Prevention of hypotension induced by combined spinal epidural anesthesia using continuous infusion of vasopressin: A randomized trial.

BACKGROUND: Central neuraxial blockade (CNB) is an established technique of providing anesthesia for surgeries of the lower limb and abdomen. Hypotension is the most common side effect of CNB. It was hypothesized that by supplementing the initial burst of vasopressin following hypovolemia, hypotension following combined spinal epidural anesthesia (CSEA) could be avoided.
MATERIALS AND METHODS: A total of 122 patients undergoing lower limb and abdomen surgeries were included in the study, with 61 patients randomized into two groups - I and II. Patients in Group I received infusion of normal saline as soon as CSEA was applied. When systolic blood pressure (SBP) decreased to <90 mmHg, they received a 6 mg bolus of mephentermine to counteract hypotension. Patients in Group II received a continuous infusion of vasopressin as soon as CSEA was applied. If despite maximum dose of vasopressin, SBP dropped to < 90 mmHg, then intravenous mephentermine was administered to counteract hypotension. Hemodynamic parameters and side effects were noted.
RESULTS: Level of block attained in both groups was comparable in terms of dermatomal height. The mean SBP and mean arterial pressure values of Group I were significantly lower than in Group II in the initial 14 min. Diastolic BP was also significantly lower in Group I. Heart rate was found to be lower in Group II, especially after 30 min (P < 0.05).
CONCLUSION: Maintaining plasma levels of the physiological burst of vasopressin helps to avoid hypotension following neuraxial blockade. Continuous infusion of vasopressin at 1-3 U/h can prevent hypotension following neuraxial blockade.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Central neuraxial blockade (CNB) is an established technique of providing anesthesia for surgeries of the lower limb and abdomen. Its beneficial effects range from rapid onset of action, decreased blood loss, and reduced need of anesthetics and analgesics.

Side effects due to CNB, include that of sympathetic blockade, such as hypotension in approximately 30–40%, bradycardia in 13%, nausea and vomiting in up to 7%, and dysrhythmias in 2% of the patients.[1] Hypotension is one of the most common side effects of CNB, and excessive hypotension produces cerebral and myocardial ischemia.

Three endogenous hormone systems are physiologically available to compensate for sympathetic blockade, namely the renin–angiotensin, endothelin, and the arginine vasopressin systems.[2] Standard treatment of spinal or epidural anesthesia-induced hypotension includes administration of intravenous fluids,[3] application of vasopressor drugs,[4] physical methods to increase venous return (leg raise), and treatment of associated bradycardia using atropine. Application of intravenous fluids increases venous return and cardiac output, but infusion of excessive volumes of crystalloid fluids may induce edema and is hazardous in patients with limited myocardial reserve. Leg raising is not feasible during surgery. In addition to above methods, vasopressor agents such as mephentermine and ephedrine are conventionally used to counteract CNB-induced decreased vascular tone. However, these agents act indirectly by recruiting catecholaminergic receptors and their use more often than not increases cardiac and metabolic work load.[4] Keeping the above facts in mind, this study was conducted to look for an alternative medication to deal with CNB-induced hypotension.

Arginine vasopressin is a potent endogenous vasoconstrictor that increases blood pressure (BP) by direct action on specific receptors (V1) located on vascular smooth muscles, and vasoconstriction is attained without tachycardia and exaggerated metabolic cost.

During hypotension caused by hypovolemia, the endogenous plasma vasopressin levels increase and this is important for preserving perfusion pressure in the normal range.[5] Experimental evidence in animals supports the concept that the endogenous vasopressin levels increase to the range of 4–22 pg/ml system and is the naturally occurring compensatory mechanism to restore arterial BP when sympathetic outflow is reduced by spinal or epidural anesthesia.[6789] However, these stores are not well sustained and diminish very soon, thus precipitating hypotension. Since reduction in endogenous vasopressin levels coincides with decrease in BP, we hypothesized that support with exogenous vasopressin infusion might prevent fall in BP after CNB.

MATERIALS AND METHODS

After obtaining the approval from the Institutional Review Board and Ethical Committee clearance, written and informed consent was obtained from all the patients planned for lower limb and lower abdominal surgeries (research cell reference number - XL ECM/B-P4, dated 11/1/2010). We performed a double blind, prospective, randomized study from January 2010 to January 2013. Taking the incidence of hypotension in central neuraxial blocks to be 33% and keeping the power of study at 80%, with alpha error at 0.05, and considering a decrease in the hypotension by 22% to be clinically significant, we required at least 51 patients in each group to avoid type I and II errors. A total of 122 subjects were enrolled in the study and were randomly distributed into two groups comprising 61 patients each [Figure 1].

Figure 1

CONSORT Flow Diagram

Patients aged between 18 and 60 years, with American Society of Anesthesiologists (ASA) Class I and II, having an ideal body weight ± 20% of normal, and undergoing surgery for the lower limb and abdomen were included in the study. Patients with cardiac disease or on cardiac medications, renal, pulmonary, endocrine, or hepatic diseases were excluded from the study. In addition, patients with hormonal therapy, pregnant and lactating women were excluded from the study. Patients were randomized into one of the two groups by the selection of a chit picked by the patient. The person administering the combined spinal epidural anesthesia (CSEA) was blinded to the contents of the infusion which was prepared by another anesthesiologist performing the study.

Patients in Group I received co-loading with lactated Ringer's solution 10 ml/kg and thereafter received continuous infusion of normal saline through an infusion device at 2–6 ml/h as soon as CSEA was applied. When systolic BP (SBP) decreased to <90 mmHg, they received a 6 mg bolus of intravenous mephenteramine to counteract hypotension.

Patients in Group II received co-loading with lactated Ringer's solution at 10 ml/kg and thereafter received a continuous infusion of vasopressin at the rate of 1–3 international units (IU) per hour as soon as CSEA was applied. If despite maximum dose of vasopressin, SBP dropped to <90 mmHg, then intravenous mephenteramine 6 mg was administered to counteract hypotension.

All patients scheduled for operation received oral ranitidine 300 mg and lorazepam 1 mg the night before surgery and in the morning. Upon arrival in the operating room, two intravenous catheters were placed in both forearms using 16-gauge cannulae. Standard monitoring with noninvasive BP (NIBP), electrocardiography, pulse oximetry, and urine output were initiated. Baseline heart rate (HR), BP systolic, diastolic, and mean along with oxygen saturation were recorded. Patients were co-loaded with lactated Ringers solution 10 ml/kg body weight over 15 min and continuous fluid therapy with maintenance requirement was provided. With all aseptic precautions, CSEA was applied in the sitting position at the level of L2–L3 inter space. Epidural catheter was secured 3–5 cm inside the epidural space. Spinal anesthesia was administered using 3 ml of 0.5% hyperbaric bupivacaine.

In Group II, a continuous infusion of vasopressin was started at the rate of 1 U/h. The infusion was prepared by diluting 20 U of vasopressin in 40 ml of saline, with 1 ml containing 0.5 U of vasopressin. Patients in Group I received an infusion of normal saline with an infusion pump at the rate of 2–6 ml/h immediately following CSEA. Thereafter, the patients were placed in the supine position for 15 min for the development of adequate block level. The patient was then positioned supine or lateral as per the surgical requirement. The level of sensory block was determined by response to pin prick. Patients were monitored for HR, NIBP (systolic, diastolic, and mean), and pulse oximetry every 2 min initially for 15 min and thereafter every 5 min for rest of the surgery.

If SBP dropped to <90 mmHg despite the infusion, then the infusion rate was increased by 1 ml/h up to a maximum dose of 6 ml/h until the BP rose to acceptable levels in both the groups. If SBP of <90 mmHg was observed in either group, despite maximum rate of infusion, then a bolus of 6 mg intravenous mephenteramine was given.

Throughout the procedure, fluids were infused at a maintenance rate of 6 ml/kg along with the losses observed. Epidural anesthesia was topped up when the level of block height reduced by four segments, using 5 ml of 0.5% bupivacaine. The infusion was stopped at the end of surgery and hemodynamic parameters were observed for 1 h afterward every 15 min.

In the postoperative period, any hemodynamic instability was treated using conventional methods such as fluid resuscitation, passive leg raise, and vasopressors, if required. Intraoperative bradycardia was diagnosed, if HR <60 beats/min was present, and was treated using a bolus of 0.01 mg/kg intravenous atropine. Nausea and vomiting was treated with intravenous 4 mg ondansetron and shivering by 5 mg/kg of injection tramadol.

The anesthesiologist who performed the CSEA and prepared the infusion drugs was not present with the patient for the rest of surgery. The anesthesiologist assessing the block height, hemodynamic profile, and any requirement of epidural top up or vasopressor was blinded to the drug being given through the infusion device.

Age, weight, surgery performed, and level of block attained were recorded. Episodes of nausea, vomiting, hypotension, bradycardia, arrhythmias, shivering, or other complications were also noted. In addition, requirement of other vasopressors, fluids given, and urine output were also recorded.

Statistical analysis

The data were analyzed using Statistical Package for Social Sciences version 15.0 (SPSS Inc., Chicago, IL). Chi-square test was used for comparing the proportional data. Parametric data were compared using independent samples T-test. Nonparametric data were compared using Mann–Whitney U-test. The confidence level of the study was kept at 95%, hence a P < 0.05 was considered statistically significant.

RESULTS

Demographic data were comparable in both the groups [Table 1]. In Group I, 13 of 61 and 16 of 61 patients in Group II achieved a sensory block above the level of T6. However, this difference was not statistically significant.

Table 1

Demographics

In Group I, 21 out of 61 patients required mephentermine to maintain BP levels in the normal range with a mean requirement of 14.86 ± 1.30 mg. Most of the patients had a sensory block level below the level of T6 [Figure 2].

Figure 2

Comparison of block height in between the groups

In Group II, all patients were given vasopressin in titrable doses at 1–3 U/h. The mean requirement of vasopressin was 1.24 ± 0.52 U. Only one patient required a single bolus of mephentermine despite maximum dose of vasopressin. The number of patients in each group requiring mephentermine or vasopressin is shown in Figure 3.

Figure 3

Patients receiving mephentermine (Group I) and vasopressin (Group II)

The level of block attained in both groups was comparable in terms of dermatomal height achieved [Table 2]. The HR of the two groups was comparable initially; but later on, the mean HR of patients in Group II was found to be lower as compared to that of Group I at all-time intervals. The difference between two groups was statistically significant at 2, 4, 45–75, and 90–115 min time interval. After 115 min, the mean value in Group II was lower as compared to that in Group I, but the difference between two groups was not significant statistically [Figure 4].

Table 2

Maximum level of block attained

Figure 4

Hemodynamic variations in the groups

The mean SBP values of Group I was significantly lower than in Group II in the initial 14 min. The SBP in two groups was comparable except from 2 to 14 min, when the mean difference between two groups was found to be significant statistically. After 14 min, there were no significant differences seen between the groups [Figure 4].

The diastolic BP was comparable in both groups at most of the occasions except at 4, 6, 8, and 12 min, when it was found to be significantly lower in Group I as compared to Group II. The mean arterial pressure (MAP) in two groups was comparable at most of the time intervals under the study except for a short duration between 2 and 12 min time interval [Figure 4].

The incidence of side effects was noted and analyzed for comparison between two groups. Hypotension was found to be significantly higher in Group I as compared to Group II (P < 0.001) [Table 3]. No significant differences were observed between the groups with regards to other side effects.

Table 3

Comparison of side effects between the groups

DISCUSSION

Vasopressin is a nano-peptide, synthesized as a large pro-hormone in the paraventricular and supraoptic nuclei of the hypothalamus. The most potent stimuli for its release are increased plasma osmolality and severe hypovolemia sensed by central and peripheral osmoreceptors. A decrease in central venous pressure causes an increase in plasma norepinephrine and renin concentrations, whereas the plasma vasopressin concentration does not increase until MAP decreases.[10] Vasopressin concentrations increases and acts as a reserve system to stabilize BP specifically during epidural anesthesia.[6]

The normal fasting vasopressin concentration in humans is <4 pg/ml. Plasma level of 50 pg/ml must be attained before a significant increase in mean arterial BP is achieved in humans.[11] However, during hypotension caused by hypovolemia, plasma levels of vasopressin would increase and this is important for preserving perfusion pressure.[12] It is a potent vasoconstrictor of skin, skeletal muscle, fat, pancreas, and thyroid gland. It causes less vasoconstriction in the coronary and cerebral circulations compared to other catecholamines. Contrary to other catecholaminergic vasopressors, vasopressin causes pulmonary vascular vasodilatation.[12] This fact emphasizes the importance of the drug in cases where a compromise of coronary and pulmonary blood flow could be detrimental such as coronary artery disease, mitral stenosis, and pulmonary hypertension. Although our study does not include high risk cases like these, its efficacy in ASA Class I/II needs to be proven before further studies in higher ASA class patients could be taken up.

Laboratory studies and clinical reports suggest that administration of 1 U of vasopressin infusions yield a plasma concentration of nearly 20–30 pg/ml. Maximal vasoconstrictor effect was seen at plasma levels of 100 pg/ml. At these concentrations, a pressor response occurs with minimal organ hypoperfusion.[1213]

Hypotension occurring after central neuraxial block is conventionally managed with sympathomimetic drugs such as ephedrine, mephenteramine, dopamine, adrenaline, and noradrenaline.[4] All these drugs except noradrenaline are known to cause tachycardia, which is not desirable in all patients. Moreover, tachyphylaxis is known to occur with repeated dosing of mephentermine. In patients who are depleted of noradrenaline stores, mephentermine has little effect in maintaining normal BP.

It has been seen in several animals[789] and few human studies[2141516] that during an episode of fall in BP, the levels of vasopressin rise from 100 to 1000 pg/ml in animals and from 4 to 22 pg/ml in humans. It has been proven by clinical and laboratory studies that a sustained plasma level of 25–30 pg/ml of vasopressin levels in the body can be maintained using 0.01 U/min drug infusion rates.[12] Taking this as the lower limit of infusion in our study, we started an infusion of 1 IU/h after giving CSEA. Since maximal vasoconstrictor effect occurs at plasma levels of 100 pg/ml, an upper limit of 3U was chosen to maintain vasopressin in the physiological range, which would approximately measure up to the plasma levels of 100 pg/ml.

In our study, most of the patients in the study group were effectively managed using vasopressin infusion, thus proving the hypothesis. Only one patient in Group II required a bolus of mephentermine beyond the maximum targeted dose of vasopressin infusion for the maintenance of BP. Hopf et al.[7] and Carp et al.[2] in their study on humans showed an important role of endogenous vasopressin to maintain BP after regional anesthesia. However, they have not commented on the role of exogenous vasopressin supplementation.

De Kock et al.[14] showed ornipressin infusion at 2 U/h as an effective alternative to counteract hypotension during combined general/epidural anesthesia. We used a titration between 1 and 2 U/h to counteract hypotensive episode in almost 94% of the patients.

Another significant finding was that the mean HR in patients in Group II was significantly lower compared to baseline values at 20 min to 120 min. This effect of vasopressin in contrast to conventionally used vasopressors can be utilized in cases where an increased heart rate is not desirable, for example, coronary artery disease.

Till date, no randomized studies have been conducted to view the role of vasopressin as a sole agent against CNB-induced hypotension excepting its description in a few case reports.[17] This study aims to provide a new safer alternative to deal with the most common side effect of spinal anesthesia. This study is limited by the fact that plasma levels of the drug were not monitored and also the side effect of splanchnic vasoconstriction was not assessed. Larger trials are required to look for any gastrointestinal or other side effects of the drug before suggesting generalized use of vasopressin in CNB.

CONCLUSION

Vasopressin is highly effective in preventing hypotension in cases of spinal and epidural anesthesia in ASA Class I/II patients without any untoward side effects. Larger multi-center trials are required to adopt this method into routine clinical practice.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.