Endotracheal intubation (ETI) remains the basic intervention in intensive care, but it carries considerable haemodynamic risks, especially in critically ill patients with reduced physiological reserves and increased sympathetic activation, often accompanied by catecholamine depletion. (1) Sedation before ETI may upset this delicate balance and often exacerbate the hemodynamic instability. Hypotension after intubation is a well-documented complication, reported in up to 46 percent of ICU cases (2), and is particularly common in patients with liver disease due to their inherent vasodilatation (3).

The optimal sedative for ETI in this vulnerable population is still under discussion, as agents such as propofol, etomidate and ketamine have different haemodynamic profiles (4-7). Etomidate offers relative cardiovascular stability through stimulation of the alpha-2b adrenoreceptors (8, 9), but raises concerns about adrenal suppression and a potential increase in mortality. (10, 11)  Ketamine, an NMDA-antagonist, maintains the hemodynamic status by releasing endogenous catecholamine (7), whereas propofol frequently causes hypotension. (12) Ketofol, a mixture of ketamine and propofol, is thought to counterbalance these effects and may offer hemodynamic stability without adrenal suppression effects. (6,9,13)  However, reliable comparative data are limited, particularly for etomidate vs ketofol in the specific context of critically ill cirrhotic patients. (14, 15)  Therefore, the aim of this study was to consistently compare the haemodynamic effects of etomidate and ketofol after intubation in this high-risk group of patients.

Objectives

1. To determine whether etomidate or ketofol is associated with a reduced incidence of early post-intubation hypotension (within the first 6 hours, with particular emphasis on critical first 15 minutes) in patients in liver ICU.
2. A comprehensive evaluation of the impact of etomidate versus ketofol on key clinical outcomes and organ function in this vulnerable population, specifically by assessing 7-day mortality, renal impairment (as measured by SOFA score at 24 hours), and the need for continued support (no vasopressor status at 24 hours).

This prospective, randomised, controlled, open-label study was conducted at the Institute of Liver and Biliary Sciences, New Delhi (July 2023-September 2024). Adults (>18 years) with chronic liver disease admitted to Liver intensive care unit requiring emergency endotracheal intubation (ETI) were included in the study. Exceptions included refusal of consent, known allergy to the medicines being used in the study, pregnancy, peri-arrest patients, anticipated anatomically difficult airway, acute liver failure or acute chronic liver failure patients.

Sample Size and Randomization

Based on the expected hypotensive events (60 percent etomidate versus 30 percent ketofol) (6), a sample size of 100 patients (50 per group) was calculated, assuming power of 80% and alpha error 5%. Patients were randomised 1:1 to ketofol (group A) or etomidate (group B). Allocation of appropriations used sealed opaque envelopes opened pre-insertion by the unrelated caregivers.

Ethical Consideration: Following Institutional Ethics Committee approval, letter no IEC/2023/100/MA06 and in accordance with the Helsinki Declaration, a written informed consent was obtained from the duly authorised representatives of the patients.

Intervention and Monitoring

Standard ICU monitoring (ECG, SpO2, invasive arterial B.P.) was done. After 3 minutes of pre-oxygenation (100% O2), patients received either ketofol (1:1 combination of ketamine and propofol, total dose 1-2 mg per kg; group A) or etomidate (0.1-0.2 mg per kg; group B) followed immediately by rocuronium (1.2 mg/kg). After 60 seconds of gentle positive pressure ventilation, direct laryngoscopy and intubation were performed. Correct placement of the endotracheal tube was confirmed, and mechanical ventilation initiated.

Baseline HR, MAP, SpO2, and vasopressor use were recorded. After ETI, they were measured immediately, at intervals of 1 minute for 5 minutes, every 5 minutes till 30 minutes, then hourly till 6 hours, and at 24 hours. Hypotension was defined as MAP < 65 mmHg, >20 percent decrease in MAP from baseline or increase in vasopressor dose. (8) Severe hypotension was MAP < 45 mmHg, doubled norepinephrine requirements or norepinephrine > 0.3 µg/kg/min. Treatment of hypotension consisted of 10 ml per kg of balanced crystalloid bolus followed by titration of norepinephrine, starting at 0.05 µg/kg/min, if necessary. If norepinephrine above 0.25 µg/kg/min then vasopressin starting at 0.2 U per hour and hydrocortisone (50 mg iv qid) were administered. Focused pulse-pressure variation of <10% was targeted. Standard protocols for the administration of fluids or blood products, including thromboelastogram (TEG) based correction of coagulopathy were implemented.

Outcome Measures

The primary outcome was the incidence of hypotension within 6 hours of intubation. Secondary outcomes included: hypotension within 15 minutes; incidence of severe hypotension; 7-day mortality; 24-hour SOFA score (total and cardiovascular), success rate of extubation; vasopressor-free status at 24 hours; 24-hour serum lactate; new onset AKI at 24 hours; and intubation difficulty score. (16)

Statistical Analysis

The continuous data were expressed as mean ±SD or median (IQR) and compared using independent t-tests or Mann-Whitney U-tests. Categorical data were presented as frequency (%) and compared using Chi-square or Fisher’s exact tests. P < 0.05 is considered statistically significant.

A total of 170 patients were evaluated for eligibility, 100 of whom met the inclusion criteria and were subsequently randomised [50 to group A (ketofol) and 50 to group B (etomidate)], as shown in Figure 1. All randomised patients received the assigned intervention and were included in the final analysis.

Table 1 depicts that both groups were well matched at baseline in terms of demographics, including age, gender and the etiology of CLD. The severity of disease scores, i.e. CTP, MELDNa and SOFA were comparable between groups A and B. The incidence of hepatic decompensation (ascites, hepatic encephalopathy, variceal haemorrhage, AKI) and baseline laboratory parameters (including haemogram, renal function, hepatic function, coagulation and arterial blood gas) were not significantly different between the groups. The proportion of patients requiring vasopressor support or NIV before treatment was also similar between the groups.

Table 1: Baseline Demographics and Clinical Characteristics

Abbreviations: SD, standard deviation; CTP, Child-Turcotte-Pugh; MELDNa, Model for End-Stage Liver Disease Sodium; SOFA, Sequential Organ Failure Assessment; ETI, endotracheal intubation; NIV, non-invasive ventilation.

Table 2 shows that the primary outcome, post-operative hypotension within 6 hours, was significantly lower in Ketofol (group A) compared to Etomidate (group B) (26% vs. 62%, p<0.01). Similarly, hypotension occurring within the first 15 minutes post-ETI was significantly less common in group A (18% vs. 48%, p<0.001). The incidence of new onset AKI was significantly lower in group A (4% vs. 20%, p=0.04). The median 24-hour CV SOFA score was also significantly lower in group A [1 (IQR 0, 4)] than in group B [2 (IQR 1, 4)], p=0.02. Although the incidence of severe hypotension within 15 minutes was lower in group A (6% vs. 18%), this difference was not statistically significant (p=0.07). There were no statistically significant differences between the groups in 7-day mortality, extubation rate, 24-hour lactate level or proportion of patients free of vasopressor at 24 hours, although trends were favouring Group A in mortality and extubation rate.

Table 2: Primary and Secondary Outcomes

Abbreviations: ETI, endotracheal intubation; IQR, interquartile range; AKI, acute kidney injury; CV SOFA, cardiovascular Sequential Organ Failure Assessment score.

Table 3: Mean Arterial Pressure (mmHg) Post-Intubation

Table 3, figure 2. Shows that the baseline MAP was comparable between the two groups (83.26 ±11.91 mmHg; 82.76 ±15.28 mmHg, p=0.776). After ETI, MAP decreased significantly from baseline in the Etomidate group (from 1 to 30 min), while there was no significant change in the Ketofol group from baseline. Therefore, MAP was significantly lower in group B compared to group A at most time points from 1 minute to 6 hours after ETI.

Mean heart rate was comparable between the groups at baseline and remained so throughout the 24-hour observation period.

Table 4. Norepinephrine dose requirement at various time points in the two groups (µg/kg/min)

Table 5. Vasopressin Dose Requirement at various time points in the two groupS (U/hr)

In line with MAP findings, the vasopressor requirements differed significantly post-ETI between the two groups. Although the initial dose of norepinephrine was similar, the required dose increased significantly in group B starting at 10 minutes after ETI and remained increased over 24 hours (Table 4, figure 3a.). Similarly, the mean required vasopressin dose in group B was significantly higher from 1 hour after ETI (Table 5, figure 3b).

Table 6. Sub group analysis of patients based on Hypotension within 15 min post-ETI.

Table 6. depicts a subgroup analysis comparing patients who developed hypotension within 15 minutes of the onset of the ETI (n=33) with those who had not (n=67) revealed significant differences. Patients with early hypotension had significantly higher baseline MELDNa, CTP, SOFAscore, lactate levels, and a higher rate of pre-existing NIV failure (p<0.01 for MELDNa, CTP, and NIV failure; p<0.02 for SOFA score). These patients had worse outcomes, including higher lactate levels at 24 hours (p<0.01), higher SOFA scores at 24 hours (p<0.01), and a higher incidence of new onset AKI at 24 hours (p<0.04) and severe hypotension at 6 hours post-ETI (p<0.02).

Median intubation difficulty score (IDS) was low and comparable between the two groups [A:1(IQR 0.5, 2); B:1(IQR 0.75, 2); p=0.76], suggesting that intubation was generally not difficult in both the groups .

The present study unveiled a significantly lower incidence of post-ETI hypotension, both within the initial 15 minutes and extending to 6 hours, in patients administered with ketofol (Group A) as compared to etomidate (Group B). This aligns with the primary objective suggesting that ketofol features a superior hemodynamic profile within this target patient demographic. A significant drop in MAP from the baseline was noticed shortly post-intubation in the etomidate group, a trend not observed in the ketofol group. Patients who received etomidate required increased doses of norepinephrine and vasopressin for maintaining target MAP which led to elevated cardiovascular SOFA scores during the initial 24-hours. These findings are particularly relevant since patients with liver disease have a baseline vasodilatation, which makes them prone to profound hypotension when sympathetic control is depressed by induction agents. Ketofol, which combines the sympathomimetic properties of ketamine an propofol, appears to be more effective than etomidate in reducing this risk in cirrhotic patients.

Our results are in contrast to some previous research. For example, Smischney et al. in a heterogeneous population of ICU patients, found no significant differences in MAP changes between ketofol and etomidate. (6) However, their study did not specifically address patients with liver disease, which is a different physiological challenge. Our findings are more consistent with studies highlighting the potential for haemodynamic instability and increased vasopressor requirements with etomidate, e.g. Geiger et al. (comparing etomidate and fentanyl with ketamine and midazolam) and Berkel et al. (when comparing etomidate with ketamine alone). (4,7) Although these studies used different combinations or formulations of drugs, they also

indicated improved haemodynamic stability with ketamine-based regimens.

The potential for adrenal suppression by etomidate, even after single administration, is a well-documented concern and may have contributed to the persistence of hypotension in our Group B. (10, 11, 17, 18) Although adrenal function was not directly evaluated in our study, the higher incidence of hypotension and vasopressor requirements in the etomidate group raise the possibility of this mechanism of action for the hypotensive episodes. Similarly, a study by Jabre et al. also reported a higher incidence of adrenal insufficiency with etomidate, although they did not find any difference in overall SOFA scores or mortality, which is consistent with our mortality findings. (5) Srivilaithon et al. and Matchett et al. also reported an increased need for vasopressor with etomidate compared to ketamine. (19,20) Matchett et al. observed an advantage in 7-day survival with ketamine, but neither of these studies found a difference in 28-day survival, suggesting that while the choice of induction agent influences immediate hemodynamics, the overall severity of the disease is likely to dictate long-term mortality. (20)

Subgroup analyses revealed that patients who experienced early hypotension (within 15 minutes) had higher baseline disease severity scores and lactate levels, highlighting the vulnerability of sicker patients. These patients had poorer outcomes, including higher levels of lactate, SOFA score and AKI at 24 hours. This reinforces the importance of selecting an induction agent that minimizes haemodynamic compromise, especially in patients with liver disease.

The present study unveiled that ketofol provides significant haemodynamic benefits post-ETI over etomidate in critically ill patients with chronic liver disease. Induction with ketofol resulted in less hypotension, reduced vasopressor requirements and a lower incidence of acute kidney injury. Despite similar short-term mortality, the improved stability indicates that ketofol appears to be a potentially safer and preferred induction agent compared to etomidate for ETI in critically ill cirrhotic patients.

Recommendation

Based on this study, ketofol should be strongly considered for ETI in critically ill CLD patients due to better haemodynamics and reduced risk of AKI compared to etomidate. Its preferential use in this high-risk group is encouraged. Further research into long-term effects and adrenal function is needed.

Limitation of the study

Key limitations include the open-label design of present study. Serum catecholamine levels, tests for adrenal cortical functions and the effects of ketofol and etomidate on systemic vascular resistance, stroke volume, and cardiac output were not conducted.

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