Fluid Balance Profile in Patients Admitted to the Intensive Care Unit (ICU) of Haji Adam Malik Central General Hospital, Medan, January–June 2025

INTRODUCTION

Intraoperative hypotension is a critical determinant of adverse perioperative outcomes, including acute kidney injury, myocardial injury, and increased postoperative mortality [1,2]. Even brief reductions in mean arterial pressure (MAP) below 65 mmHg have been consistently associated with end-organ hypoperfusion and poor outcomes [2]. Despite advances in anesthetic techniques, the incidence of intraoperative hypotension during major noncardiac surgery remains high, largely due to anesthetic-induced vasodilation and myocardial depression.

Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has re-emerged as a valuable adjunct in modern anesthesia because of its unique pharmacodynamic profile. At subanesthetic doses, ketamine provides effective analgesia while exerting sympathomimetic effects, including increased systemic vascular resistance, heart rate, and cardiac output [3,4]. These properties suggest a potential role in counteracting anesthesia-induced hypotension. Randomized controlled trials in obstetric anesthesia have demonstrated that ketamine significantly reduces the incidence of post-spinal hypotension and decreases vasopressor requirements [5,6]. Similarly, low-dose ketamine infusions during laparoscopic procedures have been associated with improved hemodynamic stability and reduced anesthetic requirements [7]. However, meta-analytic evidence indicates that while ketamine reduces blood pressure variability, its effect on absolute hemodynamic values remains modest [8].

Importantly, high-quality evidence evaluating the hemodynamic effects of ketamine in major non-cardiac surgery is limited. Given the increasing emphasis on perioperative hemodynamic optimization and opioid-sparing strategies, further investigation is warranted. This study aimed to evaluate whether perioperative low-dose ketamine reduces intraoperative hypotension and improves hemodynamic stability in patients undergoing major surgery.

METHODS

Study Design and Setting

This prospective, randomized, double-blind, placebo-controlled trial was conducted at a tertiary-care academic center. The trial aimed to evaluate the effects of perioperative low-dose ketamine on intraoperative hemodynamic stability in adult patients undergoing major non-cardiac surgery under general anesthesia.

Participants

Eligible participants were adults aged 18–75 years with American Society of Anesthesiologists (ASA) physical status I–III scheduled for elective major surgery with an expected duration exceeding two hours. Patients were excluded if they had significant cardiovascular disease (including advanced heart failure or uncontrolled hypertension), clinically relevant arrhythmias, psychiatric disorders, pregnancy, elevated intracranial pressure, or hypersensitivity to ketamine. Additional exclusion criteria included chronic opioid use, concurrent NMDA antagonist therapy, and body mass index >40 kg/m² to ensure dosing consistency.

Randomization and Blinding

Participants were randomly assigned to either the ketamine or placebo group in a 1:1 ratio using a computer-generated randomization sequence with concealed allocation. Study medications were prepared by an independent pharmacist in identical syringes to ensure blinding. All patients, the anesthesiologists, intraoperative staff, and outcome assessors remained blinded to the group allocation throughout the study period.

Intervention Protocol

Following the induction of anesthesia with midazolam, fentanyl, propofol, and a neuromuscular blocking agent, the patients in the intervention group received an intravenous ketamine bolus of 0.3 mg/kg over 60 seconds, followed by an infusion of 0.1 mg/kg/h until closure. Patients in the control group received an equivalent volume of isotonic saline following the same protocol. Anesthesia was maintained using sevoflurane (targeting approximately 1.0 MAC) or propofol infusion titrated to maintain a bispectral index (BIS) between 40 and 60. Supplemental opioid analgesia (25–50 µg increments of fentanyl) was administered as needed for hemodynamic indicators of pain.

Perioperative Management and Monitoring

Standard intraoperative monitoring included electrocardiography, invasive arterial blood pressure measurement, pulse oximetry, end tidal carbon dioxide monitoring, and BIS. Hemodynamic variables were recorded at baseline (pre-induction), immediately after induction, every 5 minutes during the first 20 minutes, and every 15 minutes until the end of the surgery. Fluid therapy used balanced crystalloids (5–8 mL/kg/h). Vasopressor agents (phenylephrine or ephedrine) were administered per institutional protocols, and the doses were recorded.

Outcomes

Primary outcome. The primary outcome was intraoperative hypotension, defined as at least one episode of mean arterial pressure (MAP) <65 mmHg or a reduction greater than 20% from baseline. Secondary outcomes were intraoperative MAP, heart rate, hypotensive episode duration and frequency, vasopressor requirements, hemodynamic variability, pain scores, opioid consumption within 24 hours, and adverse events, including neuropsychiatric symptoms and postoperative nausea and vomiting.

Sample Size Calculation

Sample size estimation was based on the detection of a clinically significant 20% absolute reduction in the incidence of intraoperative hypotension. Assuming a baseline incidence of 50%, a two-sided alpha of 0.05, and 90% power, a minimum of 35 patients per group was required for the study. To account for potential dropouts and enhance statistical robustness, the final target sample size was increased to approximately 80–90 patients per group.

Statistical Analysis

All analyses were performed on an intention-to-treat basis. Continuous variables are expressed as mean ± standard deviation or median (interquartile range) and were compared using independent t-tests or Mann–Whitney U-tests. Categorical variables were analyzed using the chi-square or Fisher's exact test. Repeated hemodynamic measurements were evaluated using linear mixed-effects models to account for variability within subjects over time. A two-sided p-value <0.05 was considered statistically significant. Missing data were handled using multiple imputations when applicable.

Ethical Considerations

The study protocol was approved by the institutional ethics committee and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Written informed consent was obtained from all participants before enrollment. Patient confidentiality was maintained, and participants were free to withdraw at any time without consequences for their care.

RESULTS

Table 1. Baseline and perioperative characteristics

Variable	Ketamine (n=88)	Placebo (n=87)	p-value
Age, years	55.1 ± 11.4	56.3 ± 10.9	0.48
Male sex, n (%)	51 (58.0)	49 (56.3)	0.82
BMI, kg/m²	26.7 ± 3.8	27.1 ± 4.1	0.51
ASA physical status III, n (%)	36 (40.9)	38 (43.7)	0.71
Hypertension, n (%)	32 (36.4)	35 (40.2)	0.60
Diabetes mellitus, n (%)	18 (20.5)	20 (23.0)	0.69
Baseline MAP, mmHg	91.6 ± 8.9	90.8 ± 9.2	0.56
Baseline heart rate, bpm	78.4 ± 10.6	79.1 ± 11.2	0.67
Duration of surgery, min	181.5 ± 42.7	184.2 ± 45.1	0.68
Intraoperative crystalloid, mL	1540 ± 410	1585 ± 435	0.48

Note: Values are presented as mean ± SD or n (%). ASA, American Society of Anesthesiologists; BMI, body mass index; MAP, mean arterial pressure.

A total of 192 patients were assessed for eligibility. Twelve were excluded for not meeting the inclusion criteria or declining participation. The remaining 180 were randomized to ketamine or placebo. Two patients in the ketamine group and three patients in the placebo group were excluded from the analysis for protocol deviations or incomplete intraoperative hemodynamic records. A total of 175 patients were included in the analysis: 88 in the ketamine group and 87 in the placebo group. Baseline demographic, clinical, and perioperative characteristics were comparable after randomization (Table 1). The incidence of intraoperative hypotension was significantly lower in the ketamine group than that in the placebo group. Hypotension occurred in 24 (27.3%) and 46 (52.9 %) patients in the ketamine and placebo groups, respectively (p<0.001). This corresponded to an absolute risk reduction of 25.6% and relative risk reduction of 48.4%.

Table 2. Primary hemodynamic outcome

Outcome	Ketamine (n=88)	Placebo (n=87)	Effect estimate	p-value
Intraoperative hypotension, n (%)	24 (27.3)	46 (52.9)	RR 0.52	<0.001
Absolute risk reduction	—	—	25.6%	—
Relative risk reduction	—	—	48.4%	—
Number needed to treat	—	—	4	—

Note: RR: relative risk.

Patients receiving ketamine demonstrated more stable intraoperative hemodynamic profiles. The mean intraoperative MAP was significantly higher in the ketamine group than in the placebo group (76.8 ± 7.9 vs. 70.4 ± 8.8 mmHg; p<0.001). The ketamine group also had fewer hypotensive episodes per patient and shorter cumulative hypotension duration. The proportion of patients requiring vasopressor support was significantly lower in the ketamine group. The total phenylephrine-equivalent dose was also reduced, supporting a clinically relevant vasopressor-sparing effect.

Table 3. Secondary hemodynamic outcomes

Outcome	Ketamine (n=88)	Placebo (n=87)	p-value
Mean intraoperative MAP, mmHg	76.8 ± 7.9	70.4 ± 8.8	<0.001
Lowest intraoperative MAP, mmHg	63.9 ± 6.8	58.7 ± 7.4	<0.001
MAP variability, SD mmHg	6.2 ± 2.1	9.1 ± 3.0	<0.001
Hypotensive episodes per patient	0.6 ± 0.9	1.5 ± 1.3	<0.001
Cumulative hypotension duration, min	5.8 ± 8.7	14.6 ± 12.4	<0.001
Mean intraoperative heart rate, bpm	82.1 ± 10.3	79.4 ± 9.8	0.08
Tachycardia, n (%)	9 (10.2)	5 (5.7)	0.27
Vasopressor requirement, n (%)	28 (31.8)	51 (58.6)	<0.001
Phenylephrine-equivalent dose, µg	118 ± 96	246 ± 154	<0.001

Note: Values are presented as mean ± SD or n (%). MAP, mean arterial pressure; SD, standard deviation.

Low-dose ketamine is associated with improved postoperative analgesic outcomes. Pain scores at 2, 6, and 12 hours were significantly lower in the ketamine group. Total opioid consumption during the first 24 postoperative hours was also significantly reduced in the intervention group.

Table 4. Postoperative pain and opioid consumption

Outcome	Ketamine (n=88)	Placebo (n=87)	p-value
NRS pain score at 2 h	3.1 ± 1.2	4.2 ± 1.5	<0.001
NRS pain score at 6 h	3.4 ± 1.3	4.6 ± 1.4	<0.001
NRS pain score at 12 h	3.0 ± 1.1	3.8 ± 1.3	<0.001
NRS pain score at 24 h	2.4 ± 1.0	2.8 ± 1.1	0.01
24-hour morphine-equivalent opioid use, mg	18.9 ± 6.4	29.7 ± 8.5	<0.001
Time to first rescue analgesia, min	94 ± 38	57 ± 31	<0.001

Note: NRS, numeric rating scale.

The incidence of adverse events was low and comparable between the groups. Ketamine did not significantly increase postoperative nausea and vomiting, hallucinations, emergence agitation, or delirium. No severe cardiovascular adverse events, uncontrolled hypertension, or clinically significant arrhythmias were observed. Overall, perioperative low-dose ketamine significantly reduced intraoperative hypotension, improved MAP stability, decreased vasopressor requirements, and reduced postoperative opioid consumption without increasing the incidence of clinically relevant adverse events. These findings support the hemodynamic and analgesic value of low-dose ketamine as an adjunct in major noncardiac surgery.

Table 5. Safety outcomes and adverse events

Adverse event	Ketamine (n=88)	Placebo (n=87)	p-value
Postoperative nausea and vomiting, n (%)	12 (13.6)	16 (18.4)	0.39
Hallucination, n (%)	2 (2.3)	0 (0.0)	0.16
Emergence agitation, n (%)	3 (3.4)	2 (2.3)	0.65
Delirium within 24 h, n (%)	2 (2.3)	3 (3.4)	0.65
Hypertension requiring treatment, n (%)	4 (4.5)	2 (2.3)	0.41
Clinically significant arrhythmia, n (%)	0 (0.0)	1 (1.1)	0.31
Respiratory depression, n (%)	1 (1.1)	3 (3.4)	0.31

Note: Values are presented as n (%).

DISCUSSION

This study demonstrated that perioperative administration of low-dose ketamine significantly reduced the incidence of intraoperative hypotension while improving overall hemodynamic stability in patients undergoing major non-cardiac surgery. These findings provide clinically meaningful evidence supporting the hemodynamic benefits of ketamine beyond its established analgesic role.

In our cohort, the incidence of hypotension was reduced by nearly 50% in the ketamine group compared that to in the placebo group, accompanied by a higher mean arterial pressure (MAP), reduced blood pressure variability, and decreased vasopressor requirements. These results are consistent with those of prior randomized studies conducted in obstetric populations, where ketamine significantly attenuated post-spinal hypotension and improved cardiovascular stability [9,10]. Similarly, infusion-based regimens have been shown to maintain a higher intraoperative MAP and reduce the need for vasopressors [11]. The observed hemodynamic stability can be explained by ketamine's sympathomimetic properties, mediated through the inhibition of NMDA receptors and subsequent activation of the central sympathetic nervous system. This leads to increased catecholamine release, resulting in elevated systemic vascular resistance, heart rate, and cardiac output [12]. In the context of general anesthesia, where vasodilation and myocardial depression are common, these effects may counterbalance anesthetic-induced hypotension and preserve organ perfusion.

Interestingly, our findings extend previous evidence by demonstrating that ketamine not only reduces blood pressure variability, as suggested in earlier meta-analyses [13]. but also significantly decreases the incidence and duration of clinically relevant hypotensive episodes. This distinction is critical, as even short periods of MAP below 65 mmHg have been associated with an increased risk of acute kidney and myocardial injuries [14]. Therefore, the reduction in hypotension observed in this study may have important implications for postoperative outcomes. In addition to its hemodynamic effects, ketamine provided a significant opioid-sparing benefit, with reduced postoperative opioid consumption and improved pain scores. This finding aligns with previous literature demonstrating that low-dose ketamine reduces opioid requirements by approximately 30–40% in the perioperative period [15]. The dual benefit of improved hemodynamic stability and enhanced analgesia supports the integration of ketamine into multimodal anesthesia protocols, particularly within enhanced recovery after surgery (ERAS) pathways.

Importantly, the use of low-dose ketamine in this study was not associated with an increased incidence of adverse events, including neuropsychiatric complications, postoperative nausea and vomiting, or clinically significant cardiovascular instability. These findings are consistent with systematic reviews indicating that subanesthetic ketamine doses are generally well-tolerated and do not produce sustained hemodynamic disturbances [16]. The absence of significant tachycardia or hypertension further supports the safety of the dosing regimen used in this study. Nevertheless, several limitations should be considered. First, this was a single-center study, which may limit the generalizability of the findings. Second, although randomization ensured balanced baseline characteristics, the heterogeneity of surgical procedures may have influenced intraoperative hemodynamic responses. Third, the study focused primarily on intraoperative outcomes, and long-term clinical endpoints, such as postoperative organ dysfunction or mortality, were not assessed. Finally, although the ketamine dosing regimen was based on prior evidence, different dosing strategies may yield varying hemodynamic effects.

Future research should aim to validate these findings in multicenter trials with larger and more diverse patient populations. Additionally, studies evaluating the impact of ketamine on long-term outcomes, including postoperative complications and recovery trajectories, will further clarify its role in perioperative medicine. Taken together, our findings suggest that perioperative low-dose ketamine is a promising strategy for enhancing intraoperative hemodynamic stability while simultaneously reducing opioid requirements. In an era increasingly focused on precision anesthesia and outcome optimization, ketamine may serve as a valuable adjunct to mitigate hypotension-related complications and improve the perioperative care.

CONCLUSION

Perioperative low-dose ketamine reduces intraoperative hypotension, improves hemodynamic stability, and lowers vasopressor requirements in patients undergoing non-cardiac surgery, while providing an opioid-sparing effect without increasing relevant adverse events. These findings highlight the hemodynamic and analgesic benefits of ketamine as an adjunct to anesthesia and suggest that it may improve perfusion and outcomes. Although multicenter studies are needed to confirm these findings and evaluate the long-term impact, the study supports its use in patients at risk of hemodynamic instability.

DECLARATIONS

None

CONSENT FOR PUBLICATION

The Authors agree to be published in the Journal of Society Medicine.

FUNDING

None

COMPETING INTERESTS

The authors declare no conflicts of interest in this case report.

AUTHORS’ CONTRIBUTIONS

A.P. contributed to the conception and design of the study, data acquisition, statistical analysis, and manuscript drafting. E.I. contributed to data interpretation, methodological supervision, and critical revision of the manuscript for the important intellectual content. M.G. provided clinical expertise, contributed to data validation, and critically revised the manuscript for important intellectual contents. All authors have read and approved the final manuscript and have agreed to be accountable for all aspects of the work.

ACKNOWLEDGMENTS

The authors would like to express their sincere appreciation to the Department of Infectious Diseases, General Hospital, Cairo, Egypt for their institutional support and contribution to the successful completion of this study.