Randomized Open-Labelled Comparative Evaluation of the Efficacy of Nitroglycerine, Esmolol and Dexmedetomidine in Producing Controlled Hypotension in Spine Surgeries.

AIM: This study was designed to evaluate the efficacy of nitroglycerine (NTG), esmolol, and dexmedetomidine (DEX) as hypotensive agents in decreasing intraoperative blood loss by producing controlled hypotension in posterior spine surgeries.
MATERIALS AND METHODS: Sixty patients aged 18-60 years, the American Society of Anesthesiologists physical status Classes I and II of either gender, were randomly assigned into three groups to receive either: NTG (0.01%) at the rate of 3-10 μg.kg-1.min-1 after positioning without a prior loading dose in Group N, esmolol 500 μg.kg-1 loading dose over 1 min before induction of anesthesia followed by 50-300 μg.kg-1.min-1 infusion in Group E, and DEX 1 μg.kg-1 over 10 min before induction followed by 0.2-0.7 μg.kg-1.h-1. infusion in Group D to maintain mean arterial blood pressure (MAP) between 60 and 65 mmHg. The three groups were compared for the achievement of target MAP, intraoperative blood loss, reversibility of hypotensive state, quality of surgical field, emergence time, and postextubation sedation score. STATISTICAL ANALYSIS: Analysis of variance was used for intergroup analysis, and for multiple comparisons, Bonferroni post hoc test was applied. P < 0.05 was considered statistically significant.
RESULTS: Patients in Group D and Group E achieved the target MAP with better heart rate control as compared to Group N. The intraoperative blood loss was significantly lesser in Group D (P < 0.001). The time to hypotension reversal and emergence time was prolonged in Group D (P < 0.001). The mean quality of surgical field score was statistically insignificant among the three groups. The mean Ramsay Sedation Scores were significantly higher in Group D compared to Groups N and E at 20th and 40th min postextubation (P < 0.001) with no significant intergroup difference at 60th min postextubation (P = 0.130).
CONCLUSION: Continuous infusion of DEX is an effective and safe method of producing controlled hypotension by achieving the target MAP, minimizing blood loss, and maintaining superior hemodynamics in comparison with NTG and esmolol in posterior spine surgeries. Copyright:

INTRODUCTION

Controlled hypotension has been employed to promote a readily visible surgical area in spine surgeries and other major orthopedic surgeries such as hip or knee replacement, oral maxillofacial surgeries, endoscopic sinus or middle ear microsurgeries, neurosurgeries, cardiovascular surgeries, and liver transplant surgeries.[1] In spine surgeries, improving the surgical field is especially important due to the vicinity of major and highly fragile neurologic structures. Decrease in hemorrhage adds to the safety of surgery in this area with better visualization of the operative field thereby decreasing possibility of nerve injury at the root level, providing more technical ease for the surgeon, and helping the surgeon to decrease the operative time, which further decreases bleeding.

Since 1978, nitroglycerine (NTG) is widely used to achieve induced hypotension because of its rapid onset, rapid offset, titrability, and low cost.[2] Esmolol an ultrashort-acting cardioselective β1-adrenergic antagonist that reduces heart rate (HR) and blood pressure and has a rapid onset and short duration of action also has been used as a drug for induced hypotension. Dexmedetomidine (DEX), a potent and highly selective α2-adrenergic agonist with sedative, anxiolytic, neuroprotective, anesthetic sparing, and analgesic action without producing respiratory depression,[3] brings about dose-dependent decrease in mean arterial blood pressure (MAP), HR, cardiac output, and norepinephrine release.

Hence, in this prospective randomized open-labeled study, we intend to compare the effects of NTG, esmolol, and DEX on intraoperative blood loss, reversibility of hypotensive state, and intraoperative hemodynamics by producing controlled hypotension in spine surgeries.

MATERIALS AND METHODS

After obtaining approval from the Institutional Ethics Committee, we conducted a randomized prospective study for 1 year from December 2014 to November 2015 in which 60 patients aged between 18 and 60 years, the American Society of Anesthesiologists (ASA) physical status Classes I and II of either gender, scheduled for posterior spine surgeries below thoracic vertebrae 10 (T10) level under general anesthesia were included after obtaining written informed consent. The patients were randomly assigned into three groups of 20 each, i.e., Group N (NTG), Group E (esmolol), and Group D (DEX). Randomization was done by sealed envelope method. Using GPOWER software version 3.0.10 (Erdfelder, Faul and Buchner, 1996), it was estimated that the least number of patients required in each group with 80% power and 5% significance level is 20. Since we had to compare three groups in our study, therefore, a total of 60 patients were included in our study. Patients who had respiratory, cardiac, renal and liver dysfunction, bleeding disorders, coagulopathies, diabetes, asthma, hemoglobin <9 gm%, hematocrit <28%, history of allergy to drug under study, history of drug/alcohol abuse, and patients on β-blockers, calcium channel blockers, and digoxin were excluded from the study.

Complete preanesthetic checkup was done a day before surgery. In the preoperative room, patients were prepared by placing two intravenous lines with 18G cannula and premedicated with injection glycopyrrolate 0.2 mg i.m and injection diclofenac sodium 75 mg i.v. diluted in 100 mL of normal saline 30 min before the operative procedure. Basic monitoring such as noninvasive blood pressure, five-lead electrocardiography, and plethysmography (SpO2) was applied. After performing modified Allen test, a 22G radial artery catheter was inserted for continuous measurement of arterial blood pressure, and baseline systolic blood pressure (SBP), diastolic blood pressure (DBP), MAP, HR, arterial saturation (SpO2), and respiratory rate (RR) were recorded. A urinary catheter was placed for the measurement of urine output.

Patients in the Group N (NTG) did not receive a prior loading dose. Group E patients received loading dose of 500 μg.kg-1 over a period of 1 min before induction of anesthesia, and Group D (DEX) patients received a loading dose of 1 μg.kg-1 (diluted in 50 mL of 0.9% normal saline) over a period of 10 min before induction of anesthesia. All the patients received injection palonosetron 0.075 mg i.v., injection midazolam 0.05 mg.kg-1 i.v., and injection tramadol 1 mg.kg-1 i.v. After preoxygenation with 100% oxygen for 3 min and induction with injection propofol 2.5 mg.kg-1 and injection vecuronium bromide 0.12 mg.kg-1, patients were ventilated with O2:N2O mixture (40:60) and isoflurane at 1% followed by intubation with flexometallic tube of appropriate size. End-tidal carbon dioxide (ETCO2) monitors were applied. The patients were then positioned prone with chest and pelvic rolls, leaving the abdomen hanging free and taking precautions to protect pressure points and avoid nerve injury and limb ischemia.

After positioning, patients in the Group N (NTG) received continuous NTG infusion (0.01%) at the rate of 3-10 μg.kg-1.min-1, whereas patients in the Group E (esmolol) received continuous esmolol infusion at the rate of 50-300 μg.kg-1.min-1 and patients in the Group D (DEX) received continuous DEX infusion at the rate of 0.2-0.7 μg.kg-1.h-1. The continuous infusions were titrated to achieve the target MAP of 60–65 mmHg before the skin incision.

Anesthesia was maintained with a mixture of N2O:O2 (60:40) and isoflurane (concentration range: 0.6%–1%). Muscle paralysis was maintained with top-up doses of injection vecuronium 0.01 mg.kg-1. Controlled mechanical ventilation with initial tidal volume of 8 mL.kg-1, RR of 14 breaths/min, and I: E ratio of 1:2 was adjusted to maintain ETCO2 between 30 and 35 mmHg. Intraoperative fluids included Ringer lactate as maintenance fluid and for deficits and losses and packed RBCs transfusion for blood loss more than 15% of total blood volume (BV).

Hematocrit value was obtained for each patient before induction (taken as initial) and at the end of procedure over the spine (taken as final) to calculate intraoperative blood loss.

Patients who reached the maximum infusion dose, i.e., 10 μg.kg-1.min-1 in Group N, 300 μg.kg-1.min-1 in Group E, and 0.7 μg.kg-1.h-1 in Group D without attaining the target MAP were given added intravenous metoprolol in 2–5 mg increments every 2–5 min, titrating to BP and HR.

During the induced hypotension phase, reflex tachycardia was defined as a persistent increase in HR of 120 beats/min (bpm) for a period of 10 min or more which was also treated with intravenous metoprolol. Bradycardia defined as HR <60 b.p.m was treated with intravenous atropine in increments of 0.2 mg i.v.

Hypotension defined as MAP <60 mmHg after stoppage of hypotensive agent for 5 min in Group N, 9 min in Group E, and 12 min in Group D was treated with injection ephedrine in increments of 6 mg intravenously. Patients who required ephedrine were excluded from the study.

Hypotensive infusions were stopped immediately at the end of procedure over the spine, and the time to reversibility of the hypotensive state was recorded which was defined as the time taken to restoration of MAP to baseline after stopping the hypotensive agent. Isoflurane was stopped at the start of the skin closure. The residual neuromuscular blockade was reversed using injection neostigmine 0.05 mg.kg-1 and injection glycopyrrolate 0.01 mg.kg-1, and the patient was extubated when obeying commands.

Emergence time defined as the interval between the discontinuation of anesthetics to response to eye opening to verbal commands was recorded.

HR and invasive blood pressure (IBP) (SBP, DBP, and MAP) were measured at the following time points: baseline (Tb); at the start of hypotensive agent (Ts); immediately after intubation (Ti); every 20-min interval after intubation; at the point of stoppage of the administration of hypotensive agent (Tt); and at extubation (Te). HR and non invasive blood pressure (NIBP) (SBP, DBP, and MAP) were measured at 20 (Te20); 40 (Te40); and 60 (Te60) min postextubation.

Intraoperative blood loss was calculated using modification of gross formula:

Blood loss: BV (Hct [i] − Hct [f])/Hct (m);

where BV = Body weight (kg) × 70 mL.kg-1; Hct (i), Hct (f), and Hct (m) were the initial, final, and mean (of the initial and final) hematocrit, respectively.

Surgeon estimated the quality of surgical field using a predefined category scale at every 20-min interval post skin incision for the assessment of intraoperative surgical field proposed by Fromme et al. and Boezaart:[4]

0: no bleeding, 1: slight bleeding – no suctioning of blood required, 2: slight bleeding – occasional suctioning required – surgical field not threatened, 3: slight bleeding – frequent suctioning required – bleeding threatens surgical field a few seconds after the suction is removed, 4: moderate bleeding – frequent suctioning required – bleeding threatens surgical field directly after suction is removed, 5: severe bleeding – constant suctioning required – bleeding appears faster than can be removed by suction – surgical field severely threatened and surgery not possible.

The ideal category scale values were predetermined to be two and three. In case of surgical field scores of four and five, early hematocrit estimation was carried out and blood loss was calculated, followed by transfusion of packed cells if the patient's blood loss level was 15% or more of his/her BV.

Sedation was evaluated using Ramsay Sedation scale at 20, 40, and 60 minutes after the tracheal extubation with scores ranging from 0 to 5. 0- Anxious and agitated, restless. 1- Cooperative, oriented, tranquil. 2- Responsive to verbal commands, drowsy. 3- Asleep, with brisk response to light stimulation. 4- Asleep, with sluggish response to stimulation. 5- Asleep, no response to stimulation. Patients falling in the scale of 4 and 5 were further monitored till they achieved a scale of 3.

Statistical analysis

All the data were compiled and statistical Statistical software SPSS version 20.0 (SPSS Inc., Chicago, Illinois, USA) and Microsoft Excel were used to carry out the statistical analysis of data. Continuous variables were summarized in the form of means and standard deviations, and categorical variables were summarized as percentages. Analysis of variance test was employed for intergroup analysis of data, and for multiple comparisons, Bonferroni post hoc test was applied. Chi-square test was used for comparison of categorical variables. P < 0.05 was considered statistically significant. All P values were two tailed.

OBSERVATIONS AND RESULTS

A total of 60 patients were included for statistical analysis. The demographic parameters of patients including age, weight, height, gender distribution, ASA physical status grade, and duration of surgery and anesthesia were comparable in all the three groups (P > 0.05) [Table 1]. Baseline hemodynamic parameters including HR, MAP, and preoperative hematocrit were similar in all the three groups.

Table 1

Comparison of demographic variables among the three groups

Variable	Mean±SD			P
	Group N (n=20)	Group D (n=20)	Group E (n=20)
Age (years)	36.7±11.64	44.2±15.34	41.6±12.07	0.199
Height (cm)	171.5±8.81	168.3±8.69	170.1±8.33	0.504
Weight (kg)	62.6±12.58	63.6±10.29	65.5±7.91	0.683
Duration of surgery (min)	208.0±55.78	228.0±52.55	229.0±43.15	0.344

P<0.05=Statistically significant, P<0.001=Statistically highly significant. SD=Standard deviation

Statistically significant difference in mean HR among the groups was found during the hypotensive phase till 60th min interval postextubation (P < 0.05). It was observed that mean HR in the NTG group was significantly higher compared to DEX group and esmolol group at all the time points during the observation with no significant intergroup differences in mean HR between Group D and Group E at any time period (P > 0.05). No patient in Group N and Group E had an episode of bradycardia during the observation. Two patients in Group D had bradycardia between the 80th and 160th min of surgery for which atropine was given.

Statistically significant difference between the groups as regard to mean SBP was found at every 20-min interval postintubation, at point of stoppage of hypotensive agent, at extubation, and at 20th and 40th min postextubation (P < 0.05). It was observed that mean SBP in the DEX group was significantly lower compared to NTG group and Esmolol group during the hypotensive period and till 40th min interval postextubation.

With regard to mean DBP, no statistically significant difference was found among the groups at all the time points during the observation.

In all the three groups, there was a significant reduction of MAP compared to baseline values intraoperatively. All the three groups reached the desired MAP (60–65 mmHg) with no intergroup significant difference after induction or during hypotensive period (P > 0.05). Sixteen patients in Group N, 6 patients in Group D, and 14 patients in Group E did not attain the target MAP of 60–65 mmHg for which added therapy with metoprolol was given. Statistically significant difference among the groups in the mean MAP value was found at extubation (P < 0.001) and at 20th and 40th min postextubation (P = 0.002 and P = 0.042), respectively. On intergroup comparison, it was found that MAP at the end of surgery was significantly higher in Esmolol group and NTG group as compared to DEX group (P < 0.001). However, no statistically significant difference was found in MAP values among all the three groups at 60th min postextubation (P = 0.341). MAP values in Group N and Group E were comparable at all the time points during the period of observation (P = 0.312).

No patient in all the three groups had reflex tachycardia and uncontrolled hypotension during the period of observation.

The mean quality of surgical field score (average category scale score) at 20-min interval post skin incision between the three groups showed no statistically significant difference (P > 0.05). The scores were <3 throughout the study. No patient had a score of four or five requiring early hematocrit estimation.

The mean intraoperative blood loss in Group D (190.2 ± 89.18) was significantly (P < 0.001) lesser than in Group N (353.1 ± 156.10) and Group E (327.0 ± 79.73). No statistically significant difference was found between Group N and Group E (P = 0.470).

The mean time to reversal of hypotensive state was maximum in Group D (87.2 ± 28.87) and statistically highly significant (P < 0.001) in comparison with Group N (15.2 ± 6.12) and Group E (20.0 ± 10.08). No statistically significant difference was found between Group N and Group E (P = 0.398).

The mean emergence time in Group N was found to be 5.1 ± 1.19, in Group D was 16.2 ± 5.06 and in Group E was (5.5 ± 1.43). Hence, emergence was prolonged in Group D and was statistically highly significant in comparison with other two groups (P < 0.001).

The mean Ramsay Sedation Scores were significantly higher in Group D in comparison with the other two groups at 20th and 40th min postextubation (P < 0.001) with no statistically significant intergroup difference at 60th min postextubation (P = 0.130).

DISCUSSION

In our study, we found that NTG, DEX, or esmolol when used to produce controlled hypotension were effective in reaching MAP of 60–65 mmHg and ensured good surgical conditions. However, there was a significant and clinically relevant reduction in intraoperative blood loss in patients who received DEX compared to esmolol and NTG while maintaining a favorable hemodynamic profile with less fluctuations in MAP and HR. DEX was associated with significantly longer extubation and recovery times and significantly high postoperative sedation scores compared with NTG and esmolol, offering the advantage of inherent analgesic, sedative, and anesthetic sparing effect. The favorable hemodynamic profile induced by DEX can be attributed to the well-established sympatholytic effects of α2 agonists.

Since it was an open-labeled study and no blinding was done, the anesthetist knew about the drug, there are chances of bias and so further similar studies should be done.

Mean HR in the NTG group was significantly higher compared to DEX group and Esmolol group at all the time points during the period of observation (P < 0.05) [Figure 1]. This is expected as esmolol is a selective β1-adrenergic receptor antagonist having negative chronotropic effect leading to bradycardia, and DEX is a highly selective α2-adrenergic agonist which by its central and peripheral sympatholytic action brings about dose-dependent decrease in MAP, HR, and cardiac output. On the other hand, NTG causes either no change or slight tachycardia which is a reflex phenomenon, produced secondary to hypotension.[5] None of our patients in Group N had reflex tachycardia (HR >120 beats/min). This could be because we maintained the MAP within the desired range by titrating the dose of NTG, thereby not allowing hypotension to occur further and produce reflex tachycardia. There was no statistically significant difference between DEX group and esmolol group as regard to mean HR values throughout the period of observation (P > 0.05).

Figure 1

Mean heart rate (beats/min) among various groups. Nitroglycerine group demonstrates a significantly higher heart rate compared to dexmedetomidine and esmolol group during steady-state hypotension

Statistically significant difference among the groups in the mean MAP value was found at extubation (P < 0.001) and at 20th and 40th min postextubation (P = 0.002, P = 0.042). MAP at the end of the surgery was significantly higher in Esmolol group and NTG group as compared to DEX group (P < 0.001) [Figure 2]. The hemodynamic stability observed during extubation in Group DEX can be explained on the grounds of selective binding of DEX to α2-receptors which results in sustained hypotension till the time drug diffuses out of its receptors. However, all the groups were comparable at 60th min postextubation with regard to mean MAP values (P = 0.341). No statistically significant difference in MAP was found between Group N and Group E at all the time points during the period of observation (P = 0.312). None of the patients in all the three groups had uncontrolled hypotension.

Figure 2

Mean invasive mean arterial pressure (mmHg) among various groups. Patients in all the three groups achieved the target mean arterial pressure. Dexmedetomidine group demonstrates significantly lower mean arterial pressure at the end of surgery

MAP was chosen as a parameter to quantify hypotension like it was done in study by Jamaliya et al., as it is the true measure of tissue perfusion.[67] We chose to limit the target MAP to 60–65 mmHg so as to minimize the risk of compromising the perfusion of spinal cord tissue resulting in neurological deficit. Hence, we avoided using profound controlled hypotension (MAP = 50 mmHg) in our study. Our findings are in accordance with those of Shams et al. and Kol et al., who found no significant intergroup difference in MAP after induction or during hypotensive period between DEX group and esmolol group. They also found a significant intraoperative reduction of MAP compared to baseline values. It was also found that MAP at the end of surgery was significantly higher in the esmolol group than in the DEX group.[89]

Intraoperative blood loss calculated using Modified Gross Formula[10] was significantly less in the DEX group in comparison with the other two groups (P < 0.001). Only two patients in Group N required whole blood transfusion. Blood loss in spinal surgeries is highly dependent on the degree of venous congestion around the vertebral bodies. NTG being a peripheral vasodilator with pronounced venous effect may have contributed to the increased blood loss in Group N requiring more blood transfusion than the other two groups. DEX by virtue of its sympatholytic action produces decrease in HR, cardiac output, and MAP thus maintains hemodynamic stability and thereby helps in the prevention of excessive blood loss during the surgery and in the immediate postoperative period [Table 2]. In another study by Rokhtabnak et al.,[11] bleeding score was lower and surgeon's satisfaction score was higher in the DEX group rather than those of the Mg group. Besides the decrease in BP and HR by DEX administration, peripheral vasoconstriction might be another reason for less bleeding and better quality of surgical field provided by this drug.

Table 2

Comparison of mean intraoperative blood loss (mL) among the three groups

	Mean±SD	95% CI	Minimum	Maximum	P
Group N	353.1±156.10	280.07-426.19	115	725	<0.001*
Group D	190.2±89.18	148.42-231.90	55	413
Group E	327.0±79.73	289.67-364.30	213	450

*P<0.001=Statistically highly significant. SD=Standard deviation, CI=Confidence interval

The difference in the meantime to reversibility of hypotensive state was found to be statistically highly significant between the three groups and was maximum in Group D in comparison with the other two groups (P < 0.001) [Table 3]. Emergence was also prolonged in Group D and was statistically highly significant in comparison with other two groups (P < 0.001) [Table 4]. It could be explained since NTG produces its hypotensive action by reacting directly with the nitrate receptors on the vascular smooth muscle cells and liberates nitric oxide (NO) which has a half-life of 0.1s. NTG also exhibits high clearance, high volume of distribution, and short equilibrium time between plasma concentration and hemodynamic effects. Hence, recovery from NTG infusion might be earlier than esmolol as half-life of esmolol is 9 min. DEX on the other hand selectively binds to α2-receptors with greater affinity and hence takes longer time to restoration of baseline MAP even after the hypotensive drugs are stopped. The hypotension in Group D can be reverted only when the drug diffuses out of its receptors.

Table 3

Comparison of mean time to reversibility of hypotensive state (min) among the three groups

	Mean±SD	95% CI for mean	Minimum	Maximum	P
Group N	15.2±6.12	12.28-18.02	3	29	<0.001*
Group D	87.2±28.87	73.64-100.66	28	140
Group E	20.0±10.08	15.28-24.72	9	42

*P<0.001=Statistically highly significant. SD=Standard deviation, CI=Confidence interval

Table 4

Comparison of mean emergence time (min) among the three groups

	Mean±SD	95% CI for mean	Minimum	Maximum	P
Group N	5.1±1.19	4.49-5.61	3	8	<0.001*
Group D	16.2±5.06	13.78-18.52	8	32
Group E	5.5±1.43	4.83-6.17	4	10

*P<0.001=Statistically highly significant. SD=Standard deviation, CI=Confidence interval

Surgeon estimated the quality of surgical field using a predefined category scale at every 20-min interval postskin incision. The concept of scoring system was introduced to enable the surgeon to make his own assessment of the operating field since it is difficult to measure and compare the blood loss in view of the minute amounts involved and the large volume of irrigating fluid used.[12] Nabil Fahmy in 1978 studied the role of NTG in producing controlled hypotension in total hip replacement surgeries and found that NTG was successful in creating effective dry operative field to surgeon's satisfaction.[2] Blau et al. studied the use of esmolol in creating dry operative field in orthognathic surgeries and found it to be efficacious.[12] The efficacy of DEX in providing better surgical field and less blood loss during controlled hypotension was also studied by Durmus et al. and Richa et al. during tympanoplasty or septorhinoplasty and maxillofacial surgeries, respectively.[1314] No statistically significant difference in mean quality of surgical field score was found among the three groups at any 20th min interval postskin incision (P > 0.05). The scores were <3 throughout the study [Figure 3]. No patient had a score of four or five requiring early hematocrit estimation.

Figure 3

Mean quality of surgical field score at 20-min interval post skin incision among the three groups. The scores were <3 throughout the study in all the three groups

Sedation was evaluated using Ramsay Sedation Scale at 20th, 40th, and 60th min after the tracheal extubation. Mean sedation scores were significantly higher in Group D (P < 0.001) in comparison with other two groups at 20th and 40th min postextubation since DEX has sedative and analgesia sparing effects through central actions in the locus coeruleus and in the dorsal horn of the spinal cord, respectively.[1516] Bajwa et al.[17] also reported higher postoperative sedation scores with the intraoperative use of DEX. No statistically significant difference was found at 60th min postextubation between all the three groups (P = 0.130) [Figure 4].

Figure 4

Mean Ramsay Sedation Scores among the three groups. Scores were significantly higher in dexmedetomidine group at 20th and 40th min interval with no significant intergroup difference at 60th min interval postextubation

CONCLUSION

That a continuous infusion of DEX is an effective and safe method of producing controlled hypotension in posterior spine surgeries by achieving the target MAP, minimizing blood loss, and maintaining superior hemodynamics in comparison with NTG and esmolol.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.