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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 5  |  Issue : 2  |  Page : 98-101

Comparison of C-reactive protein levels, neutrophil count, and clinical outcomes between low-dose ketamine given at the end of surgery and at induction in laparotomy


Department of Anesthesiology, Pain Management, and Intensive Care, Sanglah General Hospital, Udayana University, Denpasar, Bali, Indonesia

Date of Submission23-Nov-2020
Date of Decision01-Feb-2021
Date of Acceptance21-Feb-2021
Date of Web Publication16-Apr-2021

Correspondence Address:
Dr. Made Septyana Parama Adi
Department of Anesthesiology, Pain Management, and Intensive Care, Sanglah General Hospital, Udayana University, Denpasar, Bali
Indonesia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bjoa.bjoa_248_20

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  Abstract 


Background: Both surgery and anesthesia can cause an inflammatory response, rise in C-reactive protein (CRP) levels in response to the acute phase, as well as the activation and increased number of neutrophils. Ketamine with the right time of administration is expected to control the inflammatory response so that it can reduce the risk of postoperative complications such as pain and reduce the use of opioids. Patients and Methods: A total of 68 patients with physical status American Society of Anesthesiologists (ASA) I–II who underwent elective laparotomy were collected by consecutive sampling. The samples were divided into 2 groups; Group A received a low dose of ketamine at the end of the surgery, and Group B received a low dose of ketamine at the time of anesthesia induction. We measured CRP level, neutrophil count, visual analog scale (VAS), as well as total morphine consumption at 24 h postoperatively. Results: The increase in CRP levels in Group A was significantly lower compared to Group B (70.8 ± 42.7 vs. 115.0 ± 44.0 mg/L, P = 0.001). Group A has a significantly lower increase in CRP levels, VAS, and the total consumption of morphine 24 h postoperatively (P < 0.05). There was a strong positive between CRP and VAS (R = 0.702, P = 0.001). Conclusion: Administration of low doses of ketamine at the end of surgery was more effective in suppressing CRP levels, resulting in lower VAS score, and lower total morphine consumption in the 24-h postoperative period compared to low-dose ketamine given at the time of induction.

Keywords: C-reactive protein, inflammation, low dose ketamine, neutrophils, total morphine consumption, visual analog scale


How to cite this article:
Gede Widnyana I M, Pramana Suarjaya I P, Agung Senapathi TG, Ryalino C, Parama Adi MS. Comparison of C-reactive protein levels, neutrophil count, and clinical outcomes between low-dose ketamine given at the end of surgery and at induction in laparotomy. Bali J Anaesthesiol 2021;5:98-101

How to cite this URL:
Gede Widnyana I M, Pramana Suarjaya I P, Agung Senapathi TG, Ryalino C, Parama Adi MS. Comparison of C-reactive protein levels, neutrophil count, and clinical outcomes between low-dose ketamine given at the end of surgery and at induction in laparotomy. Bali J Anaesthesiol [serial online] 2021 [cited 2021 Jun 23];5:98-101. Available from: https://www.bjoaonline.com/text.asp?2021/5/2/98/313895




  Introduction Top


The effects of anesthesia and surgery can cause a stress response that results in hormonal and metabolic changes in the body. Immune system disorders expressed as an excessive pro-inflammatory immune response and suppression of cell-mediated immunity can affect the course of the postoperative period. C-reactive protein (CRP), one of the acute phase responses, plays an important role in the inflammatory process. The process of its formation is induced by the release of interleukin-6 by macrophage cells.[1] The inflammatory stress response is also characterized by an increase in the number of neutrophils that will undergo the diapedesis process to the inflammation site through the vascular endothelium.[2]

Ketamine premedication can reduce the inflammatory response characterized by decreased CRP levels caused by surgical trauma and can prevent secondary damage to tissues/organs, by reducing inflammation, it also reduces pain and postoperative analgesic need.[3] A systematic review by De Kock et al.[4] found that several studies showed different results on the administration time of low dose ketamine in suppressing the inflammatory response. The goal of this study was to compare the CRP levels, neutrophil count, and clinical outcomes between patients who received low dose ketamine given at the end of surgery and at anesthesia induction, in patients who underwent elective laparotomy.


  Patients and Methods Top


This study is a double-blind, randomized clinical trial and was conducted after obtaining approval from the institutional ethical committee and was registered on Clinical Trial Registration (NCT04462094, June 26, 2020). All participants provided written informed consent to participate in this study. A total of 68 patients with physical status American Society of Anesthesiologists (ASA) I–II, aged 18–65 years of either sex who underwent elective laparotomy procedure with general anesthesia were collected by consecutive sampling techniques.

Patients who were unwilling to participate, contraindicated to ketamine, allergic to morphine, with a history of chronic disease, chronic pain, or autoimmune disease, a history of decreased consciousness or mental disorders, body mass index (BMI) <18.5 kg/m2, or ≥30 kg/m2, or with history of regular pain killer prescription were excluded from the study. Using the permuted block randomization method, patients were divided into 2 groups. Group A received a low dose of ketamine at the end of surgery (n = 34), and Group B received a low dose of ketamine at the time of anesthesia induction (n = 34).

We withdrew the 3 mL blood sample from the subjects upon in the preparation room before surgery. All subjects received 0.05 mg/kg midazolam as premedication. In the operating room, a standard ASA monitoring was employed. The patient received 3–5 min of preoxygenation, fentanyl 2 μg/kg, and atracurium 0.5 mg/kg. In Group A, 3 ml of NaCl 0.9% was given, and Group B was given ketamine 0.3 mg/kg (diluted with 0.9% NaCl to a total volume of 3 ml). Then, intubation was carried out and maintenance with compressed air, O2, and sevoflurane mixture, fentanyl 0.25 μg/kg/h, and atracurium 0.1 mg/kg/h. At the end of the surgery, Group A was given ketamine 0.3 mg/kg (diluted with 0.9% NaCl with a total volume of 3 ml), and Group B was given 3 ml of NaCL 0.9%.

Postoperatively, the patient received morphine by patient-controlled analgesic (PCA) on the following setting: demand-only mode, concentration 1 mg/ml, demand dose 1 mg, lockout interval 6 min, and a maximum dose of 10 mg every 4 h. After 24 h, 3 ml of a second blood sample was taken. The pain scale was evaluated by visual analog scale (VAS) and the total morphine consumption was also evaluated.

The statistical calculations were performed using the software Statistical Package for the Social Sciences for Windows version 25.0 (SPSS Inc., Chicago, IL, USA). The mean and standard deviation were used for descriptive statistics. After performing the Kolmogorov–Smirnov test for normality test, the nonnormally distributed data were analyzed using nonparametric tests. Independent t-test and Mann–Whitney's U-test were used to analyze quantitative data, and the Chi-square test was used for qualitative data. A P < 0.05 indicates significance.


  Results Top


A total of 68 patients were recruited and assigned into two groups of 34 patients. Both groups were comparable concerning age, BMI, gender, ASA physical status, and duration of operation [Table 1].
Table 1: Demographic data of both groups of patients

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In this study, Group A and B were compared in terms of the differences of the CRP level (△CRP), neutrophil counts (△NEU), VAS (△VAS), and total morphine consumption [Table 2]. The increase in CRP levels in Group A was significantly lower compared to Group B (70.8 ± 42.7 vs. 115.0 ± 44.0 mg/L, P = 0.001). The increase in the neutrophil count did not differ significantly in both the groups (P = 0.557). The increase in VAS score in Group A was significantly lower compared to Group B (20[10] vs. 40 (22.5) mm). The total morphine consumption in Group A was significantly lower compared to Group B (6[4] vs. 10[4] mg). Based on Spearman's correlation test between △ CRP levels and △ VAS value, there was a strong positive correlation with a correlation coefficient of 0.702, which was statistically significant (P = 0.001).
Table 2: Comparison of the differences of C-reactive protein levels, neutrophil counts, visual analog score, and total morphine consumption between the two groups

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  Discussion Top


This study shows that the administration of low doses of ketamine at the end of surgery is more effective in reducing the CRP levels when compared with the administration of low doses of ketamine at the time of induction. CRP levels will increase approximately 4–12 h after surgery, and peak at 24–72 h, and return to baseline values about 2 weeks after surgery,[5] so that the timing of ketamine administration at the end of the surgery, works precisely when the CRP levels start to rise before reaching its elimination half-life, which ranges from 2 to 4 h.

The comparison of neutrophil count in this study did not show statistically significant differences. This is likely because neutrophils are one of the innate immunity, which responds quickly to tissue damage. Neutrophils are pulled out of the capillaries and lead to the site of damage and release their bacterial content and form cytokines that modulate the immune response. During inflammation, neutrophil in circulation increases tenfold in 5–10 h, and apoptosis of neutrophils occurs after 24 h or more,[6] so the measurement at 24 h postoperatively can be less effective because the stimulus by tissue damage due to surgery has stopped, with maximum operation duration in this study is 240 min. Another possibility is that neutrophils are less specific in assessing inflammation when compared to CRP in assessing inflammatory markers in acute appendicitis, the sensitivity, specificity, and positive predictive value of CRP was 95.6%, 77.77%, and 95.6%, while the sensitivity, specificity, and positive predictive value of neutrophils were 98.9%, 38.88%, and 89.21%.

The VAS score in Group A was significantly lower compared to Group B. Ketamine produces antinociception by interacting with μ-receptors on the spinal nerve, N-methyl-D-aspartate (NMDA) receptor antagonists, and activation of the monoaminergic descending pain inhibitory pathway. Ketamine's affinity for the NMDA receptor is greater than the μ receptor, and much greater than monoamine receptors or other non-NMDA receptors (e.g., acetylcholinesterase and sigma receptors), which results in the smaller the ketamine dose, the more selectively it interacts with the NMDA receptor.[7] Ketamine inhibits the activation of NMDA receptors by glutamate, decreases presynaptic glutamate release, and increases the effect of gamma-aminobutyric acid inhibitory neurotransmitters.[8]

This study shows that giving low doses of ketamine at the end of surgery is more effective in reducing the total consumption of morphine. This result is the same as the study of Menigaux et al.[9] regarding intraoperative ketamine administration for postoperative pain in orthopedic surgery, found in the ketamine group with a dose of 0.15 mg/kg given at the end of surgery had a significantly lower 24-h total opioids consumption than ketamine given at induction and the control group. A similar result was also seen in a study by Adam et al.[10] in patients who underwent a mastectomy. They found that ketamine administration of 0.15 mg/kg at the end of surgery had lower PCA morphine consumption at 2 h postsurgery compared to ketamine administration before surgery.

Ketamine interacts with the mu, delta, and kappa receptors of opioids. The analgesic effect of ketamine may be due to the activation of these receptors in the central and spinal areas.[8] Intravenous ketamine is said to have an opioid-sparing effect. This effect was seen as a reduction in the number of opioids administered and a prolongation of the first analgesic rescue.[11]

Statistically, there is a significant, and strong correlation between the CRP levels and the VAS score. This study is also in line with research conducted by Senapathi et al.[2] which found a positive, significant correlation between VAS values and CRP levels, but this positive correlation was obtained by comparing the administration of ketamine with placebo given before spinal anesthesia. Choi et al.[12] reported that an increase of 1 mg/dL postoperative CRP value was significantly associated with an increase in morphine consumption by 1.4%, and postoperative CRP value was positively associated with pain scores as measured by the Numerical Rating Scale on the first, second, and third postoperative days.


  Conclusion Top


Administration of low doses of ketamine at the end of surgery was more effective in reducing the increase in CRP levels, VAS scores, and total morphine consumption 24 h postoperatively when compared to administration of low doses of ketamine during anesthesia induction in patients undergoing elective laparotomy under general anesthesia. There was a strong correlation between CRP levels and the VAS score, which was statistically significant.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Cole DS, Watts A, Scott-Coombes D, Avades T. Clinical utility of peri-operative C-reactive protein testing in general surgery. Ann R Coll Surg Engl 2008;90:317-21.  Back to cited text no. 1
    
2.
Senapathi TG, Widnyana IM, Wiryana M, Aribawa IG, Aryabiantara IW, Hartawan IG, et al. Effectiveness of low-dose intravenous ketamine to attenuate stress response in patients undergoing emergency cesarean section with spinal anesthesia. J Pain Res 2016;9:689-92.  Back to cited text no. 2
    
3.
Abbas H, Ansari AJ, Arshad Z, Mahdi A, Bogra J. Effect of ketamine on inflammatory markers and postoperative analgesia in patients undergoing general anesthesia. Internet J Anesthesiol 2019;32:1:1-4.  Back to cited text no. 3
    
4.
De Kock M, Loix S, Lavand'homme P. Ketamine and peripheral inflammation. CNS Neurosci Ther 2013;19:403-10.  Back to cited text no. 4
    
5.
Caetano Júnior EM, Vieira JP, Moura-Franco RM, Fuziy RA, Serra HO, Marcondes GB, et al. Evaluation of systemic inflammatory responses in cholecystectomy by means of access. Single-port umbilical incision, transvaginal NOTES, laparoscopy and laparotomy. Acta Cir Bras 2015;30:691-703.  Back to cited text no. 5
    
6.
Florence M. Neutrophils and inflammation: Unraveling a new connection. Biol Med (Aligarh) 2016;8:6.  Back to cited text no. 6
    
7.
Price DD, Mayer DJ, Mao J, Caruso FS. NMDA-receptor antagonists and opioid receptor interactions as related to analgesia and tolerance. J Pain Symptom Manage 2000;19:S7-11.  Back to cited text no. 7
    
8.
Wiryana M, Sinardja IK, Budiarta IG, Senapathi TG, Widnyana M, Aryabiantara IW, et al. Low dose ketamine. BJOA 2017;1:13-9.  Back to cited text no. 8
    
9.
Menigaux C, Fletcher D, Dupont X, Guignard B, Guirimand F, Chauvin M. The benefits of intraoperative small-dose ketamine on postoperative pain after anterior cruciate ligament repair. Anesth Analg 2000;90:129-35.  Back to cited text no. 9
    
10.
Adam F, Libier M, Oszustowicz T, Lefebvre D, Beal J, Meynadier J. Preoperative small-dose ketamine has no preemptive analgesic effect in patients undergoing total mastectomy. Anesth Analg 1999;89:444-7.  Back to cited text no. 10
    
11.
Laskowski K, Stirling A, McKay WP, Lim HJ. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anaesth 2011;58:911-23.  Back to cited text no. 11
    
12.
Choi HR, Song IA, Oh TK, Jeon YT. Perioperative C-reactive protein is associated with pain outcomes after major laparoscopic abdominal surgery: A retrospective analysis. J Pain Res 2019;12:1041-51.  Back to cited text no. 12
    



 
 
    Tables

  [Table 1], [Table 2]



 

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