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 Table of Contents  
Year : 2017  |  Volume : 4  |  Issue : 3  |  Page : 149-155

Intraperitoneal ketamine attenuates the inflammatory reactivity associated with pneumoperitoneum

1 Anesthesia and Intensive Care Unit Department, Faculty Of Medicine For Girls, Al-Azhar University, Cairo, Egypt
2 General Surgical Department, Faculty Of Medicine For Girls, Al-Azhar University, Cairo, Egypt

Date of Submission23-Dec-2016
Date of Acceptance01-Mar-2017
Date of Web Publication5-Jul-2017

Correspondence Address:
Soad Sayed El-Gaby
Department of Anesthesiology and Intensive Care, Faculty of Medicine, Al Azhar University for Girls, Cairo
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/roaic.roaic_121_16

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Laparoscopic surgery is a common procedure that has replaced many types of open surgeries. Ketamine is an anesthetic drug that has immunomodulatory and anti-inflammatory effects. It results in ‘homeostatic regulation’ of the acute inflammatory reaction.
The primary outcome was to evaluate the anti-inflammatory effect of intraperitoneal instillation of low-dose ketamine (0.5 mg/kg) in laparoscopic pneumoperitoneum. The secondary outcome was to evaluate its analgesic effect.
Patients and methods
This study was carried out on 46 patients aged 26–46 years of ASA grade I–II. All patients were scheduled for laparoscopic cholecystectomy. The patients’ history, clinical examination, and laboratory investigations were carried out on the preoperative day. Patients were randomly allocated to one of two groups: the ketamine intraperitoneal (KIP) group (n=23 patients), in which 0.5 mg/kg ketamine diluted in 30 ml normal saline was instilled intraperitoneally; and the saline intraperitoneal (SIP) group (n=23 patients), in which 30 ml of normal saline was instilled intraperitoneally. The following parameters were recorded: time to extubation, time to first request for analgesia, numerical rating scale for pain, the total dose of pethidine postoperatively, and biochemical assay for interleukin 6 (IL-6).
No patients complained of pain in the KIP group compared with the SIP group. The time to first analgesic request postoperatively was significant longer in the KIP group than in the SIP group (P<0.013). Patients in the KIP group required a lower dose of pethidine in the first 24 h postoperatively compared with patients in the SIP group (P<0.001). The postoperative serum IL-6 levels were significantly lower in the KIP group compared with the levels in the SIP group (P<0.001).
This study suggests that low-dose ketamine (0.5 mg/kg) attenuates the increase of IL-6, which is a biomarker of inflammatory activation associated with pneumoperitoneum.

Keywords: anti-inflammatory, ketamine, pneumoperitoneum

How to cite this article:
El-Gaby SS, Mohamed SS. Intraperitoneal ketamine attenuates the inflammatory reactivity associated with pneumoperitoneum. Res Opin Anesth Intensive Care 2017;4:149-55

How to cite this URL:
El-Gaby SS, Mohamed SS. Intraperitoneal ketamine attenuates the inflammatory reactivity associated with pneumoperitoneum. Res Opin Anesth Intensive Care [serial online] 2017 [cited 2020 Jun 4];4:149-55. Available from: http://www.roaic.eg.net/text.asp?2017/4/3/149/209665

  Introduction Top

Laparoscopic surgery is a commonly performed procedure that has replaced many types of open surgeries [1]. Direct surgical touching by instruments and peritoneal trauma release acute-phase proteins, which leads to release of mediators such as C-reactive protein, interleukin 6 (IL-6), and other cytokines. These mediators initiate the inflammatory process resulting in pain perception [2]. Efforts to improve postoperative pain relief have concentrated on preventive regimens. These regimens decrease noxious input and sensitization in pain pathways [3]. Ketamine is a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptor that blocks nociceptive input and reduces hyperalgesia [4]. Ketamine is an immunomodulatory agent and anti-inflammatory drug. It avoids the extension and exacerbation of inflammation without blunting the local processes. Thus, ketamine has to be considered a drug that optimizes inflammation to restore homeostasis [5].

Therefore, the anesthesiologist should use an anesthetic agent that will result in ‘homeostatic regulation’ of the acute inflammatory reaction and stress-induced immune disturbances.

  Aim Top

The primary outcome was to evaluate the anti-inflammatory effect of intraperitoneal instillation of low-dose ketamine (0.5 mg/kg) in laparoscopic pneumoperitoneum. The secondary outcome was to evaluate its analgesic effect.

  Patients and methods Top

This study was carried out in Al-Azhar University Hospital after obtaining approval from the hospital ethics committee and signed informed consent from patients. A total of 46 patients aged 26–46 years of ASA grade I–II who were scheduled for laparoscopic cholecystectomy were included in the study. The patients’ history, clinical examination, and investigations were carried out on the preoperative day.

Patients with a history of systemic hypertension, cardiac diseases, hepatic diseases, renal diseases, diabetes mellitus, and treatment with steroids or NSAIDs were excluded from the study.

All patients were fasting preoperatively for 6 hours and premedicated with midazolam 0.05 mg/kg and ondansetron 4 mg intravenously 15 min before the operation. Preoxygenation with 100% oxygen was done for 3 min. General anesthesia was induced with fentanyl 1–2 μg/kg, lidocaine 30–50 mg, propofol 1–2 mg/kg, and rocuronium bromide 0.6–1 mg/kg intravenously to facilitate oral tracheal intubation. Anesthesia was maintained with 50% O2 in air, and isoflurane (1–2%) was adjusted to maintain adequate anesthesia and hemodynamic stability. Lung ventilation was controlled to maintain end-tidal CO2 tension at 35±5 mmHg. Incremental doses of rocuronium were given every 30 min, and fentanyl 0.5 μg/kg intravenously if intraoperative pain was suspected. Crystalloid solution 6–10 ml/kg/h was given intravenously. Heart rate was continuously monitored with ECG, and systolic, diastolic, mean arterial pressure, and peripheral oxygen saturation were monitored noninvasively.

A Veress needle was introduced towards the pubis through a small (1 cm) elliptical subumbilical incision with the patients in the Trendelenburg position. Pneumoperitoneum was achieved by CO2 insufflations at the rate of 1 l/min for the first min and then at a rate of 3–4 l/min with a maximum intra-abdominal pressure of 12–15 mmHg. A safe reusable metal trocar was introduced through the previous incision. The camera scope was then introduced. The pelvis and abdomen were inspected. Patients were randomized preoperatively using computer-generated numbers into two groups according to the type of analgesic drug used: the ketamine intraperitoneal (KIP) group (n=23 patients), in which 0.5 mg/kg ketamine diluted in 30 ml normal saline was injected intraperitoneal; and the saline intraperitoneal (SIP) group (n=23 patients), in which 30 ml of normal saline was injected intraperitoneal. Patients in both groups were in the Trendelenburg position for 5–10 min. Thereafter, all patients were placed in the anti-Trendelenburg position with their right shoulder raised to start the surgery. At the end of the surgical procedures, the CO2 was removed by manual compression of the abdomen with an open trocar. Isoflurane was discontinued, FiO2 was increased to 100%, and atropine 0.01–0.02 mg/kg and prostigmine 0.04–0.08 mg/kg were used to antagonize the residual effect of rocuronium bromide. After tracheal extubation the patients were transferred to the PACU and the following parameters were recorded:
  1. Time to extubation (min): time from the end of surgery to tracheal extubation.
  2. Pain was assessed with a numerical rating scale (NRS), which was explained to all patients preoperatively (0=no pain to 10=the worst pain). Pain was recorded at time zero (T0) (immediately postoperatively), every 2 h for the first 6h, and then at 12 h postoperatively. Patients were considered to be in pain if they scored at least 2 on the NRS. Pethidine 0.5 mg/kg intramuscularly was administered in such scenarios.
  3. Time to first request for analgesia postoperatively (min).
  4. Total dose of pethidine postoperatively (mg/24 h).

Biochemical assay

For the biochemical assay 5 ml of fasting venous blood samples was taken from each patient into a plain tube. The blood samples were left to clot and then centrifuged at 1600 rpm for 20 min. The serum was separated and used for estimation of IL-6 with an ELISA Kit (code no. 10140; Glory Science Co. Ltd, Gorgia, USA). Purified human IL-6 was used to coat the microtiter plate to produce a solid-phase antibody. Thereafter IL-6 was added to the wells. IL-6 antibody combined with labeled horseradish peroxidase (HRP) forms an antibody–antigen–enzyme–antibody complex. After washing thoroughly, TMB substrate solution was added, which turns blue on contact with HRP. The enzyme-catalyzed reaction was terminated by the addition of a stop solution and the color change was measured at a wavelength of 450 nm. The concentration of IL-6 in the samples was then determined by comparing the optical density of the samples to the standard curve. IL-6 was sampled preoperatively and 6 h postoperatively.

Statistical analysis

Data were collected, revised, coded, and entered into the statistical package for the social science (IBM SPSS; Armonk, NY: IBM Corp), version 20. The sample size was calculated using Epi Info program (Center for Disease Control and Prevention (CDC) in Atlanta, Georgia, USA). Qualitative data were presented as number and percentage and quantitative data as mean and SD when their distribution was parametric. Comparison of qualitative data between the two groups was made using the χ2-test. Fisher’s exact test was used instead when the expected count in any cell was less than 5. Comparison of quantitative data with parametric distribution between the two groups was made using the independent t-test. Confidence interval was set at 95% and the margin of error accepted was set to 5%. The P-value was considered significant at less than or equal to 0.05, nonsignificant at more than 0.05, and highly significant at less than or equal to 0.01.

  Results Top

The study design is presented in [Figure 1].
Figure 1 Flow chart of patients (study design). KIP, ketamine intraperitoneal; SIP, saline intraperitoneal.

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There were no significant differences in either the demographic data or the duration of surgery or anesthesia between the two groups ([Table 1]).
Table 1 Demographic data and surgical and anesthetic duration in the two studied groups

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No patient complained of pain in the KIP group compared with the SIP group at any assessment point ([Table 2]). Regarding the time to first analgesic request postoperatively, there was a statistically significant difference between the KIP group (237.5±4.7) and the SIP group (59.14±6.4) (P<0.001) ([Table 3]).
Table 2 Numerical rating scale for pain in both groups postoperatively

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Table 3 Time to extubation, first analgesic request, and total dose of pethidine (mg/24 h)

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Regarding the total dose of pethidine requirement, patients in the KIP group required a lower dose of pethidine in the first 24 h postoperatively (52.15±14.25) compared with the SIP group (107.65+29.18) (P<0.001) ([Table 3]).

The time to extubation was 5.54±1.67 and 4.22±1.1.78 min in the KIP group and SIP group, respectively (P=0.013) ([Table 3]).

The postoperative serum IL-6 levels were significantly lower in the KIP group (16.82±6.06 pg/ml) compared with that in the SIP group (45.77±14.86 pg/ml) (P<0.001) ([Table 4] and [Figure 2]).
Table 4 Levels of interleukin 6 (pg/ml) preoperatively and 6 h postoperatively in both groups

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Figure 2 Interleukin 6 (IL-6) levels (pg/ml). Values are expressed as mean (SD).

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  Discussion Top

Laparoscopic surgical procedures usually require the creation of a capnoperitoneum that could be responsible for peritoneal desiccation injury [6]. The pneumoperitoneum associated with short-term compartment situation has immediate, transient, lasting, local, and global consequences [7]. The acute-phase stress protein release associated with surgical procedures predisposes the peritoneum and organ structures to inflammation, resulting in pain being experienced by the patient [2]. The inflammatory process is regulated by the production of anti-inflammatory cytokines. Ketamine is an NMDA receptor antagonist with hypnotic analgesic and anti-inflammatory action at low doses [8]. Structures of benzene may play a protective role in scavenging free radicals and inhibiting the activity of inflammatory cytokines [9].

The NMDA receptors have a role in central sensitization. The blunting of central sensitization has played an important role in the prevention and treatment of both postoperative pain and chronic pain [10].

Although central NMDA receptors still receive a great deal of attention, evidence suggests that NMDA receptors located in the peripheral tissue (intraperitoneal) and viscera play an important role in nociception and peripheral sensitization [11]. Activation of peripheral NMDA receptors causes the Ca-dependent release of proinflammatory substance p and produces nociceptive behavior. Peripheral injection of NMDA receptor antagonists attenuates pain associated with neuropathic pain or inflammation [12].

The present study showed that KIP 0.5 mg/kg was associated with significant decrease in NRS and analgesic dose requirement postoperatively; this could be explained by peripheral NMDA receptor (intraperitoneal) blockade.

There are a few experimental studies that have evaluated intraperitoneal administration of NMDA receptor antagonists. Beniro et al. [13] demonstrated that intraperitoneal administration of NMDA receptor antagonists decreased the nociception observed during the late phase of the formalin test in mice.

A study performed by Sobrinho et al. [14] concluded that intra-articularly delivered ketamine during total knee replacement surgery provides effective postoperative analgesia.

Another study demonstrated that topical use of ketamine cream or gel up to 20% is successful for the treatment of pain [15].

Furthermore, in 2014, a meta-analysis by Cho et al. [16] reported that preoperative administration of ketamine in tonsillectomy, either systemically or locally, resulted in significantly decreased pain and analgesic need over 24 h. In recent times, several studies have shown that subcutaneous infiltration of ketamine decreases the pain score after surgery, prolongs the time for the first analgesic request, and reduces the total amount of analgesics consumed [17].

Similar results to our study were reported in 2015 by Gom and Abd Elhamid [18]. They stated that peripheral (peritoneal) NMDA receptor blockade by S(+) ketamine was involved in the reduction of postoperative pain and analgesic requirement following bariatric surgery [18]. Also, Moharari et al. [19] reported that intraperitoneal instillation of 0.5 mg/kg ketamine in elective laparoscopic cholecystectomy significantly reduces the postoperative pain and the analgesic requirement.

We observed that patients in the SIP group were extubated earlier than the patients in the KIP group because of the analgesic effect of ketamine and systemic absorption that could potentiate the effect of anesthetic drugs [20].

IL-6 concentration in the first 6 postoperative hours was chosen as a representative outcome for the inflammatory response because it has a proinflammatory action. Further, ketamine acts as an anti-inflammatory drug [5]. It is a reliable and particularly sensitive biomarker of inflammatory activation [21].

We found that in the KIP group there was a highly significant decrease in IL-6 concentration postoperatively compared with that in the SIP group.

This might be attributed to the ability of ketamine to inhibit the production of inflammatory cytokines and thus reduce stress responses during pneumoperitoneum. The results of the present study are in agreement with previous studies that reported that low-dose ketamine pretreatment can reduce oxidative stress and the inflammatory cytokine response associated with pneumoperitoneum in rats [22]. Also, our results are in accordance with data from a meta-analysis showing that ketamine significantly inhibits the early postoperative inflammatory response [23].

In addition, ketamine infusion decreased the level of tumor necrosis factor-α, IL-13, and IL-6 induced by lipopolysaccharides in lung tissue [24].

The analgesic effects of ketamine are mediated through the blockade of the phencyclidine binding site of NMDA receptors of the nociceptive neurons; this mechanism could be partly from the anti-inflammatory effects of ketamine. Moreover, it was reported that ketamine interacts with opioid, monoamine, cholinergic, purinergic, and adenosine receptor systems [25]. The anti-inflammatory effects of ketamine without affecting the local healing processes are considered to be due to its effect on G-protein-coupled receptor signaling [26].

Moreover, the anti-inflammatory characteristics of ketamine were revealed through various mechanisms including inhibition of transcription of nuclear factor-κB and activator protein 1 [27], proinflammatory cytokine production (IL-6 and tumor necrosis factor) [28], neutrophil functions [29], release of adenosine [30], nitric oxide production in macrophages [31], and blockade of large-conductance KCa channels on microglia (BK channels) [32]. Ketamine has been shown to downregulate the proinflammatory enzyme cyclooxygenase 2.

There are limitations to our study. A single dose of ketamine was studied, and further studies are needed to determine the most appropriate dose of ketamine intraperitoneal.

  Conclusion Top

This study suggests that intraperitoneal instillation of low-dose ketamine (0.5 mg/kg) attenuates the increase of IL-6, which is a biomarker of inflammatory activation associated with pneumoperitoneum. It reduces postoperative pain and analgesic requirement.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4]

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