Effect of ketofol versus propofol on cerebral oxygenation in patients undergoing transsphenoidal pituitary surgery under total intravenous anesthesia – A randomized control trial

INTRODUCTION

The preservation of adequate oxygen delivery to vital organs, particularly the brain, remains a fundamental objective during the administration of anesthesia. The brain is highly sensitive to even brief episodes of hypoxia, and prolonged reductions in cerebral oxygen delivery are well documented to cause irreversible neurological damage and contribute significantly to perioperative morbidity and mortality.^[1] Near infrared spectroscopy (NIRS) is a non-invasive method that measures regional oxygen saturation (SpO₂) and provides real-time information regarding cerebral and other tissue oxygenation. NIRS can give an early warning of decreased oxygen delivery before clinical signs of ischemia appear. In neurosurgical and critical care settings, where cerebral ischemia represents a major determinant of outcome, such monitoring assumes particular importance.^[2-5] Maintenance of adequate tissue oxygenation, and especially cerebral oxygenation, forms the cornerstone of safe perioperative management.

Propofol is one of the most widely used anesthetic agents in neurosurgical practice. Its favorable pharmacological profile includes a predictable onset and offset of action, excellent suppression of airway reflexes, and reduction of intracranial pressure (ICP). The latter occurs because propofol induces a dose-dependent reduction in cerebral blood flow and cerebral blood volume, which in turn lowers ICP. Importantly, propofol also decreases the cerebral metabolic rate of oxygen, thereby reducing oxygen demand. These properties make it an attractive choice in patients with raised ICP. However, propofol is not devoid of limitations. It produces systemic hypotension in a dose-dependent manner, particularly in hypovolemic patients, which may compromise cerebral perfusion pressure (CPP) and oxygen delivery to the brain. Reports have documented temporary decreases in cerebral SpO₂ following induction with propofol at conventional doses (1.5–2 mg/kg), largely attributable to the associated fall in mean arterial pressure (MAP).^[2]

On the other hand, ketamine, due to sympathomimetic effects, maintains hemodynamic parameters but has the potential to cause a rise in ICP. However, recent literature has shown that ketamine is safe to be used in neurosurgery and does not cause a rise in ICP when used with controlled ventilation, and may even cause a decrease in ICP.^[6-8] Ketamine has several other advantages, like potent analgesia,^[9-12] thereby decreasing opioid requirements,^[13,14] preservation of respiratory drive and protective airway reflexes during anesthesia,^[12] along with newly found neuroprotective,^[6,15] anti-inflammatory,^[16] and antitumor effects.^[17,18] Moreover, it maintains MAP and thus CPP and cerebral oxygenation.^[6,19,20]

The combination of propofol and ketamine, often termed ketofol, has been proposed as a means of harnessing the beneficial properties of both agents while minimizing their individual drawbacks. Ketofol is thus thought to provide improved hemodynamic stability, thereby maintaining better cerebral perfusion and oxygenation.^[7,19] Although several studies have evaluated the role of intravenous anesthetic agents on hemodynamics, not many have explored their impact on cerebral oxygenation in neurosurgery. We studied the effects of propofol and ketofol on cerebral oxygenation in patients of pituitary surgery through a transsphenoidal approach that obviates the need for open craniotomy, thus avoiding major handling of intracranial vessels and brain tissue (like retractor applications), thereby minimizing the effects of surgical factors on cerebral oxygenation.^[21]

We hypothesized that induction and maintenance of anesthesia with ketofol would result in superior cerebral oxygenation compared with propofol alone. The primary outcome of this study was to evaluate the effect of these drugs on regional cerebral oxygenation (rSO₂). Secondary outcomes included intraoperative hemodynamic stability, anesthetic and opioid consumption, emergence profile, and post-operative analgesia.

MATERIALS AND METHODS

This was a prospective, randomized, and double-blind clinical trial conducted at a tertiary care center after approval by the Institute Ethics Committee (Ref. No. IECPG-392/26.08.2020, RT-18/November 25, 2020; dated: December 01, 2020). The trial was registered prospectively with the Clinical Trial Registry of India (CTRI) (/2022/01/039533, Ref/2020/10/037762; dated: October 23, 2020). All participants provided written informed consent before enrollment.

The required sample size was estimated using data from Bhaire et al.^[19] Assuming a standardized effect size of 0.8 per standard deviation, with a confidence level of 95% and statistical power of 80%, a minimum of 25 patients per group was required. As intraoperative follow-up was expected to be complete, a total of 50 patients were enrolled between December 2020 and July 2022. Adult patients aged 18–65 years of either gender, classified as American Society of Anesthesiologists (ASA) physical status I or II, and scheduled for elective endoscopic transsphenoidal pituitary surgery were enrolled for the study. Patients with a history of previous pituitary surgery, pituitary apoplexy, uncontrolled hypertension, heart, lung, renal or liver disorders, morbidly obese patients (body mass index >40), pregnant patients, allergy to study drugs, psychiatric disorder, drug abuse, or who refused to participate were excluded.

All patients were evaluated a day before surgery. They were instructed to breathe through the mouth after surgery due to nasal packing and were familiarized with the visual analogue scale (VAS) for pain assessment. Pre-operative fasting guidelines were followed, and no sedative premedication was administered.

Patients were randomized to receive either propofol (Group P) or ketofol (Group K) using a computer-generated randomization sequence. Allocation concealment was ensured by sequentially numbered, opaque sealed envelopes. Study drugs were prepared in identical syringes by an anesthesiologist not involved in subsequent patient management or data collection, thus ensuring blinding of both patients and outcome assessors. For Group P, 20 mL propofol (10 mg/mL) for induction and 60 mL propofol (10 mg/mL) for maintenance was prepared in 20 mL and 60 mL syringes, respectively, while for Group K, 10 mL propofol (10 mg/mL) + 2 mL ketamine (50 mg/mL) diluted to 20 mL for induction and 50 mL propofol (10 mg/mL) + 10 mL ketamine (10 mg/mL) for maintenance was prepared in 20 mL and 60 mL syringes respectively.

In the operating room, standard ASA monitoring was initiated, and an intravenous line was secured. The radial artery was cannulated under local anesthesia for invasive blood pressure monitoring. Additional monitoring included cerebral oximetry using the Radical-7^® Pulse COOximeter^® (Masimo, Irvine, USA) and depth of anesthesia using the patient state index (PSI). Baseline hemodynamic parameters, SpO₂, regional cerebral oxygenation bilaterally [rSO₂ (R, L)], and PSI were recorded. After preoxygenation with 100% oxygen for 3 min, anesthesia was induced with fentanyl 2 mg/kg and the induction agent (propofol or ketofol) 0.2 mL/kg intravenous (i.v.) as per group allocation.

Additional small boluses (1–2 mL) were given as required to achieve loss of verbal response. Rocuronium 1 mg/kg facilitated tracheal intubation. Patients were ventilated with an air-oxygen (60:40) mixture at 2 L/min flow to maintain end-tidal CO₂ between 35–40 mmHg. Pin insertion sites for head fixation were infiltrated with 2% lignocaine.

Maintenance was achieved with continuous infusion of either propofol (Group P) or ketofol (Group K), titrated to achieve adequate depth of anesthesia (PSI between 25 and 50).^[22] Analgesia was provided with fentanyl infusion (1 mg/kg/h), and muscle relaxation was maintained with rocuronium (5 mg/kg/min). Tachycardia or hypertensive responses (>20% increase from baseline) were managed sequentially with fentanyl boluses (1 mg/kg), propofol bolus (0.5 mg/kg), and labetalol 10 mg increments (maximum 60 mg). Hypotension (>20% decrease from baseline) was treated with fluid boluses and ephedrine 5 mg i.v., repeated if necessary. Bradycardia [heart rate (HR) <50/min] was treated with atropine (0.6 mg i.v.) bolus.

Rocuronium and fentanyl infusions were tapered 30 min before anticipated surgical closure and discontinued at completion. The study drug infusion was stopped after pin removal. Residual neuromuscular blockade was reversed, and tracheal extubation was performed once adequate recovery was ensured.

Continuous monitoring included electrocardiogram, HR, MAP, SpO₂, rSO₂, PSI, EtCO₂, and temperature. Data points were recorded at baseline (pre-induction), after induction, post-intubation, and every 30 min until completion of surgery. Additional values were recorded during key surgical stages: Pin insertion, nasal packing, sphenoid bone dissection, extubation, and 15 min post-extubation. Arterial blood gases were measured at baseline (pre-induction), 2 h, 4 h, and pre-extubation. Emergence times (eye-opening and verbal response after stopping the anesthetic drug infusion) and extubation time were noted. Intraoperative drug requirement (fentanyl, ketamine, and propofol), fluid administered, blood loss, urine output, and complications were documented. Postoperatively, patients were monitored in the neurosurgical intensive care unit, and pain was assessed using the VAS scale. Time to first rescue analgesia (VAS ≥6) was recorded. All observations were recorded by an anesthesiologist blinded to the group allocation.

RESULTS

A total of 72 patients were screened, out of which 22 were excluded for not meeting eligibility criteria. The remaining 50 patients were randomized into Group P (propofol) and Group K (ketofol), with 25 patients each. No patients were lost to follow-up (CONSORT diagram, [Figure 1]).

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Figure 1:

Consolidated standards of reporting trials (CONSORT) diagram.

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Baseline demographic and clinical characteristics were comparable between the two groups [Table 1]. All rSO₂(R, L) values remained within the physiological range of 60–80% throughout. Baseline (pre-induction) rSO₂ values were comparable bilaterally between the groups. However, following induction and initiation of study drug, rSO₂ values were consistently higher in the ketofol group compared with propofol, with statistically significant differences (P^[b] < 0.05) [Table 2]. Over time, rSO₂(R, L) values in the ketofol group were maintained above baseline, whereas those in the propofol group trended below baseline. These patterns were evident throughout the course of surgery (recorded at regular intervals as well as at specific stages of surgery/anesthesia). Except for left rSO₂ at 60 min (T2), all differences were statistically significant (P^[a] < 0.05) [Table 2].

Hemodynamic stability was superior in the ketofol group. Patients receiving propofol exhibited more pronounced fluctuations in HR and MAP intraoperatively [Figure 2]. Furthermore, patients in the propofol group experienced greater surges in HR and/or MAP during anesthetic or surgical stimuli, compared with ketofol (P < 0.05; [Figure 2]). Hypotension occurred in 60% of propofol patients versus 12% in ketofol patients (P < 0.001).

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Figure 2:

Comparison of mean heart rate and mean arterial pressure over time (a, c) and at specific stages of surgery/anesthesia (b, d) between the two groups.

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Total intraoperative propofol and fentanyl consumption were significantly lower in the ketofol group (P = 0.045 and <0.001, respectively; [Table 3]). Emergence was significantly faster with ketofol. Time to eye opening, verbal response, and extubation were all shorter in Group K (P < 0.001), resulting in decreased total duration of anesthesia (P = 0.031). Other intraoperative parameters, including duration of surgery, were similar between the groups [Table 3]. Patients in the ketofol group demonstrated prolonged postoperative analgesia. The time to first rescue analgesic (VAS ≥6) was significantly longer than in the propofol group (P < 0.001), [Table 3].

DISCUSSION

Preservation of cerebral perfusion and oxygenation is an important goal during neurosurgical anesthesia. Ketofol has recently captured interest as an anesthetic agent in neurosurgical patients for its useful properties, such as potent analgesia, stable hemodynamics, and some evidence on neuroprotection. However, not much has been explored about its effect on cerebral oxygenation. The present study evaluated the impact of ketofol on cerebral oxygenation among patients undergoing transsphenoidal pituitary surgery. Our study demonstrated that ketofol provided superior cerebral oxygenation compared to propofol, as evidenced by higher rSO₂ values throughout the intraoperative period. This probably resulted from more stable hemodynamics and fewer episodes of hypotension with ketofol compared to propofol. This finding is clinically significant, as even subtle reductions in cerebral oxygenation can have adverse neurological consequences.

Our results are consistent with prior studies. Duran et al.^[7] in elderly patients undergoing laparotomy, observed higher cerebral oxygenation during induction with ketofol compared to propofol. Similarly, Bhaire et al.^[19] in patients undergoing clipping for aneurysmal subarachnoid hemorrhage, reported higher jugular venous SpO₂ (SjVO₂) with ketofol compared to propofol, both intraoperatively and postoperatively. Together, these findings reinforce that ketofol is advantageous not only for hemodynamic reasons but also for maintaining cerebral oxygenation.

The superior hemodynamic stability with ketofol observed in our study aligns with extensive literature. Singh^[23] and Maheswari et al.^[24] in patients with traumatic brain injury reported that ketofol attenuated intraoperative hypotension and reduced vasopressor needs compared with propofol. Hailu et al.^[25] observed significant blood pressure drops with propofol induction but stable hemodynamics with ketofol. Similarly, lower blood pressures with higher requirements of fluids and vasopressors were noted in the propofol group compared to ketofol in patients undergoing thoracolumbar spine surgery by Khandelwal et al.^[26] Kayalha et al.^[27] and Kumar et al.^[28] noted blunted HR and MAP responses to intubation with ketofol. These consistent findings highlight the favorable hemodynamic profile of ketofol, likely due to the sympathomimetic effects of ketamine counteracting the vasodilatory properties of propofol.

Another important observation of our study was the reduced intraoperative opioid and anesthetic requirement in the ketofol group. The intrinsic analgesic properties of ketamine account for the opioid-sparing effect, as corroborated by prior studies.^[28] This effect translated to more stable hemodynamics, reduced propofol requirement, and consequently shorter anesthesia duration. Furthermore, post-operative analgesia was prolonged with ketofol, delaying the need for rescue analgesics. This property is particularly relevant in neurosurgical patients, where minimizing opioid use helps avoid respiratory depression and sedation that can mask neurological assessment.

Rapid and smooth emergence from anesthesia is vital in neurosurgery to enable early neurological evaluation. In our study, patients receiving ketofol exhibited faster eye-opening, verbal response, and extubation compared to propofol. Similar results have been reported in studies involving different surgical populations.^[29,30] These favorable recovery profiles can be attributed to reduced total anesthetic and analgesic consumption with ketofol, resulting in earlier return of consciousness.

Our study had a few limitations. It was a single-center trial with a relatively small sample size and included only ASA I-II patients undergoing transsphenoidal pituitary surgery. Thus, results may not generalize to patients with higher perioperative risk or those undergoing craniotomy for other pathologies. Furthermore, this study only included adult patients; hence, the results may not extrapolate to pediatric patients. Moreover, different surgeons with varied experience operated on these patients, which might have affected the results of this study. We also did not assess postoperative cognitive outcomes or long-term neurological recovery, which would have provided a more comprehensive understanding of cerebral oxygenation effects. Finally, our study used a fixed ketofol ratio, and future studies may explore different propofol–ketamine combinations that provide the most optimal cerebral oxygenation effects.

CONCLUSION

Ketofol provides better cerebral oxygenation, superior hemodynamic stability, and faster recovery compared to propofol in patients undergoing transsphenoidal pituitary surgery. Ketofol also reduced intraoperative opioid and anesthetic requirements and prolonged postoperative analgesia. Within the limitations of our study, ketofol appears to be a promising anesthetic agent for transsphenoidal pituitary surgery.