Table 2 shows preoperative hemodynamic, peripheral oxygen saturation, and intraoperative blood gas data, which did not significantly differ between groups. Nor did BIS (mean ± SD) differ between groups throughout surgery (44.5 ± 6.2 in control and 46.3 ± 6.4 in the AVP group; 95% CI, −2.9 to 6.5). Effect-site TCI concentrations of propofol ranged from 2.2 to 3.0 µg/mL and those of remifentanil from 2.0 to 4.3 ng/mL. No patients developed gross neurological or cognitive dysfunction postoperatively in either group.
Hemodynamic data are presented in Figure 2. MAP and HR before induction of anesthesia did not differ between groups (Table 2). After anesthetic induction, MAP decreased significantly (P < 0.0001) in both groups, with no significant alterations in HR (difference 1 bpm with 95% CI, 6–8 bpm in control, and mean difference −2 bpm with 95% CI, −7 to 3 bpm in the AVP). AVP significantly increased MAP by 26 mm Hg (31%) (95% CI, 22–31 mm Hg), with no significant alterations in HR (95% CI, −9 to 4 bpm). When positioned sitting upright, MAP decreased in both groups, though being higher in the AVP group than in the control group (2-way ANOVA: significant main effect of time [P < 0.0001], significant main effect of group [P < 0.0001], significant interaction between time and group [P < 0.0001]; Fig. 2A).
Although HR remained unaltered in the control group, it was progressively decreased by BCP in the AVP group. Consequently, the difference of HR between the groups became greater with time, revealing a time by group interaction (2-way ANOVA: significant main effect of time [P < 0.0001], significant main effect of group [P = 0.012], significant interaction between time and group [P < 0.0001]; Fig. 2B).
SjvO2 values are presented in Figure 3. Before AVP administration (postinduction baseline), they did not differ between groups (mean difference −5.0%, 95% CI, −13.1% to 3.1%; P = 0.26). AVP decreased SjvO2 values by 9% (95% CI, −12% to −6%), thus being lower even before taking BCP (P = 0.0001) in the AVP group than in the control group. When positioned sitting upright, however, they decreased in the control and remained unaltered in the AVP group. Neither the actual value of SjvO2 nor the magnitude of its maximum decreases (22% ± 14% in control vs 16% ± 9% in AVP, 95% CI, −14.8% to 2.8%; P = 0.14) differed between groups in BCP (2-way ANOVA: significant main effect of time [P < 0.0001] but no significant main effect of group [P = 0.22] and no significant interaction between group and time [P = 0.57]).
Figure 4 shows SctO2 values. They were comparable between groups before (mean difference 2.3%, 95% CI, −3.3% to 7.9%; P=0.41) and after (mean difference 4.0%, 95% CI, −10.6% to 2.6%; P = 0.23) induction of anesthesia (postinduction baseline). They decreased after BCP in the control group. In the AVP group, there were 10% decreases by AVP itself, and they further decreased after BCP (P < 0.0001), thus being lower from presitting to the end of the study in the AVP group (2-way ANOVA: significant main effect of time [P < 0.0001], significant main effect of group [P<0.0001], and significant interaction between time and group [P < 0.0001]).
The adverse effects are presented in Figure 5. The incidence of hypotension (MAP <50 mm Hg) was lower in the AVP group than in the control group, along with a less frequent use of ephedrine (2 [13%] of 15 patients in AVP vs 10 [67%] of 15 in control; P = 0.003). The hypotensive episodes occurred shortly after BCP (within 5 minutes) and lasted from 2 to 15 minutes in the control group. The episodes occurred 10 to 15 minutes after BCP and lasted from 1.5 to 2.5 minutes in the AVP group. Of 10 patients who had hypotension in the control group, 7 (70%) had ≥2 episodes, whereas no patient experienced repetitive bouts of hypotension in the AVP group. Of the 30 patients studied, SjvO2 values decreased below 50% in 20 (67%, 95% CI, 49%–81%) and below 40% in 11 (37%, 95% CI, 22%–54%). However, neither the incidence of SjvO2 <50% (73% in AVP vs 60% in control; 95% CI, −19% to 42%, P = 0.44) nor that of SjvO2 <40% (47% vs 27%; 95% CI, −13% to 48%, P = 0.26) differed between groups. The incidence of cerebral oxygen desaturation (>20% decrease of SctO2 from presitting values) was higher in the AVP group than in the control group (80% vs 13%; P=0.0003).
The present study demonstrated the efficacy of AVP given as a prophylactic bolus for the prevention of hypotension associated with BCP in patients undergoing shoulder surgery under general anesthesia. However, its use negatively affected cerebral oxygenation as shown by a reduced SctO2 with upright positioning, which needs to be considered in clinical practice. To our knowledge, this is the first study to determine the effects of AVP on cerebral oxygenation with systemic blood pressure in humans with intact systemic circulation.
AVP, acting through V1 receptors that mediate vasoconstriction in vascular smooth muscles, is increasingly used in the perioperative setting. Although it uniformly increases MAP in most studies,14,15,24 whether it improves cerebral oxygenation remains controversial. Dudkiewicz and Proctor14 found improved brain tissue oxygenation when AVP was administered to increase CPP in an animal model of polytrauma with severe traumatic brain injury. Wenzel et al.15 also demonstrated that AVP improved CBF in a pig model of cardiopulmonary resuscitation using a radioactive microsphere technique. In contrast, AVP provoked a sustained decrease of both cerebral oxygenation (measured by NIRS) and cerebral blood volume with an impaired oxygen supply at the cellular level (as evidenced by reduced cytochrome oxidase) in pigs with intact systemic circulation.24 This finding is in agreement with ours in that AVP administered before BCP, when hemodynamics were stable, decreased cerebral oxygenation as determined by SjvO2 and SctO2.
CBF in humans is independent of changes in MAP within a range of 60 to 150 mm Hg.7 When arterial blood pressure is below the limit of autoregulation, vasopressor-induced increases in arterial blood pressure would enhance CBF as a pressure-passive effect. In previous studies with favorable cerebral results, AVP was administered when CBF had already been inadequate14,15 so that it may have predominantly increased systemic vascular resistance and shifted blood to the brain, ameliorating cerebral oxygenation. In contrast, AVP may negatively affect cerebral oxygenation via vasoconstriction in subjects with intact systemic circulation.24 AVP produces a dose-dependent decrease in vertebral blood flow probably through direct constriction of small arteries (via crossing the blood-brain barrier)25 without affecting MAP when administered into the vertebral artery in dogs.26 The impact of AVP on CBF and cerebral oxygenation may vary depending on one’s hemodynamic state and the dose used. A large bolus of AVP may impair cerebral oxygenation in subjects with intact systemic circulation, while it may improve cerebral oxygenation where systemic hemodynamics and cerebral perfusion are severely compromised.
One may speculate on the possible mechanisms underlying the reduction of SctO2 by AVP despite an elevated CPP. First, it may be attributed to AVP-induced cerebral vasoconstriction, resulting in reduced CBF. SctO2 decreased concomitantly with SjvO2 after an IV AVP bolus in the present study. SjvO2 depends on CBF, cerebral metabolic ratio for oxygen, arterial oxygen content, and hemoglobin concentration. A direct AVP-mediated change in brain tissue metabolism has not been documented. It is thus hypothesized that tissue metabolism remains unchanged. When other variables are constant, the reduction in SjvO2 may be a decrease of CBF. Moreover, AVP has been reported to reduce cardiac output in humans,12 which may in turn decrease SctO2.27 Second, NIRS assumes a fixed arterial/venous ratio and thus output of the device may be altered if the ratio changes in the absence of real changes in oxygen availability to neuronal mitochondria.28,29 Intraarterially administered AVP increased the resistance of small vessels interrogated by NIRS in the brain tissue in dogs in vivo.26 The cerebral vasculature may have been constricted directly by AVP and indirectly as a consequence of high CPP (which would not have substantially changed net CBF) in the present study. Vasoconstriction may then decrease cerebral arterial volume fraction and arterial/venous ratio, resulting in decreased SctO2. Phenylephrine was similarly shown to reduce SctO2 measured by NIRS via an altered cerebral contribution of arterial versus venous blood to the NIRS signal, without affecting CBF, in healthy volunteers.30 Third, NIRS values are influenced by extracerebral blood flow (e.g., skin blood flow).31,32 The effect of AVP to decrease skin blood flow via peripheral vasocontriction33 may also in part have affected our results. In fact, administration of vasoconstrictors, such as norepinephrine32 and phenylephrine,34 have been paradoxically reported to result in cerebral desaturation (reduction of SctO2) via cutaneous vasoconstriction and hence reduced blood flow of extracranial tissue without affecting CBF.
SjvO2 is an indirect assessment of global cerebral oxygen use.17 Normal SjvO2 ranges from 50% to 75% (average 62%) in awake healthy humans,35 and its value below 50% is indicative of cerebral hypoperfusion.36 In the present study, SjvO2 was reduced by AVP itself (absolute value 9%) and hence was significantly lower than that in the control group. However, the decrease was only transient for the first minute of BCP and the magnitude of maximum decreases of SjvO2 in BCP was no more than that seen in the control group. Furthermore, the incidence of jugular desaturation (SjvO2 <50%) was comparable between the groups, suggesting that AVP increased CPP and thereby CBF. This finding agrees that AVP is a potent vasopressor enhancing cerebral perfusion when the cardiovascular systems are collapsed (such as in cardiopulmonary resuscitation).15
On the contrary, SctO2 was significantly lower in BCP (Fig. 4), and the incidence of cerebral desaturation (>20% decrease of SctO2 from presitting values) was higher in the AVP group than in the control group (Fig. 5). It has been recently demonstrated that cerebral oximetry values are reduced by potent vasoconstrictors such as phenylephrine and norepinephrine via an altered cerebral contribution of arterial versus venous blood to the NIRS signal30 and/or a cutaneous vasoconstriction,31,32 both without affecting CBF. Moreover, the reliability of the SctO2 methodology in BCP is not well established. In fact, in an earlier study of our group, SctO2 was found to be only weakly correlated with SjvO2 in patients undergoing surgery in BCP, using SjvO2 as the standard reference,37 being consistent with previous findings in various clinical settings.38,39 In this context, SctO2 may not reliably detect the changes of cerebral oxygenation in BCP especially when a potent systemic vasoconstrictor is used. Anyone who uses NIRS both clinically and experimentally should view it with great caution.
In the AVP group, SjvO2 did not return to baseline even at 30 minutes into BCP (Fig. 3), and SctO2 was kept lower than in the control group at the end of study (Fig. 4), implying sustained vasoconstriction and reduced CBF. Similarly, AVP given as a bolus was shown to provoke a sustained decrease of both cerebral oxygenation (measured by NIRS) and cerebral blood volume in pigs with intact systemic circulation.24 In their study,24 cerebral tissue oxygenation index (the ratio of oxygenated to total tissue hemoglobin) did not return to its baseline values even after 50 minutes, which was markedly longer than the increased systemic vascular resistance after administration of AVP in humans.40 Other adverse effects of AVP include coronary vasoconstriction41 and impairment of cardiac index and systemic oxygen delivery.12 Although no patients had any new major neurological (i.e., stroke) or cognitive deficits in the early postoperative period, the frequent prevalence of cerebral desaturation and reduced SjvO2 values until the end of study after AVP administration are potentially worrisome. When AVP is used to augment CPP, one should be cautious. Adequate and well-controlled studies involving a larger number of patients are needed to establish the safety and efficacy of bolus AVP.
An IV bolus of AVP produces a peak effect within 1 to 2 minutes.11 However, data to guide bolus dosing are limited. A dose ranging from 10 to 20 U was given to restore arterial blood pressure after pheochromocytoma resection in 1 study,10 and a dose from 2 to 40 U was used to treat anaphylactic shock in another.10,42 Based on these studies, we administered 0.07 U/kg of AVP (equivalent to approximately 5 U in a 70-kg subject) 2 minutes before postural change, reducing the incidence of hypotension as compared with the control group (13% vs 67%; P = 0.0029).
Our study has several limitations, some of which have already been elucidated. First, all patients were free of cerebral pathology. It remains unclear how SjvO2 and SctO2 would have responded to AVP after shifting to BCP in patients with cerebral pathology or impaired autoregulation. Second, we did not measure CBF or cerebral metabolic rate of oxygen, which made it impossible to differentiate the changes of flow from oxygen consumption. Third, propofol-remifentanil was used to maintain anesthesia because they preserve cerebral autoregulation.43 However, volatile anesthetic drugs have an intrinsic cerebral vasodilating effect,44 and thus, the margin of safety against impaired cerebral oxygenation is greater, and SjvO2 is more preserved with sevoflurane-nitrous oxide than with propofol-remifentanil anesthesia.37 It remains unclear how SjvO2 and SctO2 would have responded to AVP in BCP under sevoflurane-nitrous oxide anesthesia. Fourth, most patients have dominant right-sided drainage for the jugular vein. Although we did not examine the drainage system by angiography in each patient, the SjvO2 catheter was inserted contralateral to the side of surgery for better handling. The lack of catheterization in the dominant drainage system in every patient may have affected the results, while the laterality was balanced with most placed in the left side. Finally, we administered AVP 0.07 U/kg as a rapid bolus. SjvO2 and SctO2 responses may differ when AVP is administered in other doses or continuously infused.
In conclusion, AVP administered as a prophylactic bolus was effective in preventing hypotension when patients were positioned sitting upright while undergoing shoulder surgery under propofol-remifentanil anesthesia. However, it caused sustained regional cerebral but not jugular venous desaturation with upright positioning. We advise caution with the routine use of AVP until its effects on cerebral oxygenation and hemodynamics are well established.
Name: SooY. Cho, MD.
Contribution: This author designed and conducted the study, collected the data, analyzed the data, and wrote the manuscript.
Attestation: Soo Y. Cho approved the final manuscript.
Name: Seok J. Kim, MD, PhD.
Contribution: This author helped design and conduct the study and prepare the manuscript.
Attestation: Seok J. Kim approved the final manuscript.
Name: Cheol W. Jeong, MD, PhD.
Contribution: This author helped design the study, analyze the data, and prepare the manuscript.
Attestation: Cheol W. Jeong approved the final manuscript.
Name: Chang Y. Jeong, MD, PhD.
Contribution: This author helped analyze the data, and write the manuscript.
Attestation: Chang Y. Jeong approved the final manuscript.
Name: Sung S. Chung, MD, PhD.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: Sung S. Chung approved the final manuscript.
Name: JongUn Lee, MD, PhD.
Contribution: This author helped design the study, review the analysis of original data and prepare the manuscript.
Attestation: JongUn Lee approved the final manuscript.
Name: Kyung Y. Yoo, MD, PhD.
Contribution: This author helped design and conduct the study, collect the data, analyze the data, and prepare the manuscript.
Attestation: Kyung Yeon Yoo approved the final manuscript.
This manuscript was handled by: Gregory J. Crosby, MD.
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© 2013 International Anesthesia Research Society
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