthetic drug, which is available as an optically pure solution. Ropivacaine-hydrochloride is the hydrochloride salt of 1-propyl-2′, 6′-pipecoloxylidide and is prepared as a pure S-enantiomer. Because of the N-propyl-group, ropivacaine is less lipid-soluble than bupivacaine [6], but with a similar pharmacokinetic disposition for protein binding in plasma and blood/plasma concentration ratio. Studies showed that 94% of ropivacaine will be bound to plasma proteins [7]. In vivo, ropivacaine has shown less cardiotoxicity than equal concentrations of bupivacaine and lidocaine and had a significantly higher threshold for central nervous system (CNS) toxicity than bupivacaine [8]. The significantly lower cardiotoxicity could be explained by its faster dissociation from cardiac Na⁺ channels and studies suggested, that the “S”-enantiomer was less toxic than the “R”- enantiomer [5, 9].

Due to its good tolerance and low side-effects, ropivacaine has been a well-known drug, which is used in postoperative pain management for adults [8] and children [10].

The terminal elimination half-life (t½) of ropivacaine after epidural administration (regardless of dosage) ranges from 5–7 h, and the t ½ after intravenous administration is about 2 h [11]. After intravenous application, ropivacaine undergoes extensive hepatic metabolism, with only 1% of the drug being eliminated unchanged in urine [12].

There are different known biotransformations for ropivacaine, like oxidative metabolism and dealkylation. Based on urinary analysis in humans, 3-hydroxy-ropivacaine, 4-hydroxy-ropivacaine, 2,6-pipecoloxylidide, 3-hydroxy-2′,6′-pipecoloxylidide and 2-hydroxymethyl-ropivacaine have been identified as metabolites [12, 13]. The major metabolite of ropivacaine in urine is 3-hydroxy-ropivacaine. About 37% of the administered ropivacaine dose will be hydroxylated to this metabolite. Responsible for the formation of major and minor metabolites are two cytochrome P450 (CYP450) isoenzymes like CYP1A2 and CYP3A4 [12, 13]. 3-OH-ropivacaine has significantly less pharmacological activity than ropivacaine [14].

Typical symptoms for CNS-toxicity occur 2–8 min after infusion of ropivacaine. The most common symptoms are visual and hearing disturbances, dysarthria, tingling, perioral numbness, dizziness, paraesthesia, light-headedness, muscular twitching and muscular rigidity [15]. Also reported are nausea, vomiting, urinary retention and bradycardia [5, 12]. CNS symptoms of local anaesthetic toxicity occur before cardiovascular symptoms and signs [15].

This paper describes the circumstances of two deaths and four intoxications and discusses the autopsy results and toxicological findings. The detection and quantification of ropivacaine and its main metabolite 3-OH-ropivacaine are presented in blood and urine with gas chromatography–mass spectrometry (GC–MS) as an analytical method.

After orthopaedic surgeries, it is common practice that hospitalized patients receive analgesics metamizole and piritramide in the form of infusions. In cases of higher doses and multiple infusions, the medication is normally applied via intravenous catheters in medical saline solutions as a transporter. In the cases at hand, instead of using ineffective medical saline solutions, infusion with the active substance ropivacaine were applied. Instead of receiving the drug through controlled infusion pumps to avoid overdose, the patients were given it intravenously through solutions. Due to the visual similarity of the saline solution and ropivacaine-solution bags, a night nurse mistakenly gave 0.2 L bags with 0.2% (400 mg/bag) ropivacaine solution via venous infusion to suspected seven patients. In one case it was not possible to reconstruct which solution had been applied. Because of the high workload, time pressure, and understaffing, the nurse did not accurately register the time of medication. It could be reconstructed that the time interval of the infusion set up with ascertainment of wrongfully applied solution, and sampling was 4 h. During the night in question, two of these patients, a 62-year-old woman, and a 78-year-old man died. The remaining other patients (56–83 years old) survived. All six patients received intravenous ropivacaine solution as a carrier solution for metamizole as well as piritramide. The negative results of the toxicological analyses could exclude the possible seventh mistreatment (case 7, Table 3). In all cases, the examination of the applied ropivacaine bags was not possible. Venous blood samples and urine were immediately taken from all patients. Two of the surviving patients showed symptoms of poisoning like discomfort, racing heart, tachycardia, nausea, numbness, tingling of the skin, and near-death experience. After treatment with saline infusion and intensive observation, all surviving patients were free of ropivacaine symptoms and could be discharged from the hospital in accordance with their individual diagnosis and stage of healing. In both death cases, an autopsy was performed the following day.

A 78-year old man with a body length of 167 cm and a bodyweight of 81 kg (BMI: 29) was autopsied. He was operated on in the hospital for a hip prosthesis implantation a few days earlier. The deceased showed fresh injection marks in the cubital fossa of the right arm and on the back of the left hand. There were signs of slightly developed intracranial pressure (brain: 1280 g), haemorrhagic lung oedema (left lung: 790 g, right lung: 830 g) and a filled urinary bladder (ca. 400 mL). A hypertrophic heart was detected (heart: 460 g) with coronary arteriosclerosis and sclerotic changes on the aortic valve. A tumorous change was visible in the right kidney without any signs of metastasis. A clear cause of death could not be determined during autopsy. A toxicology analysis was requested.

A 62-year old woman with a body length of 156 cm and a bodyweight of 69 kg (BMI: 28.4) was autopsied. She suffered from breast tumour with metastasis with the thoracic vertebrae and from back pain. The deceased showed fresh injection marks in the cubital fossa of both arms. There were signs of intracranial pressure (brain: 1050 g) and haemorrhagic lung oedema (left lung: 585 g, right lung: 650 g). A moderately to strongly developed coronary arteriosclerosis was visible. Fibrotic changes in the liver could be detected (liver: 1470 g). A clear cause of death could not be determined during autopsy. A toxicology analysis was requested.

Due to the clear results of the toxicological analyses, no further examinations (such as histology) were ordered from the state attorney.

The methods for ropivacaine and 3-OH-ropivacaine were validated in accordance with the recommendation for the validation of new methods [16]. The validation results are summarized in Table 1. For validation, calibration curves (each measured six times) and quality control samples (low 0.15 mg/L and high 0.45 and 0.75 mg/L), with spiked blood were analyzed. The recovery rate was between 112 and 88.5%. Statistical evaluation of the data was carried out using Valistat 2.0 GTFCh (Jena, Germany). The validation of the method covered linearity, the limit of detection (LOD), limit of quantification (LOQ), accuracy, precision, and recovery.

Both analytes calibration curves showed good linearity over the validated concentration range of 0.1–2.0 mg/L and 0.02–0.5 mg/L with coefficient of determination (R²) value as high as 0.999 for ropivacaine and 0.998 for 3-OH-ropivacaine.

The validated analytical ropivacaine method for examinations in blood was applied to all samples from the two postmortem as well as the intoxication cases.

All samples were tested for common drugs, medication, and for alcohol as ordered by the public prosecutor. Alcohol was not detected in either of the cases and the concentration of metamizole was within the upper limit of therapeutic values for pain treatment. Piritramide was only detectable in urine.

Ropivacaine was detected in six cases (Tables 2, 3). Because of the low amounts of retrieved biological material in the surviving patients, we could not quantify 3-OH-ropivacaine in blood.

In case 7 (Table 3), we could only find 3-OH-ropivacaine in urine. In this case, the patient did not show any symptoms and there was also a low level of creatinine. The analytic results could prove that the medication was given in medical saline solutions as a transporter and not in a ropivacaine-bag. Thus, the detection of 3-OH-ropivacaine in urine could be explained by the medication given during his operation one day before; thus, the case 7 was excluded.

The concentration of ropivacaine in peripheral blood was higher in the autopsy than in the surviving cases (Tables 2, 3), but close to intoxication levels.

In both fatal cases, the concentrations of ropivacaine and 3-OH-ropivacaine were lower in peripheral blood than in heart blood. Postmortem distribution was investigated calculating the mean ratios of heart to peripheral blood concentrations, which was 3.5 for ropivacaine probably due to the postmortem redistribution.

After analyses, all samples were stored in a frozen state at − 20 °C for one year. Then we repeated the analyses for ropivacaine. Ropivacaine was stable in all samples (maximum storage time: 1 year). Due to insufficient quantity, we could not repeat the analyses for 3-OH-ropivacaine.

The use of ropivacaine as an analgesic and as a local anaesthetic during a variety of surgical procedures has been studied extensively. All studies and case reports agreed upon the necessity of clinically controlled treatments. Thus, the proper way of ropivacaine-solution administration is to use infusion pumps to avoid overdose. However, very little is known about fatal threshold concentrations. Until now, there are reported therapeutic and toxic blood/plasma concentrations for ropivacaine, but no reported comatose/fatal threshold concentrations [17]. In one toxicity study with animals, ropivacaine concentrations of 9.8 mg/L were applied to dogs with one fatal outcome [18]. In addition to blood concentration, the manner of ropivacaine administration also plays an important role in terms of its toxicity. Several animal studies suggest electrocardiographic and blood pressure alterations by intravenous ropivacaine application [19‐21].

In clinical experiences from 60 studies involving 3000 patients with ropivacaine dosages, there were six reports of probable accidental intravascular injections with given amounts of ropivacaine (intravenous 75–200 mg). In these cases, only one patient showed signs of cardiotoxicity, and no signs of CNS toxicity were recorded [22].

Ruetsch et al. [3] described seizure and serve cardiac arrhythmia after accidental intravascular injection of 225 mg ropivacaine in a short time with measured concentrations of 3.6 and 0.69 mg/L for total and free ropivacaine, respectively. These concentrations for total and unbound ropivacaine were clearly over the range of the experimental human threshold for CNS toxicity symptoms [15, 23].

Another accidentally intravascular application was described by Pfeiffer et al. [24]. Their drawn conclusion of different studies [15, 23] was, that CNS-symptoms occur at arterial blood levels of 0.34–0.85 mg/L and that neurological symptoms start after concentrations of 5 mg/mL ropivacaine, depending on the injection speed and concentration [24].

In our cases, six patients received low concentration ropivacaine bags (0.2% 200 mL) intravenously without a controlled infusion pump. Two of the patients died and only two of the survived patients complained about typical symptoms. It seems that the proclaimed symptoms do not correlate with the detected amount of ropivacaine in peripheral blood, especially because all patients received the same amount.

One essential factor for this phenomenon seems to be firstly the speed of injection because the rapid infusion results in more free ropivacaine reaching the target molecules to exert its toxic effects. This could partly explain the lack of a clear correlation between drug concentration in blood and the occurrence of symptoms.

Furthermore, the amounts of serum binding proteins including α₁-acid glycoprotein [25, 26], which are variable in different individuals, are the second factor for the manifestation of toxic symptoms. The combination of the speed of ropivacaine infusion and the amounts of binding protein(s) in blood seems to cause quite different outcomes (fatal to surviving without toxic symptoms, Tables 2, 3) even under similar ropivacaine exposure conditions.

To our knowledge, ropivacaine has been considered the safest long-acting local anaesthetic [5] and no fatal cases of ropivacaine intoxication have been reported. However, we have presented two fatal cases of ropivacaine with its blood concentrations in this article. The doctors and nurses should be more cautious upon handling ropivacaine-solution bags.

In the cases at hand, the hospital management reacted with obligatory training courses for nursing staff and extra labelling of the ropivacaine-solution bag. At the request of the public prosecutor’s office, the court issued a penalty order for negligent homicide in two cases and for negligent bodily harm in three cases against the nurse. She was sentenced to 1-year probation and had to pay a fine.

For postoperative pain treatment, intravenous 0.2% ropivacaine is recommended. In the cases at hand, the application of ropivacaine was unintentional and thus not monitored.

Even though ropivacaine is considered to be a safe pain medication drug, it should always be administered in a controlled environment, independently from the concentration of the applied ropivacaine solution.

In case of overdose, typical symptoms might not necessarily be present. Thus, in suspicious cases, patients should be treated immediately according to reliable treatment guidelines [27] and if blood results are negative for ropivacaine, its main metabolite 3-OH-ropivacaine can be analyzed in urine to prove previous administration.

It should be stressed, that when ropivacaine solution is administered intravenously, relatively slow infusion is essential to assure its safety.

The presented report is the first demonstration of fatal cases of ropivacaine together with their blood concentrations of ropivacaine and its metabolite.