Acute hypertension is frequently encountered during the perioperative period, particularly during cardiovascular and neurosurgical procedures. Because there are significant postoperative complications associated with perioperative hypertension, it is usually aggressively treated with potent antihypertensive drugs. Such drugs may be also used to induce hypotension in major spine, orthognatic, neurovascular, radical pelvic, and shoulder surgery. This technique provides a dry surgical field and reduces blood loss. However, an excessive reduction of arterial blood pressure is one of the most common adverse effects of antihypertensive therapy and perioperative hypotension is implicated in an array of postoperative complications including cognitive impairment.1,2,3
Several drugs are available to control perioperative hypertension. It is generally believed that the degree and rate of arterial blood pressure reduction rather than the drug itself determine the extent of cognitive deterioration. However, in one study we have found that administration of nimodipine (NIMO) concurrent with acute nitroglycerin (NTG)-induced hypotension to levels below cerebral bloodflow (CBF) autoregulation was protective of long-term memory consolidation despite similar levels of mean arterial blood pressure (MAP) and CBF between treatment and the NTG/saline control groups.4 In addition, clinical benefits to calcium channel blocker (CCB) therapy have been noted in a 6-year study of cognitive function and antihypertensive therapy in the elderly. CCBs were found to improve cognitive function without hampering survival compared to β blockers and angiotensin-converting enzyme inhibitors.5 However, the relationship between antihypertensive treatment and cognitive impairment in the acute setting was never examined.
The aim of this study was to determine if matched levels of hypotension induced by the L-Type CCBs (LTCCB) NIMO and nicardipine (NICA) would be protective of immediate long-term associative memory consolidation and subsequent short-term working memory function compared to a matched level of hypotension induced by NTG alone. A passive avoidance (PA) memory retention paradigm and an object recognition test (ORT) were used to measure long and short-term memory (STM), respectively. In addition, we examined whether the protective effect of LTCCB-induced hypotension would be associated with differences in physiologic variables such as CBF or cerebral oxygenation.
Permission for this study was granted by the Institutional Animal Care and Use Committee of the New York University Langone Medical Center. Swiss-Webster young adult mice (30 to 35 g, 6 to 8 weeks) were housed in groups of 5 with 12 hour day/night cycles. Testing was in the daylight phase. Food and water were available ad libitum.
Behavioral Testing I: Passive Avoidance Testing Latencies
These methods follow those of our previous study.4 For long-term memory testing 40 mice were randomized into 4 groups for IP injection immediately after PA learning: (1) NTG (30 mg/kg); (2) NICA (40 mg/kg); (3) NIMO (40 mg/kg); and (4) saline. The doses were determined by the matched degrees of induced hypotension determined as set forth below. PA performance is an adaptive response to a stress that serves as a measure of long-term associative memory. The step-through PA apparatus consisted of a Plexiglas tube 20 cm long and 7 cm in diameter attached to a solid base. The lower half of the tube was lined with 2 semicircular aluminum inserts separated at the bottom by 0.5 cm through which shock could be administered. The mice could enter the tube via a 14 × 3 cm platform that was suspended 1 meter above floor level. A clear plastic guillotine door was positioned at the entrance of the tube. After the trial, mice were removed from the apparatus through a hinged doorway in the upper half of the tube. The training trial was commenced by placing the mouse on the entry platform and opening the guillotine door. When the mouse entered the tube the door was lowered and shock (0.3 mA; 2-second duration) was automatically delivered. Time to enter the tube was automatically recorded. After training, animals had an immediate injection according to their randomized group. Mice had no other exposure to the apparatus before testing 48 hours later. Retention was tested 48 hours later by placing the animal on the entry platform and opening the door to the tube. Time to reenter the tube was automatically recorded. Animals failing to enter within 900 seconds were assigned this value as a test score. No shock was given upon entry during the testing phase. After each session, animals were returned to their housing cages, and the apparatus was cleaned with a 50% ethanol/50% water solution. Lower testing latency is indicative of an impairment of long-term associative memory. The timetable for the PA studies is presented in Figure 1.
Behavioral Testing II: Object Recognition Testing
For STM working memory testing 49 mice were randomized into 4 groups for IP injection of (1) NTG (30 mg/kg); (2) NICA (40 mg/kg); (3) NIMO (40 mg/kg); and (4) saline. Five mice were excluded from consideration. Two mice died after NTG injection and 1 mouse died after NICA injection. One mouse in the NIMO and 1 mouse in the NTG group did not approach either object. The ORT of working STM was performed as described previously.6 The ORT exploits the tendency of animals to selectively explore novel objects in preference to familiar objects. Two different pairs of objects served alternately as novel and familiar objects. Each pair was validated as eliciting equal exploratory interest when dissimilar pairs were presented together (data not shown). Each mouse was only tested once to negate the possibility of a learning effect on their behavior. Measures of distance traveled were obtained during ORT for all groups and no significant differences were found among groups (data not shown). The apparatus consists of a circular Plexiglas 48-cm diameter open field arena with 18-cm high walls. On day 4, a 15-minute adaptation session to the arena and to the presence of objects was performed. On day 5, the testing day, a new pair of identical objects was placed symmetrically in the arena and mice were permitted to explore them for 15 minutes. Mice were removed to their home cages for 1 hour before the testing session when mice were presented with 1 of the objects seen during training (the familiar object) and a new object, which they had never seen (the novel object). The arena and objects were cleaned with a 50% ethanol/50% water solution and the positions of the novel and familiar objects were alternated with each testing session. Neurologically normal mice spent approximately 60% to 65% of their time exploring the novel object. Mice with poor working STM spent closer to 50% of their time with either object. ORT results are expressed in the recognition index (RI). RI is the time spent exploring the novel object divided by the time spent exploring both of the objects, the novel plus the familiar, with the resultant ratio converted to a percentage. The amount of time spent exploring each object was monitored by the SMART tracking system (San Diego Instruments, San Diego, CA). Exploratory behavior was defined as physical interaction with an object or the approach of the head of a mouse within a 4-cm circle around an object. Each object zone accounted for 4.7% of the arena surface area. The timetable for the ORT studies is presented in Figure 2.
Physiologic Studies: Cerebral Blood Flow
The required dosage for each treatment to elicit similar degrees of hypotension from IP injection of NTG, NIMO, and NICAR were determined in separate groups of mice (n = 3 per group). Rodents were anesthetized with isoflurane 1.2% for insertion and externalization of a 32-gauge femoral arterial catheter connected to a pressure transducer and MC 110 bridge amplifier. Arterial blood pressure was measured continuously for approximately 5 hours after injection and recorded on a Power-Lab/200 data acquisition system (AD Instruments, Sydney, Australia). After injection for hypotension, the anesthetic dose was rapidly reduced because mice became unresponsive to prodding or repositioning as their MAP decreased. In a further group of 9 mice (n = 3 per group) further physiologic variables were measured under the hypotensive and anesthetic conditions noted above. Using a stereotactic device (Kopf Model 900 Small Animal Stereotaxic Instrument, Tujunga, CA), an OxyLite/OxyFlo system (Oxford Optronix, Oxford, UK) cerebral tissue monitoring probe was placed to record local parenchymal perfusion (perfusion index [PInd]) and brain tissue oxygenation (PbtO2). The fiberoptic probes (diameter 250 um) were positioned approximately 2 mm lateral to the midline and 2 mm inferior to the bregma at a depth of 1 mm. Regional tissue oxygen tension was expressed in millimeters of mercury. Laser Doppler flowmetry was used to measure relative changes in CBF (PInd). The probes were inserted slowly under visual control using a surgical microscope, and special care was taken not to injure blood vessels. Animals were not used if superficial hemorrhages were seen. PInd was measured throughout the hypotension period. Data were expressed as mean percent of the baseline value. In addition a MouseOx pulse oximetry device (STARR Life Sciences, Allison Park, PA) was used to measure oxygen saturation (SpO2) and heart rate.
The measure of long-term associative memory retention in the PA paradigm was latency in seconds for the mouse to enter the shock compartment during testing. However, 4 mice in the saline group and one in the NIMO group did not enter the tube within the 900 seconds allotted and were therefore given 900 seconds as their latency score. The indeterminate nature of those scores excluded the use of parametric statistics, so we used rank analysis for comparisons involving the PA latencies. First, we tested the null hypothesis that all 4 distributions were identical with the Kruskal-Wallis test (P < 0.05), and followed this with pairwise comparisons using the Mann-Whitney U-test. All post hoc tests were protected from excessive type I error by using Bonferroni-corrected α levels. For significant pairwise differences, estimated differences of population medians, along with Bonferroni adjusted 95% Hodges-Lehman confidence intervals (CI), were provided.
RI was the measure of ORT working STM. RI is a percentage derived from the ratio of time spent exploring the novel object divided by the time spent exploring both objects. RI values indicative of poor memory are close to 50%. Because the RI data were consistent with the assumption of normal population distributions, the ordinary one-way ANOVA was used to test the null hypothesis that all 4 population means were equal; planned pairwise comparisons, based on the significant results of the PA latency analysis, were then performed, protected by a Bonferroni correction. All data were analyzed with IBM SPSS for Windows (version 19).
Behavioral Testing I: Passive Avoidance Testing Latencies
All groups exhibited short mean training latencies (18 ± 1 second SEM [SEM]) as compared to testing latencies. Because the testing latencies include indeterminate scores, the medians are given for each group, together with the semi-interquartile range: (1) NTG 219.5 ± 93.5 seconds; (2) NICA 372.5 ± 75.5 seconds; (3) NIMO 540 ± 200 seconds; and (4) saline 804 ± 257.5 seconds (Fig. 3).
We rejected the null hypothesis that all the PA latency distributions were identical, Kruskal-Wallis test: χ2 (3) = 18.2, P < 0.001, which justified using the Mann-Whitney U-test to compare each pair of conditions. As expected, NTG latency was significantly shorter than saline latency (P = 0.006, 2-tailed, with Bonferroni correction); the estimated difference of medians = 469 seconds, 95% CI =.[108,706] NTG latency was also significantly shorter than NIMO latency (P = 0.012, 2-tailed, with Bonferroni correction); the estimated difference of medians = 305.5 seconds, 95% CI =.[37,566]. There was a trend for the NICA latency to be shorter than the saline latency, but this trend fell short of significance after the Bonferroni correction (P = 0.09, 2-tailed); the estimated difference of medians = 390 seconds, 95% CI = [−33,553]. None of the remaining 3 pairwise comparisons approached significance after the Bonferroni correction.
Because all 3 methods of inducing severe hypotension resulted in approximately the same change in systemic blood pressure, as well as other measured physiological variables, it appears that the change in passive avoidance latencies is dependent on hypotension, but also significantly on the pharmacological intervention which caused it (as discussed below).
Behavioral Testing II: Object Recognition Testing
ORT scores were found to be affected in a delayed transient manner with normal scores on day 1, poor scores on day 5, and normal scores again on day 9 (Fig. 4). Data for days 1 and 9 are not shown and were not significantly different among groups. That pattern of a delayed transient decrease of ORT scores is well established in our studies. The mean ORT scores for day 5 were NTG RI (47.2 ± 5.9% SEM); NICA RI (60.2 ± 4.6% SEM); NIMO RI (62.5 ± 5.0% SEM); and saline (66.9 + 3.7% SEM) (Fig. 4).
For the intergroup variable day 5 scores, we performed an analysis on the ORT RI scores informed by the examination of the PA effects. That is, we focused on comparing the interventions shown in the PA study to be both statistically significant and physiologically meaningful, namely the comparisons of NTG with NIMO, and NTG with saline. First, however, we tested the null hypothesis of equal population means across all 4 conditions, F(3,40), P = 0.039, which was rejected. The 2 pairwise differences of interest were then each tested as 1-tailed (in the direction of the PA results) planned comparisons. For the difference between NTG RI and saline RI, t (40) = 2.89, P = 0.006 (with Bonferroni correction), 95% CI = [5.9%, 33.5%]. For the difference between NTG RI and NIMO RI, t (40) = 2.23, P = 0.031 (with Bonferroni correction), 95% CI = [1.4%, 29.1%]. Post hoc pairwise comparisons with Tukey's HSD test failed to find any additional significant differences. Measures of distance traveled were obtained during ORT testing for all groups and no significant differences were found among groups (data not shown).
Physiologic Studies: Effect of Treatments on Physiologic Variables
The intergroup differences for MAP, CBF, brain oxygenation (PO2), body PO2, heart rate, and respiratory rate were statistically insignificant. Table shows the results of the physiological studies.
An acute decrease in MAP to 45 to 50 mm Hg induced by the LTCCB NIMO was relatively protective of long-term associative memory consolidation compared to matched levels of hypotension-induced by NTG. The same degree of NICA-induced hypotension held an intermediate position between NTG and NIMO. In addition, NIMO was relatively protective of posthypotensive working STM function compared to NTG. Again, NICA held an intermediate position. These findings suggest a protective role for LTCC blockade in procedures where hypotension or low flow states may occur or are induced. Similar levels of depressed MAP and CBF were experienced by all groups.
The relationship between intraoperative hypotension and cognitive dysfunction has been examined in cardiac and noncardiac patients.3,7,8,9 Although some of these studies found an association between hypotensive episodes and postoperative cognitive impairment, particularly in the immediate postsurgical period, the results were not consistent. For example, in healthy young adults, induced hypotension may be well tolerated but those assumptions cannot be made in patients with existing major organ dysfunction.10 Cerebral hypoperfusion due to hypotension was linked to cognitive dysfunction after cardiac surgery and in the setting of critical illness.11 Yocum et al. specifically addressed postoperative neurocognitive performance in preoperatively hypertensive patients, establishing that there is an association between systemic intraoperative blood pressure and cognitive decline.2 However, the abovementioned studies did not report which antihypertensive treatments were used. The degree and duration of hypotension, rather than the drug itself, are generally accepted as the determinants of cognitive impairment. As of today, there is no compelling evidence that any antihypertensive drugs used in the acute clinical setting have cognitive advantages over any others.
Numerous animal studies have documented the neuroprotective potential of LTCCB in the setting of cerebral ischemia/infarction induced by cerebral vessel occlusion.12 However, these investigations did not address subtle differences in cognition after hypotension without overt ischemia. Our previous study suggested that treatment with NIMO may improve cognitive performance in adult mice after NTG-induced hypotension.4 However, the results were not clinically applicable because it is unlikely that 2 antihypertensives would be used simultaneously. The results of this study are the first direct documentation of the advantages of CCB over NTG (and presumably other nitric oxide donors) in relation to the preservation of cognition after drug-induced hypotension.
The systemic administration of NIMO and NICA has central effects. Systemically administered NIMO has improved cognitive function in our murine studies of hypotension and hypoxia.4,6 NIMO has improved several categories of memory immediately after learning and when tested 24 or 72 hours later.13,14 Moreover, NIMO preserved object recognition memory dysfunction caused by ethanol15 and scopolamine16 and has improved PA performance in rodents after hypoxia.17,18 The reduction of calcium entry through LTCC in different models of brain ischemia correlates with the improvement of cognitive function.19 The potential cognitive effects of LTCCB are a function of (1) the potential vascular activity of the drug, (2) the drug's ability to penetrate the blood-brain barrier (BBB), and (3) the effect of LTCCB on neuronal ion channels.
LTCCB such as NIMO are protective of learning and memory in the setting of hypoxia and ischemia independent of vascular effects.20 NIMO improves neurological outcomes in patients with vasospasm presumably because of its effect on the vasculature. NICA also decreases the incidence of vasospasm but it does not improve neurological outcome. This differential neuronal effect between the 2 drugs is similar to the differential effects that we report herein. In this study, local parenchymal perfusion (PInd) and PbtO2 were measured. Intergroup differences for MAP, PInd, and PbtO2 (in addition to body PO2, heart rate, and respiratory rate) were statistically insignificant. Whereas MAP decreased by 56% across all groups, PInd decreased by 67% and PbtO2 decreased by 70%. All groups had profound somnolence for the 5 to 6 hour duration of hypotension and awoke as MAP increased above 50 mm Hg. This indicates that oxygen and substrate delivery to the brain was insufficient for functionality but sufficient for minimal metabolic requirements. The PbtO2 levels we saw were decreased from baseline but are not associated with ischemia. Our physiological studies showed a baseline PbtO2 of 31.8 mm Hg over all groups and subsequent levels of 24.9 ± SEM 2.7 for NTG; 21.9 ± 2.2 for NICA; and 23.0 ± 3.6 for NIMO over 5 hours of hypotension. The critical oxygen tension where neuronal energy stores are decreased and cell failure begins to occur is at a cortical PbtO2 of 6.0 mm Hg21 to 6.8 to 8.0 mm Hg.22 Histological analysis would definitively address the nature of the injury but it appears that the levels of PbtO2 we observed were well above the threshold where ischemic or hypoxic injury is likely to occur. Our results suggest that PInd and PbtO2 were equally well preserved at matched levels of hypotension by all drugs. Thus, it is unlikely that differential vascular effects of NTG, NIMO, or NICA could explain the observed differences in memory retention.
Penetration of the BBB is dependent upon lipid solubility and molecular size. NIMO is more likely to penetrate the BBB than NICA23,24 because NIMO's lipid solubility is higher than that of NICA and because NIMO has a slightly lower molecular size than NICA (418.44 g/mol vs 479.525 g/mol). BBB penetration correlates with the relative cognitive improvement effects of NIMO versus NICAR that we have observed.
LTCC are widely present in neurons and glia in the central nervous system where they are involved in the regulation of neuronal functions such as gene expression, synaptic efficacy, and memory formation.25 Hypoperfusion may lead to adenosine triphosphate depletion and consequently to membrane depolarization and the unregulated opening of calcium and sodium channels. Energy-dependent mechanisms located in the mitochondria, endoplasmic reticulum, and plasma membrane that remove and sequester Ca2+ from the cytosol may also be degraded. During periods of neuronal stress caused by low energy states, LTCC are the principal source for calcium (Ca2+) leak and subsequent cellular injury.26 Indeed, LTCC are linked to each of the deleterious events noted above. Synaptic communication and memory formation are linked to calcium metabolism. Presynaptic nerve impulses cause local intracellular Ca2+ increases that lead to the release of glutamate. Glutamate, in turn, causes Ca2+ entry into the cell via the postsynaptic N-methyl-d-Aspartate receptors at the postsynaptic density where fine regulation of Ca+ controls signaling pathways and plasticity. CaM kinase II, which is activated by Ca2+, is known as a “memory molecule” essential to long-term potentiation. Long-term potentiation is a possible mechanism of learning and memory.27 LTCCB, such as NIMO, significantly reduce intracellular Ca2+ levels and membrane depolarization.28
Our investigation of the time course of STM performance using the ORT showed a delayed and transient pattern of dysfunction. This time course is possibly associated with the delayed development of neuro-inflammation and its subsequent resolution. Acute29 and chronic30,31 neuro-inflammations interfere with cognition. Delayed phases of brain inflammation have been noted after penetrating brain injury33 and hypoxia-ischemia where inflammation was not present up to 4 days after insult.32 After ischemic injury, microglial activation peaked at 24 to 72 hours while a further delayed microglial response was observed as much as 14 days later.33 We also observed a transient delayed impairment of STM in our study of NTG-induced hypotension that was ameliorated by treatment with the nonsteroidal anti-inflammatory drug, meloxicam.34 NICA has been found to have anti-inflammatory properties35 and NIMO inhibits the microglia-mediated inflammatory response.36 Following long-term hypoperfusion, NIMO corrected cognitive deficits and associated inflammation.37 Inhibition of cyclooxygenase and platelet aggregation as well as mitigation of the glutamate-induced neuronal damage may contribute to the salutatory effects of LTCCB.38
There are several limitations to this study. The interpretation of the results is principally limited by the lack of physiologic measurements in the experimental animals. Invasive monitoring would have limited movement that is required for behavior testing. Available noninvasive arterial blood pressure monitors do not perform reliably at low blood pressures. Although we did measure systemic blood pressure, PInd, and PbtO2 in the similar experimental conditions using separate groups of mice, there is no guarantee that animals that underwent memory testing had the reported blood pressures. Physiologic studies were conducted under isoflurane anesthesia. Although anesthetic requirements were much reduced during hypotension, the measurements could have been affected by the effects of isoflurane on cerebral circulation (i.e., venodilation). Thus, the reported results are largely phenomenological. In addition, NIMO is not well suited as a drug to induce hypotension but in research and in clinical practice clearly has demonstrated a role in neuroprotection. However, the exact mechanism by which NIMO preserves memory consolidation during hypotension remains unknown.
We conclude that a decrease in MAP to 45 to 50 mm Hg induced by the LTCCB NIMO was protective of 2 categories of memory formation relevant to a clinical posttreatment period. Both immediate long-term associative memory consolidation as measured by the PA learning paradigm and delayed working STM function as measured by the ORT paradigm were significantly improved compared to matched levels of hypotension induced by NTG. The same degree of NICA-induced hypotension held an intermediate position between NTG and NIMO in both cases. Because there was no difference in PInd and PbtO2 among groups it is possible that the different neuronal effects of CCB explain the preservation of memory. These results indicate the utility of further investigation of LTCCB as a potential means of preserving cognition in the setting of hypotensive and low flow states.
Name: Michael Haile, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Michael Haile has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and Is the author responsible for archiving the study files.
Name: Samuel Galoyan, PhD.
Contribution: This author helped conduct the study, analyze the data, and write the manuscript.
Attestation: Samuel Galoyan has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Yong-Sheng Li, MD.
Contribution: This author helped conduct the study and analyze the data.
Attestation: Yong-Sheng Li has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Barry H. Cohen, PhD.
Contribution: This author helped analyze the data and write the manuscript.
Attestation: Barry H. Cohen has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: David Quartermain, PhD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Attestation: David Quartermain has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Thomas Blanck, MD, PhD.
Contribution: This author helped analyze the data and write the manuscript.
Attestation: Thomas Blanck has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Alex Bekker, MD, PhD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Attestation: Alex Bekker has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
This manuscript was handled by: Gregory Crosby, MD.
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