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Table of Contents    
ORIGINAL ARTICLE
Year : 2022  |  Volume : 70  |  Issue : 4  |  Page : 1568-1574

Reliability of Pre-Induction Inferior Vena Cava Assessment with Ultrasound for the Prediction of Post-Induction Hypotension in Neurosurgical Patients Undergoing Intracranial Surgery


1 Department of Neuroanesthesia and Neurocritical Care, Eternal Hospital, Jaipur, Rajasthan, India
2 Department of Neuroanesthesia and Neurocritical Care, National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka, India

Date of Submission26-Dec-2020
Date of Decision13-Jun-2022
Date of Acceptance01-Jul-2022
Date of Web Publication30-Aug-2022

Correspondence Address:
Amit Goyal
Department of Neuroanesthesia and Neurocritical Care, Eternal Hospital, Jaipur - 302 017, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.355107

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 » Abstract 


Background: Hypotension is one of the most common complications following induction of general anesthesia. Preemptive diagnosis and correcting the hypovolemic status can reduce the incidence of post-induction hypotension. However, an association between preoperative volume status and severity of post-induction hypotension has not been established in neurosurgical patients. We hypothesized that preoperative ultrasonographic assessment of intravascular volume status can be used to predict post-induction hypotension in neurosurgical patients. Our study objective was to establish the relationship between pre-induction maximum inferior vena cava (IVC) diameter, collapsibility index (CI), and post-induction reduction in mean arterial blood pressure in neurosurgical patients.
Materials and Methods: A prospective observational study was conducted including 100 patients undergoing elective intracranial surgeries. IVC assessment was done before induction of general anesthesia. Receiver operating characteristic (ROC) curve analysis was used to determine the cutoff values of maximum and minimum IVC diameter (IVCDmax and IVCDmin, respectively) and CI for prediction of hypotension.
Results: Post-induction hypotension was observed in 41% patients. Patients with small IVCDmax and higher CI% developed hypotension. The areas under the ROC curve (AUCs) were 0.64 (0.53–0.75) for IVCDmax and 0.69 (0.59–0.80) for IVCDmin. The optimal cutoff values were1.38 cm for IVCDmax and 0.94 cm for IVCDmin. The AUC for CI was 0.65 (0.54–0.77) and the optimal cutoff value was 37.5%.
Conclusion: Pre-induction IVC assessment with ultrasound is a reliable method to predict post-induction hypotension resulting from hypovolemia in neurosurgical patients.


Keywords: Collapsibility Index, hypotension, hypovolemia, inferior vena cava diameters, neurosurgery, ultrasonography
Key Message: Post-induction hypotension can be harmful during neurosurgical procedures. The neuroanesthesiologist can manage intraoperative hypotension by preemptively diagnosing and correcting hypovolemia. Pre-induction ultrasonographic IVC assessment is a reliable method to predict post-induction hypotension resulting from hypovolemia in neurosurgical patients.


How to cite this article:
Goyal A, Pallavi K, Krishnakumar M, Surve RM, Bhadrinarayan V, Chakrabarti D. Reliability of Pre-Induction Inferior Vena Cava Assessment with Ultrasound for the Prediction of Post-Induction Hypotension in Neurosurgical Patients Undergoing Intracranial Surgery. Neurol India 2022;70:1568-74

How to cite this URL:
Goyal A, Pallavi K, Krishnakumar M, Surve RM, Bhadrinarayan V, Chakrabarti D. Reliability of Pre-Induction Inferior Vena Cava Assessment with Ultrasound for the Prediction of Post-Induction Hypotension in Neurosurgical Patients Undergoing Intracranial Surgery. Neurol India [serial online] 2022 [cited 2022 Oct 2];70:1568-74. Available from: https://www.neurologyindia.com/text.asp?2022/70/4/1568/355107




Hypotension is one of the most common complications during induction of general anesthesia (GA),[1] with a prevalence of 7.7%–12.6%.[2],[3] Its occurrence is affected by several factors, mainly hypovolemia, old age, American Society of Anesthesiologists (ASA) physical status III and higher, anesthetic drugs,[3] impaired compensatory mechanisms, and impaired cardiac function. Intraoperative hypotension can increase the morbidity and mortality in cardiac and non-cardiac surgical procedures.[4],[5],[6] Intraoperative hypotension during non-cardiac surgery has been found to increase the risk of postoperative acute kidney and myocardial injury.[5] Although post-induction hypotension over short periods may not have clinical significance in general surgical patients, it can be potentially harmful during neurosurgical procedures and may have significant impact on outcome. Hypotension is harmful both in patients with intact autoregulation as well as in patients with defective autoregulation and may result in poor neurological status. In patients with intact autoregulation, hypotension leads to reflex vasodilation and hence increases cerebral blood volume with a subsequent rise in intracranial pressure (ICP).[7],[8] In patients whose autoregulation is not intact, the hypotension leads to cerebral ischemia.[9],[10],[11],[12],[13]

Patients with intracranial pathological conditions are more prone for developing hypovolemia due to the following factors:

  • Poor oral intake due to low Glasgow Coma Scale (GCS) or lower cranial nerve palsies,
  • Vomiting due to raised ICP,
  • Effect of antiedema drugs (e.g., mannitol), and
  • Complications due to some intracranial pathologies such as diabetes insipidus (DI).[14],[15]


The neuroanesthesiologist plays a key role in management of intraoperative hypotension by preemptively diagnosing and correcting the hypovolemic status. However, an association between preoperative volume status and the severity of post-induction hypotension has not been established in neurosurgical patients.

Before the advent of modern technology and monitoring, the diagnosis of hypovolemia was mainly dependent on clinical parameters (high pulse rate, low pulse volume, oliguria, cold and clammy skin, decreased capillary refill time, decreased skin turgor, etc.)[16],[17],[18] and laboratory values (hematocrit, serum lactate, plasma osmolarity, urine osmolarity, urine specific gravity, blood urea nitrogen level, etc.).[19],[20],[21] However, these clinical parameters may get affected by factors like pain and reduced temperature,[17],[18] while laboratory values are not always reliable individually.[22] In the last decade, we have relied predominantly on estimation of volume status with parameters like central venous pressure, pulse pressure variation, stroke volume variation, and systemic pressure variation, but these parameters require the use of invasive monitors. More recently, ultrasonographic examination of inferior vena cava (IVC) diameter was introduced to assess the intravascular volume status, as well as to guide fluid therapy.[23],[24],[25],[26],[27],[28] However, the usefulness of this modality has not been explored in neurosurgical patients for the prediction of the post-induction hypotension.

Therefore, we hypothesized that preoperative ultrasonographic assessment of intravascular volume status can be used to predict post-induction hypotension in neurosurgical patients. We aimed to predict the incidence of post-induction hypotension based on pre-induction IVC assessment with ultrasonography (USG) in patients undergoing intracranial surgery. The primary objective of this observational study was to establish the relationship between pre-induction maximum IVC diameter (IVCDmax), collapsibility index (CI), and post-induction reduction in mean arterial blood pressure (MAP) in neurosurgical patients. The secondary objectives were to correlate the IVCDmax and CI with the duration and severity of post-induction reduction in MAP. In addition, the total dose of mephentermine required to correct the hypotension was also studied.


 » Materials and Methods Top


After obtaining approval from the institutional ethical committee, this prospective observational study was conducted at the National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, India. After explaining the procedure to patients, written and informed consents were obtained from them. The study was registered with the Clinical Trials Registry-India (registration number CTRI/2018/04/013515). Adult patients (age group 18–65 years), conforming to ASA status I–III, undergoing elective intracranial surgeries under GA were studied. Exclusion criteria were age group <18 or >65 years, patients in whom IVC could not be visualized, ASA status ≥IV, patients on mechanical ventilation or not having regular spontaneous breathing, difficult airway or multiple intubation attempts (≥2) (prolonged intubating time can induce exaggerated stress response precipitating significant increase in blood pressure [BP]), significant cardiac impairment, baseline MAP <65 mmHg (increased risk of post-induction hypotension), patients for emergency neurosurgical procedures, history of recent upper abdominal surgery, prior use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), and refusal of consent.

IVC ultrasonography

IVC assessment was performed by the primary investigator who had expertise in basic echocardiography, using MyLab Gamma (esaote) machine and a convex array (AC2541) transducer (3.5–5 MHz). IVC assessment was done with the patient breathing spontaneously in a supine position through subcostal approach in a long-axis view. IVC diameters were measured 2 cm (20 mm) distal to the cavoatrial junction, and measurements were made perpendicular to the IVC long axis [Figure 1]. Respiratory variations in the IVC diameter were assessed in M-mode with measurement of maximum IVC diameters (IVCDmax) and minimum IVC diameter (IVCDmin) and calculation of CI as CI = (IVCDmax – IVCDmin)/IVCDmax. To reduce the error, both the diameters were measured twice by the same investigator and an average of the two was selected.
Figure 1: Ultrasonographic view of IVC through subcostal approach. (a) IVC with right atrium in long axis. (b) M-mode with respiratory variation in IVC diameter. IVC = inferior vena cava

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Anesthesia management

All the patients were monitored with electrocardiogram (ECG), pulse oximeter (SpO2), and noninvasive BP (NIBP). Intravenous fluid 0.9% isotonic saline was given at an initial rate of 10 ml/kg/h. Induction of GA was performed in supine position with fentanyl 2 mcg/kg, thiopentone 5 mg/kg, and vecuronium 0.1 mg/kg intravenously, followed by endotracheal intubation under direct laryngoscopy. Anesthesia was maintained with sevoflurane (minimum alveolar concentration 0.7–1.0) in oxygen and air mixture. Hemodynamic parameters (heart rate and MAP) were measured at various time points – before induction, before intubation, and post-intubation for 10 min (1, 3, 5, and 10 min). MAP value measured before induction was defined as the baseline MAP. During this period, change in patient position or any other stimulation was not allowed. Episodes of hypotension (decrease in MAP by more than 30% or MAP <60 mmHg) were treated by administering intravenous bolus of mephentermine (3 mg), and the total dose of mephentermine was noted for each patient.

Data collection

We collected demographic and clinical data of the study subjects, which included age; sex; weight; height; clinical diagnosis; radiological finding; surgery performed; associated illnesses – obesity, coronary artery disease (CAD), arrhythmias, heart failure, hypertension (HTN), diabetes mellitus (DM), hypothyroidism (HT); systemic abnormalities – neurological, cardiovascular, respiratory, airway; treatment history; and ultrasonographic variables (IVCDmax, IVCDmin, CI).

Statistical analysis

With 1% level of significance, confidence interval of 95%, power of 80%, and anticipating correlation of 0.3 between IVC diameter and reduction in MAP, the minimum sample size calculated was 85. Data collected was tabulated, and Statistical Package for the Social Sciences (SPSS) 17 was used for statistical analysis. Quantitative data was described as mean ± standard deviation (SD) or median interquartile range (IQR) and qualitative data as frequency or percentage. The normality of data was assessed using Shapiro–Wilk test. Student's t-test and Chi-square test were used for normally distributed data, and nonparametric tests like Mann–Whitney U test and Fischer's test were used for non-normally distributed data, as appropriate. Repeated measures were analyzed using repeated measures analysis of variance (ANOVA). Correlation between continuous variables was determined using Spearman's correlation. A P value <0.05 was considered significant. All the variables that were found to be significant in univariate analysis were entered into a binary logistic regression model to determine the predictors of hypotension. The cutoff values of IVC diameter and CI for prediction of hypotension were determined using the receiver operating characteristic (ROC) curve, and the sensitivity and specificity were determined.


 » Results Top


Demographic variables

The demographic variables of the patients are presented in [Table 1].
Table 1: Demographic variables

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One hundred and forty-four patients were assessed for eligibility. A total of 100 patients were included in the study based on inclusion and exclusion criteria [Figure 2]. Sixty-three patients were males, while 37 were females. Median age was 40 years (18–65), mean weight was 59.9 ± 11.3 kg, mean height was 162.5 ± 9.5 cm, and mean body mass index (BMI) was 22.6 ± 3.4 kg/m2. Out of 100, 79 patients had supratentorial and 21 patients had infratentorial lesions.
Figure 2: Consort diagram showing the number of patients screened for eligibility, number of patients included in the study, and number of patients with successful IVC assessment. ACEI = angiotensin-converting enzyme inhibitor, ARB = angiotensin receptor blocker, IVC = inferior vena cava

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Clinical characteristics

Clinical characteristics of all patients are described in the supplementary material [Table 2]. Among the 100 patients, 12 were known hypertensives and were taking calcium channel blockers or thiazide diuretics. None of them were on beta-blockers, ACEI, or ARB. Eight patients had DM, and three patients had HT. Nineteen patients were overweight, and three patients were obese. None of the patients had any other cardiovascular or systemic disease.
Table 2: Clinical characteristics

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BP was measured noninvasively in all the patients. Baseline mean MAP was 94.5 ± 13.6 mmHg. None of the patients had baseline MAP of less than 75 mmHg. According to the criteria of hypotension as defined, 41% of the patients developed post-induction hypotension. Six patients had MAP <60 mmHg after induction of anesthesia. Mephentermine 3 mg was given intravenously to treat all hypotension episodes, and total cumulative dose of mephentermine was calculated for each patient.

Post-induction hypotension was seen in patients with increased age. Patients with smaller IVCDmax (P = 0.019), smaller IVCDmin (P = 0.002), and higher CI% (P = 0.002) developed hypotension after induction of anesthesia. Percentage drop in MAP was 34.9% ± 5.47% (P < 0.0001) in patients who developed post-induction hypotension [Table 3].
Table 3: Comparison of patients and clinical variables between patients who did or did not develop hypotension after induction of anesthesia

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Predictors of hypotension

Patients with small IVCDmax and higher CI% developed hypotension. There was a weak association between IVCDmax and occurrence of post-induction hypotension, whereas the association between CI% and post-induction hypotension was good. The percentage decrease in MAP was negatively correlated with IVCDmax (r = −0.19, P = 0.04) and positively correlated with CI (r = 0.11, P = 0.27).

The diagnostic accuracy as demonstrated by ROC curve analysis was less with IVCDmax, with a sensitivity of 36.6% and a specificity of 39%. The area under the ROC curve (AUC) was 0.64 (95% confidence interval, 0.53–0.75; P = 0.012), and the optimal cutoff value of IVCDmax was 1.38 cm [Figure 3]a. CI demonstrated good diagnostic accuracy with a sensitivity of 63.4% and a specificity of 66.1%. The AUC was 0.65 (95% confidence interval, 0.54–0.77; P = 0.007), and the optimal cutoff value of CI was 37.5% [Figure 3]c. We also analyzed the diagnostic accuracy of IVCDmin [Figure 3]b. The AUC was 0.69 (95% confidence interval, 0.59–0.80; P = 0.001). The optimal cutoff value of IVCDmin was 0.94 cm, with a sensitivity of 78% and a specificity of 58%.
Figure 3: ROC curves showing the diagnostic ability of preoperative maximum inferior vena cava diameter (a), minimum inferior vena cava diameter (b), and collapsibility index (c) to predict post-induction hypotension. ROC = receiver operating characteristic

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Total duration and severity of post-induction hypotension

The post-induction percentage decrease in MAP correlated significantly with IVCDmax (rho = −0.198, P = 0.048), IVCDmin (rho = −0.205, P = 0.04), and CI (rho = 0.113, P = 0.264). Even the total duration of post-induction hypotension was affected by IVCDmax (rho = −0.246, P = 0.014), IVCDmin (rho = −0.32, P = 0.001), and CI (rho = 0.254, P = 0.011).

Mephentermine dosage and IVC parameters

The median requirement of mephentermine was 9 mg in patients developing post-induction hypotension. There was a significant correlation between mephentermine dose and IVCDmax (rho = −0.245, P = 0.0139), IVCDmin (rho = −0.331, P < 0.001), and CI (rho = 0.267, P = 0.007).

Logistic regression analysis

A logistic regression was performed to ascertain the effect of various factors (IVCDmax, IVCDmin, CI, age) on the likelihood of patient developing hypotension. The logistic regression model was statistically significant (χ2 (2) = 15.03, P = 0.001). The model explained 18.8% of variance in hypotension and correctly classified 68% of patients. CI (P = 0.002) and age (P = 0.028) were independent predictors of post-induction hypotension, while IVCDmax (P = 0.295) and IVCDmin (P = 0.301) were not. Increase in CI was associated with an increased likelihood of developing hypotension. For every unit change of CI, there was 1.045 times increased likelihood of developing hypotension. For every unit change of age, there was 1.037 times increased likelihood of developing hypotension.


 » Discussion Top


In our study, we found that preoperatively assessed IVC diameters and CI were good predictors of post-induction hypotension. There was a negative correlation between IVC diameters and post-induction hypotension, whereas CI was positively correlated with post-induction hypotension. The cutoff value for IVCDmax was 1.38 cm, IVCDmin was 0.94 cm, and CI was 37.5% for prediction of post-induction hypotension.

Fluid management is critical in neurosurgical patients to maintain optimal Cerebral perfusion pressure (CPP). Errors in management of intravascular volume status can increase the risk of intraoperative hypovolemia or hypervolemia and thus lead to negative outcomes secondary to cerebral ischemia or cerebral edema. Hypovolemia can induce hypotension because of the lower circulating volume (absolute hypovolemia) reducing preload.[29] The goal of ultrasound-guided IVC assessment here was to identify the patients with hypovolemia who were at increased risk of developing post-induction hypotension.

IVC assessment has been frequently used to assess the volume status and to predict fluid responsiveness in emergency and intensive care settings.[23],[24],[25],[26],[27],[28] A large number of studies have shown that IVC diameter is a reliable indicator of intravascular volume status, and respiratory changes in IVC diameter can predict fluid responsiveness. The American Society of Echocardiography and the European Association of Cardiovascular Imaging also suggest that IVC diameter and CI can be used to predict fluid responsiveness as they indicate right atrial pressure.[30] IVC diameter <21 mm with collapsibility >50% indicates hypovolemic state with a good reliability.

Hypotension under anesthesia is a frequent occurrence, and its definition varies in the literature due to variable thresholds used by different authors.[31] We defined hypotension as >30% decrease in MAP or MAP <60 mmHg, as it forms the lower limit of cerebral autoregulation and MAP may affect CPP. Hemodynamic variables were observed from induction of anesthesia to 10 min after endotracheal intubation to avoid any external stimuli or other confounding factors (pain, blood loss, diuresis, and so on) causing hemodynamic changes. We used thiopentone as the induction agent in our study because of its potential for cerebral protection and as an institutional protocol.

We evaluated the usefulness of ultrasonographic IVC assessment to establish a relationship between pre-induction IVC diameters, CI, and post-induction hypotension. A CI >37.5% and IVCDmin <0.94 cm were better predictors of post-induction hypotension, whereas IVCDmax <1.38 cm was less predictive with a sensitivity of 36.6% and a specificity of 39%. Consistent with our findings, Zhang et al.[32] reported that CI is a better predictor of post-induction hypotension than IVCDmax. They found that the CI >43% and IVCDmax <1.8 cm were predictive of post-induction hypotension. However, their study was limited by heterogeneous patient population and surgical procedures and use of different methods of BP measurement in patients. In our study, similar cutoff value of CI 37.5% was found, although the cutoff value of IVCDmax (1.38 cm) was lower. The possible explanation for smaller IVCDmax could be the increased prevalence of hypovolemia in neurosurgical patients secondary to decreased oral intake, diuretic effect of antiedema drugs, and occurrence of complications like DI. In addition, the size of IVC may be affected by the body surface area (BSA),[33] and Asian patients have small BSA compared to those from other parts of the world. Purushothaman et al.[34] also concluded that patients with IVC collapsibility of > 43% are more likely to develop hypotension after propofol induction. In contrast to our study, Mohammed et al.[35] found that IVC parameters had poor diagnostic accuracy for prediction of post-induction hypotension. However, their study was limited by heterogeneous surgical procedures, varying anesthetic dose regimen, and presence of catheterization stimulus (which may induce hemodynamic changes) during the study observation period. IVC indices have also been found to be poor predictors of post-spinal hypotension.[36],[37],[38] The poor correlation between IVC and hemodynamic parameters in these studies could result from different mechanisms of hypotension after spinal anesthesia (peripheral vasodilatation and blood pooling). These studies were also limited by a small sample size.

The predictive ability of IVCDmax was lower as the IVC size may vary among individuals independent of the right atrial pressure due to variable abdominal venous compliance and the impact of oxygen consumption (VO2), cardiac index, and ventricular end-diastolic dimensions.[27],[39],[40] In addition to IVCDmax, we also analyzed the predictive ability of IVCDmin for post-induction hypotension. The cutoff value of IVCDmin (0.94 cm) was similar to the finding of Ilyas et al.[41] who found that IVCDmin (0.94 ± 0.17 cm) was significantly lower in the hypovolemic group.

Age was also an independent predictor of post-induction hypotension with an odds ratio of 1.037. Patients developing hypotension were older in age (P = 0.044). This was similar to the finding of Reich et al.[3] who found old age to be a significant predictor of post-induction hypotension.

Percentage decrease in MAP was significantly more (34.9 ± 5.47, P < 0.0001) in patients who developed post-induction hypotension. It negatively correlated with IVCDmax and IVCDmin and positively correlated with CI. However, duration of hypotension and requirement of mephentermine dose were high in patients with smaller IVC diameters and larger CI. We used a fixed dose of mephentermine to treat each episode of hypotension, which may not be sufficient for all patients due to variable body weight. Since individual response to mephentermine may vary depending upon their noradrenaline levels and metabolism by enzyme monoamine oxidase, requirement of mephentermine dose and, subsequently, duration of post-induction hypotension may vary.[42]

Intracranial pathologies may induce autonomic dysfunction, which may affect the BP.[43] Although we did not measure the ICP in any patient, none of our patients had clinical or radiological signs of severe intracranial HTN. Mild to modest increase in ICP has not been shown to induce significant changes in BP.[44] Therefore, we assume that our results were not affected by ICP.

Most anesthesiologists use various invasive or noninvasive monitors to assess fluid responsiveness during the intraoperative period, but the preoperative use of such monitoring is uncommon in usual practice. Ultrasound is an easy, rapid, noninvasive, and painless examination tool, which is easily available in current medical practice. In recent times, it has become increasingly popular in perioperative care because of its application in nerve blocks, vascular access, and point-of-care systemic examination. We evaluated its efficacy for prediction of post-induction hypotension in neurosurgical patients who frequently develop hypovolemia and are at an increased risk of cerebral ischemia secondary to reduced cerebral perfusion during hypotension. We found that pre-induction IVC assessment is a reliable method to screen the patients for hypovolemia in the preoperative period and to predict post-induction hypotension.

Our study had several limitations. First, only one BP reading was taken before induction to define the baseline MAP, which could have acted as a potential source of bias. Some patients may have elevated BP due to anxiety, overestimating true baseline BP. Second, BP data was collected only for 10 min after induction. However, data collection beyond that period could have affected the result due to the effect of external stimuli or other confounding factors like pain, blood loss, diuresis, and others on hemodynamic changes. Third, IVC assessment was not performed in post-induction period during the episodes of hypotension due to change in mode of ventilation. Fourth, autonomic dysfunction secondary to raised ICP in intracranial pathologies was not ruled out, which may have caused exaggerated hypotension. But it has been observed in previous studies that modest increase in ICP does not have a significant effect on BP. Fifth, there was no control group in our study. Sixth, we did not assess the effect of post-induction hypotension on neurological outcome.

To conclude, perioperative BP management is a key factor in successful outcome after intracranial surgeries, as its lability may be associated with adverse events. Pre-induction ultrasonographic IVC assessment is a reliable method to predict post-induction hypotension resulting from hypovolemia in neurosurgical patients. In our study, we found that CI >37.5% and IVCDmin <0.94 cm were good predictors of post-induction hypotension. Age was also an independent predictor of post-induction hypotension. Knowledge of these measures preoperatively will enable effective intervention and prevent post-induction hypotension. Further multicenter larger trials are required to verify these results and to establish the criteria for accurate prediction of post-induction hypotension and its timely prevention in neurosurgical patients.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published, and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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