Impact of intra-operative ketamine on postoperative outcomes in abdominal surgery: a narrative review

Introduction

Acute pain management stands as a cornerstone in anesthetic care, with inadequate analgesia being linked to adverse postoperative outcomes such as immunosuppression, hyperglycemia, and the potential onset of chronic pain. While opioids remain the primary option for acute pain management, their application is often supplemented with adjuncts including non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, gabapentin, and regional anesthesia techniques to foster more comprehensive pain management and reduce opioid consumption.

Ketamine is a dissociative anesthetic and analgesic agent that primarily exerts its effects through binding to the N-methyl-D-aspartate receptor (NMDAR), disrupting the transmission of pain signals in the central nervous system. It has been increasingly recongized for its therapeutic potential in various medical conditions, with its ability to interact with several opioid receptors, specifically µ, δ, and κ, enhancing its analgesic properties. S-ketamine, the S-enantiomer of ketamine, binds to NMDARs with four times the affinity of ketamine, resulting in more potent effects at lower doses and fewer psychotropic side effects. In a recent study, ketamine has been shown to improve treatment-resistant chronic pain, improving pain severity, mood, and quality of life (1).

Ketamine has also been investigated for its potential in preventing postoperative delirium and treating refractory asthma exacerbations, yet these results have been inconsistent (2,3). While some studies suggest benefits in delirium prevention, others indicate increased risk, necessitating cautious evaluation (2). In asthma care, the evidence for ketamine’s efficacy remains inconclusive, highlighting the need for further research in these areas (3).

Notably, ketamine has been extensively discussed in the literature as a supplemental analgesic for perioperative pain control. Some reviews highlight the effectiveness of ketamine or S-ketamine in improving acute pain in perioperative settings, noting reduced pain scores (4,5). Other studies indicate a statistically significant reduction in opioid analgesic consumption with the use of ketamine (6,7). However, whether this holds true specifically for intraoperative administration of ketamine in abdominal surgery remains uncertain.

Ketamine and its more potent enantiomer, S-ketamine, have emerged as notable agents for reducing pain (8). Because S-ketamine exhibits higher NMDAR affinity as well as fewer psychotropic effects than ketamine, it is progressively replacing it in clinical settings (9,10). Additionally, low-dose ketamine serves as a promising candidate for pain management regimens, offering analgesic benefits that are yet to be fully understood (11). It can be administered through several routes, including continuous intravenous (IV) infusion, intravenous patient-controlled analgesia (IV-PCA), or epidural infusion (8). However, defining the optimal dosing and duration remains a complex task, despite its acknowledged morphine-sparing effects during intraoperative periods.

Typical postoperative challenges for abdominal surgery include pain management, postoperative nausea and vomiting (PONV), and adverse effects secondary to opioid administration. Ketamine may address these challenges effectively, as studies have shown that it use reduces morphine consumption substantially in the initial 24-hour postoperative window with little to no severe adverse events (12). Despite the emergence of minor side effects such as vague feelings and hallucinations, its benefits seemingly outweigh the risks, opening avenues for deeper exploration into its applicative benefits in abdominal surgeries (8).

Previous research into the intraoperative use of ketamine in abdominal surgeries has produced inconclusive results, partly due to the heterogeneity of study designs. Our study aims to fill this gap by focusing exclusively on randomized controlled trials (RCTs) that investigate the intraoperative administration of these agents in abdominal surgery. We further differentiate our review by including a sub-analysis on the timing of administration, a critical factor in drug efficacy yet underexplored in the existing literature.

The goal of this review is to carefully analyze the benefits and potential adverse effects of the intraoperative utilization of ketamine and its S-enantiomer, S-ketamine, in the pain management regimen during abdominal surgeries. This analysis draws on a diverse range of administration techniques and emphasizes RCTs to ensure a robust evaluation. This rigorous approach facilitates a deeper understanding of pain management strategies in abdominal surgeries and provides insights into secondary outcomes such as morphine/opioid consumption and the occurrence of PONV. We present this article in accordance with the Narrative Review reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-23-97/rc).

Methods

Two independent reviewers conducted a narrative review by conducting a systematic search (D.K.M. and J.S.L.) of PubMed and Ovid (MEDLINE). The search strategies included “abdominal surgery”, “ketamine”, and “intraoperative” and were restricted to RCTs and clinical trials (Table 1). We combined the results of the searches and duplicates were eliminated. Articles were screened by title and abstract by two reviewers. Discrepancies were resolved by a third reviewer (U.R.P.). Studies were included if they targeted adult patients and evaluated intra-operative use of ketamine for abdominal operations. We excluded descriptive articles including commentaries, editorials, and reviews to maintain the focus on primary research. Two reviewers assessed each article included for full-text review based on relevance and significance. The search strategy can be found in Table 2.

In this narrative review, we exclusively included RCTs for their gold standard status in establishing causal relationships between interventions and outcomes. These trials offer high internal validity by minimizing selection bias and controlling for confounding variables. Thus, by focusing solely on RCTs, this review aims to provide the most reliable and ethically sound insights into the role of intraoperative ketamine in anesthesia.

Results

We identified 13 studies that met our criteria (Table 3). The main outcomes measured across these studies include postoperative pain intensity at various time points, analgesic effects, and opioid consumption, while secondary outcomes encompass factors such as hemodynamics, side effects, and cognitive function.

Pain and analgesia

The major outcomes studied in the intraoperative administration of ketamine included pain scores and quality of analgesia. One commonly used method to determine pain is the visual analog scale (VAS), which is a pain rating scale that represents a continuum between “no pain” (0 cm of the scale) and the “worst pain” at the end of the scale (10 cm) (25). Studies have shown that the intraoperative administration of ketamine lowers VAS pain scores postoperatively (7,13-15). Bilgin et al. (2005) investigated the influence of ketamine administration timing on postoperative pain relief (13). The study revealed that pain scores were lower at 2 and 4 hours postoperatively in the group that received ketamine before and during surgery. Moreover, VAS scores were significantly lower after 24 hours in the groups that administered intraoperative ketamine compared to preoperative administration alone (13). Zhang et al. (2023) also found a statistically significant reduction in pain scores after 24 hours (14).

Other studies have emphasized the improved analgesic effects of intraoperative ketamine administration determined by various metrics like a reduced need for additional analgesics, reporting better analgesia, a smaller area of hyperalgesia, and lower verbal pain scores in the verbal rating scale (VRS) (16-18). Argiriadou et al. (2004) demonstrated the effectiveness of repeated intraoperative s(+)-ketamine administration in improving postoperative pain relief and mood after abdominal surgery, with patients in the intraoperative group reporting lower pain scores, reduced need for additional analgesics, and improved mood states compared to single pre-incisional s(+)-ketamine and placebo groups (16). Webb et al. (2007) revealed that ketamine administration led to a significantly higher proportion of patients reporting excellent analgesia during the 0–24-hour postoperative period, and reduced pain scores (VRS) at rest and with movement over 48 hours (17). Bornemann-Cimenti et al. (2016) found a significantly smaller area of hyperalgesia in groups receiving intraoperative ketamine, signifying its potential to reduce hyperalgesia following surgery (18). Moreover, the postoperative hyperalgesia that results from a large dose of intraoperative remifentanil can be alleviated with a small dose of ketamine as studied by Joly et al. (2005), and even minimized morphine consumption (19).

Opioid consumption

Patient-controlled analgesia (PCA) is a method of self-administration of pain medication during the postoperative period. It allows for monitored tracking of a patient’s opioid consumption, from the time of administration to the number of doses. Webb et al. (2007) found that compared to a control group, the addition of intraoperative ketamine and postoperative infusion significantly lowered PCA morphine use by up to 48 hours post-surgery. Additionally, they noted that the control group required a significantly more frequent need for analgesic interventions during the 0–24 h period compared to the ketamine group, decreasing the need for physician intervention (17). Similarly, Fu et al. (1997) studied morphine consumption in two groups that received ketamine either intraoperatively or at wound closure. They found that cumulative morphine consumption was reduced by approximately 40% in the intraoperative group up to 48 hours, long after the normal expected duration of ketamine’s pharmacological action (20). Guignard et al. (2002) not only measured morphine consumption but also the time to first morphine administration and found that the ketamine group had a delay in requesting morphine (21). They also found lower morphine consumption in the ketamine group up to 24 hours postoperatively. Other studies also support the evidence from the findings above consistently demonstrating that intraoperative ketamine significantly reduces opioid consumption during the postoperative period (13,15,18).

Side effects

Several psychological side effects were noted. Bornemann-Cimenti et al. (2016) evaluated delirium using the Intensive Care Delirium Screening Checklist (ICDSC) 48 hours postoperatively (18). This tool gives eight points for eight different dimensions of delirium, including level of consciousness, inattention, disorientation, hallucination-delusion-psychosis, psychomotor agitation or retardation, inappropriate speech or mood, sleep/wake cycle disturbance, and symptom fluctuation (26). Delirium was defined as a score of more than three. Postoperative delirium scores were highest in the more conventional low-dose group, with no significant difference in delirium scores between the minimal dose and placebo groups (18). Similarly, Edwards et al. (1993) reported a significant correlation between higher doses of ketamine and an increase in postoperative dreaming. One of the patients in the highest dose ketamine group (20 mg.hr⁻¹) found these dreams to be very distressing and had to be withdrawn from the study (22). Similarly, Webb et al. (2007) noted that although the incidence of brief, non-disturbing hallucinations were not significantly increased in the ketamine group compared to the control group, three out of fifty-six patients in the ketamine group had to be withdrawn due to experiences of disturbing hallucinations/confusion. Additionally, they reported no significant increases in postoperative dreaming between the ketamine and control groups (17). Wu et al. (2000) found one incidence of psychomimetic emergence delirium from ketamine but no incidence of hallucinations (23). Zakine et al. (2008) observed no difference in, psychiatric disorders, delusions, nightmares, and sleep disorders between the intraoperative ketamine, perioperative (intraoperative and postoperative ketamine), and control groups (7).

Other postoperative analgesic-related side effects varied between the studies. The ketamine group in Webb et al. (2007) was found to have lower median sedation scores compared to the control group in the 0–24-hour period, but other side effect data, including nausea score, antiemetic administration, psychomotor, sleep quality, and Trail Making test scores were not significantly different between the two groups (17). Zakine et al. (2008) found no difference in sedation scores between their groups but reported that significantly lower nausea and vomiting scores in the perioperative group compared to the control group (7). Subramaniam et al. (2001), in contrast, noted elevated sedation scores in the initial two hours following surgery, though no hallucinations or respiratory depression were observed. Pruritis, nausea, and vomiting were similar between in both their groups (24). Wu et al. (2000) reported with no serious analgesic-related adverse effects as well as no significant difference in nausea, vomiting, urinary retention, and respiratory depression between their ketamine and control groups (23). Zhang et al. (2023) found no postoperative delirium, oliguria, or emergence agitation in the S-ketamine group. Additionally, side effects including dizziness, nausea, vomiting, or flatulence/bloating adverse events were comparable between the S-ketamine and control groups (14).

Postoperative recovery

Notably, Zhang et al. (2023) found that S-ketamine improved postoperative gastrointestinal (GI) recovery, reflected by a significantly shorter time of first postoperative flatus. The mean first postoperative flatus time for the S-ketamine group (50.3 hours) was 6.2 hours earlier than in the control group (56.5 hours) (14). However, additional research is essential to further elucidate effects of ketamine on postoperative GI recovery.

Discussion

Pain and analgesia

The results from the included studies collectively highlight the efficacy of intraoperative ketamine in improving pain outcomes. The consistent reduction in pain scores, as measured by VAS and VRS illustrate the potential of intraoperative ketamine to provide effective pain relief during the crucial early postoperative period following abdominal surgery (13-15,17). Furthermore, the observed improvements extend beyond subjective pain scores, encompassing metrics such as, reduced need for additional analgesics, reporting better analgesia, alleviation of hyperalgesia, and improved mood (16,18). Ketamine may also prove essential in comprehensive pain management strategies as demonstrated by its ability to alleviate hyperalgesia, and counteract the hyperalgesic effects of remifentanil (18,19).

Opioid consumption

Another major outcome studied in the intraoperative administration of ketamine is the level of opioid consumption postoperatively. Studies have shown that ketamine use reduces morphine consumption substantially in the initial 24-hour postoperative window with little to no severe adverse events (17). This reduction in opioid consumption reflects improved pain management and patient comfort and aligns with the broader healthcare goal of minimizing opioid usage. Additionally, a reduced need for opioids may mitigate opioid-related side effects, such as respiratory depression and ileus following abdominal surgery, thus promoting a faster and safer recovery for patients.

Notably, in the study by Fu et al. (1997) the reduced incremental use of morphine later in the study period is strongly suggestive of the sustained analgesic effect of intraoperative ketamine use. The time to morphine administration can also assess decreased opioid consumption as it reflects how quickly a patient requires pain relief and the effectiveness of pain management (20). The use of PCA as a self-administering method further supports the sustained analgesic effect of ketamine. The observed delay in time to first morphine administration and reduced need for physician intervention in the ketamine groups suggests prolonged and effective postoperative pain relief (17,21). These findings are indicative of improved pain management and reduced opioid consumption following intraoperative ketamine use.

Side effects

In evaluating the side effects associated with intraoperative ketamine, diverse findings have been reported across the medical literature, ranging from psychological and physical impacts to no adverse effects at all. The intraoperative use of ketamine is considered generally safe, but it has been associated with varying side effects such as delirium and hallucinations that could complicate post-operative care after abdominal surgery.

Overall, there were variable psychiatric side effects observed in these studies. Most mentioned minimal psychiatric side effects, but a few patients reported disturbing hallucinations or distressing dreams, resulting in their withdrawal of the study (17,22). However, there was no mention of the effect of these psychiatric side effects on postoperative recovery in these patients. These studies support minimal side effects with the use of intraoperative ketamine rather than serious adverse effects that would significantly impact postoperative recovery.

Ketamine’s adverse effects are predominantly dose-dependent, with more severe effects in subcutaneous infusions compared to oral intake (27). These include psychotomimetic effects like euphoria and hallucinations, as well as physical symptoms including hypertension and tachycardia. Notably, it can cause urinary tract toxicity, which can manifest as increased frequency, urgency, urge incontinence, dysuria, and hematuria (28). High doses in anesthesia are linked to tonic-clonic movements in a significant number of patients, highlighting the importance of stringent dosing and vigilant monitoring when administering ketamine (27).

Strengths and limitations

The use of two independent reviewers for study selection and the use of multiple databases enhances the validity and reliability of our conclusions. Additionally, we limited our results to randomized studies with the hope of decreasing selection bias and confounding.

However, there are several limitations to consider. We exclusively used PubMed and Ovid (MEDLINE) for our literature search, potentially omitting relevant studies published in other databases. The narrative format of the review, while informative, precludes a quantitative meta-analysis of the data. Finally, the focus on adult patients undergoing abdominal surgeries limits the generalizability of our conclusions to other patient populations.

Conclusions

In this review we highlight the findings from RCTs, which point to ketamine as a beneficial adjunct for managing post-operative pain and reducing opioid consumption. Additionally, ketamine was shown to extend the time until the first administration of morphine after surgery, reflecting the sustained analgesic effects of ketamine. While ketamine’s benefits are promising, these findings highlight the importance of adopting a systematic approach for further validation. Given the differences in study methodologies and patient demographics, a comprehensive meta-analysis would be essential to solidify our understanding of ketamine’s effects and inform clinical guidelines, ensuring its use in abdominal surgeries optimally balances efficacy with safety.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-23-97/rc

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-23-97/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-23-97/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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