Paravertebral Block and Perioperative Ketamine in an Opioid-Sparing Analgesia Approach in Thoracic Surgery: A Retrospective Single-Centre Study

2. Materials and Methods

2.1. Study Population

This retrospective study utilised prospectively collected data as part of an internal audit on the management of APOP in patients undergoing VATS between March and October 2020 at the Thoracic Surgery Unit of the University Hospital of Siena. Ethical approval for using these data was obtained from the local ethical committee (Comitato Etico Regionale per la Sperimentazione Clinica della Regione Toscana; Protocol 18862).

Our audit included all adult patients undergoing VATS lung resection. We excluded patients younger than 18 years, pregnant individuals, those requiring postoperative intensive care unit monitoring, re-do surgeries or emergency procedures, those with known allergies to local anaesthetics, and individuals with a history of neuro-psychiatric conditions that could preclude accurate pain assessment. Patients receiving chronic opioid therapy or regular non-steroidal anti-inflammatory drugs before surgery were also excluded to avoid confounding effects on postoperative analgesia.

Patients were grouped according to their usage of OS, in particular, in intraoperative PVB and ketamine infusion (case group), or the intra- and postoperative use of opioids (control group). General anaesthesia induction was identical in both groups and was performed in all patients with propofol (1–3 mg/kg), fentanyl (1–2 mcg/kg), and rocuronium (0.5 mg/kg) boluses. Endotracheal intubation was achieved with a double-lumen tube (Robertshaw type), and intraoperatively, general anaesthesia was maintained in all patients with sevoflurane (1.0–1.5 minimum alveolar concentration). The control group received intraoperative fentanyl boluses (0.1–0.3mcg/kg every 30 to 45 minutes). Conversely, the OS group did not receive intraoperative opioids (apart from the induction of anaesthesia) and was managed with PVB and ketamine. Specifically, the thoracic PVB was performed before inducing general anaesthesia with the patient in the lateral decubitus position [21]. The T4 paravertebral space was identified using a high-frequency (6–18 MHz) linear ultrasound probe (Epiq 5-Philips® Eindhoven, Amsterdam, Netherlands) with an in-plane approach, placing the probe parallel to the vertebral column [22]. The block consisted of a single injection of 0.5% ropivacaine, titrated based on the patient’s ideal body weight (0.1 ml/kg or a maximum of 15 ml total volume), using a 100-mm nerve block needle (Stimuplex A' B. Braun). At the end of surgery, sedation was discontinued, and patients were extubated upon being neurologically appropriate and demonstrating adequate spontaneous ventilation.

2.2. Postoperative Analgesia

At the end of surgery, both groups received intravenous paracetamol (1 gram) and ketorolac (30 mg), which were also administered perioperatively at regular intervals. Specifically, intravenous paracetamol was administered at doses of 1 gram every 8 hours, and ketorolac 30 mg was given every 12 hours, except in cases of contraindications (allergies, chronic kidney disease stage > 2, or a history of gastrointestinal bleeding). Apart from the use of paracetamol and ketorolac (common to both arms), the control group received intravenous morphine (starting dose of 0.1 mg/kg followed by an infusion of 0.2 mg/kg over 24 hours for 30 hours), while the OS group received a starting dose of ketamine (variable dose of 0.20–0.25 mg/kg) just before extubation, followed by continuous infusion at a dose of 20 mcg/kg/h for 30 hours via an elastomeric pump.

Whenever the nurse's assessment of analgesia revealed uncontrolled pain (defined as Numeric Rating Scale (NRS) > 4), a rescue analgesic dose (oral morphine 10 mg) was administered. The ward nurse on duty was unaware of the contents of the elastomeric pump (ketamine or morphine), nor of the execution of PVB. Assignment to one of the two groups was related to the ability or otherwise of the anaesthetist on duty to perform the PVB.

2.3. Data Collection and Analysis

Demographic characteristics, including age, sex, BMI, and ASA classification, were recorded for all patients. Additionally, detailed perioperative data were gathered, encompassing the type and duration of surgery, haemodynamic parameters (systolic, diastolic, and mean blood pressure, SpO2, and heart rate), and the administration of anaesthetic and analgesic drugs. Postoperative pain scores were assessed using the NRS and documented immediately after extubation and subsequently at six other postoperative time points (every 8 hours for 48 hours). The need for rescue opioid therapy (intravenous morphine 0.01 mg/kg) was also recorded, along with any reported complications (such as postoperative nausea and vomiting–PONV, respiratory depression, or itching) and the total length of hospital stay (LOS).

The primary outcome was the incidence of the rescue dose of oral morphine (10 mg), which was administered when the NRS score was above 4. The assessment according to the NRS and the administration of rescue doses were by a nurse blinded to the intraoperative management to ensure an unbiased evaluation. The secondary objectives included 1) postoperative pain intensity (NRS), recorded immediately after surgery and then every 8 hours up to 48 hours; 2) the development of chronic postoperative pain, which was assessed three months later via telephone interview; 3) the differences in oxygen saturation (SpO2) and blood pressure; and 4) the LOS.

2.4. Statistical Analysis

A minimum sample size of 59 patients was estimated considering a Fisher exact test, with the first type error set at 0.05 and a power of 85%, using an estimated relative difference in rescue opioid dose administration between groups of 30% with a between-group ratio of 1:2. This ratio was determined according to the local availability of anaesthesiologists rotating in the thoracic surgery theatre and their ability to provide PVB and willingness to use ketamine infusion in the context of an OS approach. Power analyses were performed using G*Power. Categorical variables were summarised using absolute numbers and percentage frequencies, while quantitative variables were summarised using median and interquartile range as the Kolmogorov-Smirnov test showed that the distribution of data was not normal. Hence, we used the non-parametric Mann-Whitney tests. Differences between categorical variables were tested with Fisher’s exact test. A p-value of < 0.05 was considered statistically significant. Analyses were carried out with R (The R Foundation for Statistical Computing 2023, version 4.3.2).

3. Results

3.1. Sudy Population

A total of 62 consecutive patients were included in the study (Figure 1), 39% of whom were male (n = 24). Patients underwent VATS lung resection, specifically enrolling 55 lobectomies and 7 segmentectomies. Among the enrolled patients, 41 were assigned to the OS group and 21 to the control group. Descriptive preoperative and perioperative characteristics are presented in Table 1. No differences were observed between groups in the intraoperative parameters, and no complications directly attributable to the PVB or the administration of analgesic drugs during the perioperative period were reported.

Outcome

As shown in Table 2, the incidence of rescue oral morphine administration within 48 hours after surgery was significantly lower in the OS group (n = 8/41, 19.5%) compared to the control group (n = 10/21, 47.6%, p = 0.021). Particularly, eight doses were given to eight patients in the OS group (one rescue each), while 22 doses were given to the 10 patients in the control group (eight patients received two doses and two patients received three doses of rescue analgesia; p < 0.001). Considering the overall number of APOP evaluations (seven per patient), the occurrence of rescue dose administrations was significantly lower in the OS group (n = 8/287 vs 22/147, p < 0.0001). A post-hoc exploratory analysis was conducted according to the different starting doses of ketamine and showed a negative correlation between the ketamine starter dose and the need for rescue oral morphine (Spearman’s Rho = -0.380; p = 0.002).

Patients in the OS group reported significantly lower NRS scores upon awakening (Table 2 and Figure 2), but no statistically significant differences in NRS scores were detected at later time points (from the 8th until the 48th postoperative hour) with median values consistently ranging between 1 and 2 points of the NRS (Table 2).

Upon telephone interview three months after surgery, chronic postoperative pain was reported with significantly lower prevalence in the OS group (n = 10/41, 23.8%) compared to the control group (n = 11/21, 53.4%, p = 0.028; Table 2).

We found no differences in haemodynamic values and SpO2, apart from higher SpO2 levels and lower heart rate at awakening in the OS group. Similarly, there was no statistically significant difference in the hospital LOS between the two groups (OS group vs control group 5 [5,6,7,8]vs 6 [5,6,7] days; p = 0.541) (Table 3).

4. Discussion

In this retrospective study, we report data from an internal audit of patients undergoing VATS with the aim of evaluating the potential benefits of an OS approach. We applied a multimodal analgesia protocol that included a thoracic PVB and an OS analgesia regimen with intravenous ketamine supported by paracetamol and ketorolac at the end of the surgical procedure.

Our findings support the hypothesis of clinical benefits from our multimodal intervention with PVB and ketamine. Indeed, this approach significantly reduced the need for postoperative rescue doses (oral morphine); interestingly, we also noted a possible dose-dependent effect of the ketamine starting dose on opioid-sparing, with a greater initial dose correlated to a lower number of rescue doses. The latest ERAS guidelines in the context of lung surgery recommend a standardised multimodal pain management strategy incorporating locoregional anaesthesia to minimise postoperative opioid consumption[16]. Reducing opioid use is crucial due to the well-documented adverse effects including PONV, paralytic ileus, excessive sedation, and prolonged hospital stays [23,24]. Additionally, multimodal analgesia incorporating locoregional techniques shortens the duration of postoperative mechanical ventilation, facilitates early mobilisation and physiotherapy, and reduces the risk of atelectasis and pneumonia [25]. Our results align with the available evidence, adding scientific information on the value of combining a locoregional anaesthesia approach (PVB in our cohort) with ketamine. Our study demonstrates that multimodal analgesia incorporating both PVB and ketamine might be superior to an opioid-based protocol, with improved pain scores on awakening and reduced rescue doses, although the NRS scores between groups were not significantly different at later time points [26]. This finding highlights the potential of enhancing OS strategies not only with the implementation of locoregional anaesthesia but also with the addition of intravenous ketamine to achieve comparable pain relief while mitigating opioid-related side effects.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is also a known and effective adjuvant for analgesia in the perioperative period, reducing opioid use and preventing opioid tolerance and central sensitisation to nociceptive signalling [23,24,25,26,27]. However, its optimal dosing regimen remains controversial [23], and the drug is not easy to handle due to its possible side effects. Suzuki and colleagues reported reduced pain at three months postoperatively when ketamine was combined with preoperative TEA [28], whereas Dualè et al. found improvements only in immediate postoperative pain, with no long-term benefits [29]. The OS effect of ketamine observed in our study aligns with existing literature and current ERAS recommendations for thoracic surgery. Chumbley et al. conducted a randomised study on 70 patients undergoing thoracotomy, comparing a ketamine infusion (0.1 mg/kg/min preceded by a 0.1 mg/kg bolus) with a control group receiving placebo. Patients in both groups received TEA, patient-controlled analgesia with morphine, or PVB infusion. Opioid use and numeric pain scores at 24 and 48 hours were significantly lower in the ketamine group [30], suggesting its positive modulation on APOP. Furthermore, Jouguelet et al. reviewed the available literature concluding that five meta-analyses and 39 clinical trials were published on this topic with a total of 2482 patients enrolled, 1403 of whom received ketamine[31]. Their summary of the evidence indicated that among the studies reporting a dose of ketamine similar to our approach, six reported a significant reduction in APOP and in opioid consumption within the first 24 hours.

Importantly, unlike previous studies, we did not find evidence of ketamine-related side effects, such as hypertension, tachycardia, hallucinations, or delirium. This finding highlights that ketamine could be well tolerated in the context of a multimodal analgesia protocol, reinforcing its potential as an adjuvant and OS strategy.

According to our study protocol, ketamine infusion was preceded by an ultrasound-guided PVB immediately after the induction of general anaesthesia [32,33]. As emphasised by ERAS guidelines, regional anaesthesia is strongly recommended to reduce postoperative opioid use, with PVB providing analgesia equivalent to TEA, particularly for VATS [16,32,33]. Numerous studies have compared PVB and TEA for thoracic surgery pain management. In a recent narrative review, Hamilton et al. concluded that these techniques provide equivalent analgesia for thoracotomy, although TEA could still be considered the gold standard [25]. However, in the case of VATS, the APOP is of a lower degree, and PVB is preferred as it offers comparable pain relief with fewer perioperative complications. A randomised study by Turhan et al. compared the erector spinae plane block, PVB, and intercostal nerve block after VATS. The authors found that all three techniques provided adequate analgesia, though PVB demonstrated superior pain control and reduced morphine consumption [33].

Interestingly, we observed a significant, albeit weak, inverse correlation between the ketamine starting dose and the need for postoperative rescue morphine (p = 0.002). Indeed, patients receiving a higher initial dose of ketamine (0.25 mg/kg) exhibited superior pain control compared to those receiving (0.20 mg/kg).

In our study, patients in both groups remained haemodynamically stable throughout surgery, with no need for vasopressors or advanced haemodynamic monitoring, and a lower heart rate at awakening may be the result of better-controlled APOP. Overall, it seems that the PVB did not induce clinically relevant sympatholytic effects. Additionally, no complications related to the locoregional technique (e.g., bleeding, pneumothorax, LAST syndrome, inadvertent intrathecal or intravenous local anaesthetic injection) were observed.

An interesting finding in our study was the reduced incidence of chronic pain at three months after surgery, with the incidence more than halved in the OS group (23.8% compared to 52.4%). This finding further highlights the value of reducing exposure to perioperative opioids, which is a hot topic in anaesthesia. The incidence of chronic pain after thoracic surgery varies between 29% and 35% of patients [34,35]. Huan et al. studied 159 patients undergoing VATS and showed that the opioid-free group (in which a postoperative analgesic block was performed) had a reduced incidence of chronic pain compared to the group in which anaesthesia was conducted with opioids only [36]. However, in a meta-analysis pooling data on 1018 patients, Hyo-Seok et al. did not find a decrease in chronic pain in patients who received PVB or other types of thoracic wall blocks compared to those treated without a block [37]. We had similar findings to Yan et al., but it should be noted that in our study, the intervention group received PVB before surgery, which was associated with ketamine infusion. We believe our encouraging results may be partly due to the execution of PVB before the surgical stimulation, reducing neuronal firing and nociceptive activation following surgical stress [34,38].

Our study has several limitations that should be acknowledged. First, it was conducted in a single-centre setting, which may limit the generalisability of the findings to other institutions with different perioperative management protocols. Second, although we prospectively collected data as part of an audit, its retrospective nature introduces potential selection and information biases, which could affect the robustness of our conclusions. Third, the sample size was limited and unbalanced with a ratio of 2:1. This limitation does not allow for the detection of smaller positive effects from the protocol (i.e., reduction of APOP at time points after awakening) nor complications related to ketamine or PVB. Larger, multicentre studies would be necessary to confirm our results and offer external validity. Fourth, our study evaluated chronic postoperative pain over a longer timeframe with only a telephone interview, without a structured questionnaire that may be more appropriate for assessing the development of chronic post-thoracotomy pain syndrome. We believe that future studies should incorporate longer follow-up periods and adequate assessment of chronic post-surgical pain to determine whether the sustained benefits of ketamine and regional anaesthesia extend beyond the immediate postoperative phase. Fifth, while we compared a multimodal OS protocol (PVB and ketamine) to a conventional opioid-based regimen, we did not include control groups with the use of each of the two components of our protocol. This exclusion limits our ability to distinguish the specific contributions of the two strategies in reducing opioid consumption.

5. Conclusions

A multimodal analgesia protocol integrating ultrasound-guided PVB and perioperative ketamine infusion may reduce the need for postoperative rescue doses of opioids while providing effective pain control in the context of an OS approach. Such an approach aligns with the ERAS guidelines for OS strategies in thoracic surgery. However, larger randomised studies are needed to determine the clinical benefits of this association and the incidence of ketamine-related side effects.