Armodafinil improves wakefulness and long-term episodic memory in nCPAP-adherent patients with excessive sleepiness associated with obstructive sleep apnea

Residual excessive sleepiness (ES) and impaired cognition can occur despite effective and regular nasal continuous positive airway pressure (nCPAP) therapy in some patients with obstructive sleep apnea (OSA). A pooled analysis of two 12-week, randomized, double-blind studies in nCPAP-adherent patients with ES associated with OSA evaluated the effect of armodafinil on wakefulness and cognition. Three hundred and ninety-one patients received armodafinil (150 or 250 mg) and 260 patients received placebo once daily for 12 weeks. Efficacy assessments included the Maintenance of Wakefulness Test (MWT), Cognitive Drug Research cognitive performance battery, Epworth Sleepiness Scale, and Brief Fatigue Inventory. Adverse events were monitored. Armodafinil increased mean MWT sleep latency from baseline to final visit by 2.0 min vs a decrease of 1.5 min with placebo (P < 0.0001). Compared with placebo, armodafinil significantly improved quality of episodic secondary memory (P < 0.05) and patients’ ability to engage in activities of daily living (P < 0.0001) and reduced fatigue (P < 0.01). The most common adverse events were headache, nausea, and insomnia. Armodafinil did not adversely affect desired nighttime sleep, and nCPAP use remained high (approximately 7 h/night). Adjunct treatment with armodafinil significantly improved wakefulness, long-term memory, and patients’ ability to engage in activities of daily living in nCPAP-adherent individuals with ES associated with OSA. Armodafinil also reduced patient-reported fatigue and was well tolerated.
Introduction
Obstructive sleep apnea (OSA) syndrome includes excessive sleepiness (ES), fatigue, sleep fragmentation, impaired alertness, cognitive dysfunction, and mood disturbances [1, 2]. OSA is typically characterized by recurrent complete or partial airway collapse during sleep, resulting in frequent apnea and hypopneic events lasting at least 10 s [1]. Although the reported prevalence of OSA in the general population varies as a function of diagnostic criteria [2], OSA syndrome has been estimated to occur in 4 and 2% of middle-aged North American men and women, respectively [3]. OSA can lead to serious medical, social, and public safety consequences, and patients are at an increased risk for cardiovascular disease [4] and motor vehicle and occupational accidents [5, 6]. Quality of life and social functioning are also significantly impaired in this patient population [7, 8]. Fatigue, in particular, can contribute to reduced quality of life [1, 9]; thus, the assessment of patient-rated fatigue is an important outcome to evaluate and monitor in patients with OSA.
Nasal continuous positive airway pressure (nCPAP) therapy is the recommended standard of care for treating patients with moderate to severe OSA [10]. In a comprehensive review of 36 clinical studies, nCPAP therapy was shown to effectively reduce objective and subjective measures of sleepiness and improve quality of life in patients with moderate and severe OSA [11]. However, despite receiving adequate nCPAP therapy, half of patients with OSA still experience residual ES as measured by objective assessments as well as impairments in mood or cognition [12–18]. Cognitive impairment in patients with OSA is characterized by deficits in attention, learning and memory, and executive function (planning and problem solving) and may persist despite nCPAP therapy [12, 15–17]. A review of the literature suggests that while nCPAP therapy can substantially improve quality of life for patients with OSA, it has a smaller effect on improving cognitive performance [7].
Modafinil, a racemic mixture consisting of equal amounts of R- and S-enantiomers, has been shown to improve wakefulness in patients with OSA who experience residual ES despite regular nCPAP use [19, 20]. Pharmacokinetic studies have shown that the half-life of R-modafinil (10–14 h) is significantly longer than the half-life of S-modafinil (3–4 h) [21–23]. Armodafinil has higher plasma concentrations later in the day compared to modafinil on a “milligram-to-milligram” basis and improves healthy subjects’ wakefulness and ability to sustain attention for a longer period of time compared with modafinil [24]. Armodafinil has also recently been shown to improve wakefulness in patients with ES associated with narcolepsy in a 12-week double-blind, placebo-controlled study [25].
Recent findings from two 12-week, double-blind, placebo-controlled studies of similar design indicate that armodafinil improved wakefulness and overall clinical condition in nCPAP-adherent patients with OSA and residual ES [26, 27]. In the present pooled analysis of the two OSA studies [26, 27], the effects on wakefulness, cognition, and fatigue and the safety and tolerability of armodafinil compared with placebo were evaluated in OSA patients adherent to nCPAP therapy.
Materials and methods
Study design and procedures
Data from two 12-week, multicenter, double-blind, placebo-controlled, parallel-group clinical studies were pooled for analysis. The pooling of these data was based on similarities in patient population, study design, and treatment duration in the two studies [26, 27]. One study was conducted in 36 centers across the USA, Australia, Russia, Germany, and France [26], and the other study was conducted in 37 centers across the USA and Canada [27]. The study protocols were approved by an Independent Ethics Committee or Institutional Review Board at each center. Both studies were conducted in accordance with the Good Clinical Practice: Consolidated Guideline [28] and national and local laws and regulations.
Patients were randomized to receive armodafinil 150 mg (n = 129) or placebo (n = 130) daily in the first study [26] and armodafinil 150 (n = 131) or 250 mg/day (n = 131), or placebo (n = 130) in the second study [27]. Study drugs were initiated with a dose of 50 mg/day on day 1 and then increased in increments of 50 mg starting on day 2 and every 2 days thereafter until the assigned dose was reached (i.e., 150 mg/day on day 4 for both studies or 250 mg/day on day 8 for the second study). The study drugs were taken once daily in the morning (before 08:00 and approximately 30 min before breakfast). Monitoring of patients’ compliance with study drug administration was the responsibility of the investigator at each center and was assessed by completed study drug accountability records and reviews of patient diaries. nCPAP use at home was also monitored objectively by investigators at each visit to the study center, using the REMstar® Auto CPAP System (Respironics, Murrysville, PA). The REMstar Auto CPAP System was used in CPAP mode.
Patient selection criteria
Methods for selecting patients in both studies have been described previously [26, 27]. Men and women 18 to 65 years of age with a current diagnosis of OSA as defined by the International Classification of Sleep Disorders [1] were included in both studies. Patients were at least moderately ill (Clinical Global Impression of Severity of Illness rating greater than or equal to 4) [29] and had a complaint of ES. Patients were eligible if ES was determined to be pathological, based on an Epworth Sleepiness Scale (ESS) score greater than or equal to 10 [30]. All patients were receiving stable (greater than or equal to 4 weeks) and effective nCPAP therapy on a regular basis (greater than or equal to 4 h per night on greater than or equal to 70% of nights) during the 2-week evaluation period. The CPAP use was monitored using the REMstar Auto CPAP System. Effectiveness of therapy was determined by an apnea–hypopnea index (AHI) less than or equal to ten events per hour on nighttime polysomnography (PSG).
Patient exclusion criteria
Patients were excluded if they had any of the following: a diagnosis of a sleep disorder other than OSA, symptoms of ES associated with a clinically significant uncontrolled medical or psychiatric condition as determined by the investigator, any disorder that might interfere with drug absorption, distribution, metabolism, or excretion, a history of drug or alcohol abuse, as determined by the Diagnostic and Statistical Manual of Mental Disorders IV criteria [31] or by a positive result from the urine drug screen given at screening and again at the final visit, caffeine consumption greater than 600 mg/day, or a clinically significant sensitivity to central nervous system stimulants or modafinil. Women who were pregnant or breast feeding were also excluded. The use of any substance that could affect wakefulness or sleepiness (e.g., modafinil, sodium oxybate, melatonin, lithium, St. John’s wort, methylphenidate, amphetamines, pemoline, antipsychotic agents, benzodiazepines, zolpidem, anticonvulsants, or barbiturates), use of other excluded agents (e.g., monoamine oxidase inhibitors, anticoagulants), use of clinically significant amounts of nonprescription drugs within 7 days of screening, and use of investigational drugs within 1 month of screening was prohibited. All patients provided written informed consent before participation in these studies and were compensated for their participation.
Assessments
Efficacy assessments
Efficacy assessments were performed for both studies at baseline and weeks 4, 8, and 12. The primary efficacy variables in the two individual studies were the change from baseline to final visit (week 12 or last postbaseline measurement) in mean Maintenance of Wakefulness Test (MWT) [32, 33] sleep latency averaged across the first four tests and the proportion of patients with at least minimal improvement on the Clinical Global Impression of Change (CGI-C) [29]. The MWT was conducted as six separate 30-min sessions at 09:00, 11:00, 13:00, 15:00, 17:00, and 19:00. Sleep latency was defined as the time to onset of the first of three consecutive epochs of stage 1 sleep or the time to onset of any epoch of stages 2, 3, and 4 sleep or rapid eye movement sleep [34]. Sleep latencies were averaged across the first four tests (09:00, 11:00, 13:00, 15:00) and the last three tests (15:00, 17:00, 19:00) to distinguish between early- and late-day effects, respectively. The proportion of patients with at least a minimal improvement on the CGI-C was assessed to determine patients’ overall clinical improvement in the individual studies; however, these data were not poolable for this analysis because of a substantial difference in the percentage of responders to placebo between the two studies.
The Cognitive Drug Research (CDR) battery of tests [35, 36] was administered by computer as six separate 25-min sessions conducted at 09:30, 11:30, 13:30, 15:30, 17:30, and 19:30. The CDR battery includes five memory tests (immediate word recall, delayed word recall, numeric working memory, word recognition, and picture recognition) and three attention tests (simple reaction time, choice reaction time, and digit vigilance). Two composite factors are derived from the memory tests in the CDR: quality of episodic secondary memory, a measure of long-term memory that measures the ability to recall verbal and visual information, and speed of memory, which assesses the time it takes to decide whether information is held in memory. Two composite factors are derived from the CDR for attention: power of attention, which measures the ability to focus attention and avoid distraction (concentration), and continuity of attention, which measures the ability to sustain attention (vigilance). Similar to the MWT, the CDR scores were averaged across the first four test sessions (09:30, 11:30, 13:30, 15:30) and the last three test sessions (15:30, 17:30, 19:30) to assess cognitive effects on early- and late-day measurements.
The patients’ ability to engage in daily activities was assessed at each visit by the ESS [30]. ESS total scores range from 0 to 24, with higher scores indicating greater sleepiness. An ESS score greater than or equal to 10 indicates pathological sleepiness [30]. The severity and impact of patient-rated fatigue on daily functioning were assessed at each visit by the nine-item Brief Fatigue Inventory (BFI) [37] and were based on changes in global fatigue (average of all nine questions) and worst fatigue in the past 24 h (item 3). The rating scale for the BFI ranges from 0 (no fatigue) to 10 (as bad as you can imagine). A score of greater than or equal to 7 for either global fatigue or worst fatigue in the past 24 h is indicative of severe fatigue. Both the ESS and BFI were administered before the first MWT session (09:00) at each visit.
Safety and tolerability assessments
Adverse events were monitored and recorded by the study investigators at each center throughout both studies. Clinical laboratory tests (blood chemistry, hematology, urinalysis), vital signs (resting heart rate and systolic and diastolic blood pressure 3 and 13 h postadministration), and electrocardiograms were obtained at screening, baseline, and weeks 4, 8, and 12. Physical examinations were performed at baseline and week 12. Patients’ use of nCPAP was monitored at least 2 weeks before baseline and throughout both studies using the Respironics REMstar Auto CPAP system. Effect on nighttime sleep was determined by PSG, which was performed the night immediately after the measurement of daytime MWT during the second screening visit and the final visit. The PSG was conducted for 8 h, starting within 30 min of the patient’s usual bedtime but not earlier than 21:30.
Clinically significant elevations in resting systolic and diastolic blood pressure were defined a priori as greater than or equal to 140 mmHg with an increase of greater than or equal to 10% and greater than or equal to 90 mmHg with an increase of greater than or equal to 10%, respectively. Patients with worsening hypertension included those who had a history of hypertension at baseline and who started new antihypertensive medication and/or increased the dose of previously used antihypertensive medication during the studies. Patients with newly diagnosed hypertension included those who had no history of hypertension at baseline and who started antihypertensive medication during the studies. Patients at risk for hypertension included those who had at least two clinically significant elevations in blood pressure readings between baseline and final visit.
Statistical analysis
Descriptive statistics were used to summarize continuous and categorical demographic variables. Efficacy assessments were analyzed at weeks 4, 8, and 12 using observed cases and at final visit (week 12 or last postbaseline measurement) using the last observation carried forward approach. Efficacy analyses included randomized patients who received at least one dose of study drug and had a baseline measurement with at least one postbaseline measurement on the MWT and CGI-C. Safety and tolerability analyses included all randomized patients who received at least one dose of study drug. All efficacy assessments were analyzed by analysis of variance (ANOVA) with treatment and study as factors. Tests of poolability for all continuous efficacy variables across the two studies were conducted using an ANOVA with treatment and study and treatment by study interaction as factors. Vital signs and data from nighttime PSG were analyzed by Wilcoxon rank-sum test. For nCPAP use, the change from baseline to on-treatment values was analyzed using one-way ANOVA. All statistical tests were two-tailed, and the 5% level of significance was used.
Results
Patient demographics and disease characteristics
Of 658 patients randomized, 651 were included in the safety analysis, and 601 were evaluable for efficacy (Fig. 1). Patient demographics and disease characteristics for all patients in the safety analyses are summarized in Table 1. The mean body mass index was 36.6 kg/m2. Patients reported high nightly nCPAP usage (mean [SD] hours of nightly use, armodafinil 6.9 [1.2] h; placebo 6.9 [1.0] h). The nCPAP therapy was effective, as shown by mean (SD) AHI values of 1.5 (3.3) and 1.2 (2.1) events/h in the armodafinil and placebo groups, respectively. Overall, 41% of patients had a history of hypertension at baseline.
Fig. 1Patient dispositionTable 1Patient demographics and baseline characteristicsCharacteristicArmodafinil (n = 391)Placebo (n = 260)Age (years)Mean (SD)49.7 (9.0)50.3 (9.1)Sex, n (%)Men283 (72)183 (70)Women108 (28)77 (30)Race, n (%)White327 (84)224 (86)Black36 (9)21 (8)Asian6 (2)3 (1)Other22 (6)11 (4)Missing01 (<1)Weight (kg)Mean (SD)110.4 (24.6)111.2 (23.7)BMI (kg/m2)Mean (SD)36.4 (8.0)36.9 (7.5)CGI-S, n (%)Moderately ill219 (56)138 (53)Markedly, severely, or extremely ill172 (44)122 (47)nCPAP (h)Mean (SD)6.9 (1.2)6.9 (1.0)AHIMean (SD)1.5 (3.3)1.2 (2.1)History of hypertensionn (%)159 (41)108 (42)AHI Apnea–hypopnea index, BMI body mass index, CGI-S Clinical Global Impression of Severity of Illness, nCPAP nasal continuous positive airway pressure
Effects on wakefulness
Mean (SD) sleep latency at baseline across the first four MWTs (09:00, 11:00, 13:00, 15:00) was 22.8 (8.4) and 23.2 (7.9) min for the armodafinil and placebo groups, respectively. At all study visits, armodafinil significantly improved mean sleep latency across the first four MWTs compared with placebo (Fig. 2a). The mean change from baseline in sleep latency at final visit was 2.0 min for the armodafinil group compared with −1.5 min for the placebo group (P < 0.0001).
Fig. 2Mean (SEM) change from baseline in sleep latency from the Maintenance of Wakefulness Test (MWT). a Sleep latencies averaged across the first four tests (09:00–15:00). b Sleep latencies averaged across the last three tests (15:00–19:00)
Armodafinil also improved patients’ ability to maintain late-day wakefulness (MWTs at 15:00, 17:00, 19:00) compared with placebo (Fig. 2b). Mean (SD) sleep latency at baseline across the last three MWTs was 24.4 (7.8) and 24.6 (7.4) min for the armodafinil and placebo groups, respectively. The mean change from baseline in sleep latency at final visit was 1.1 min for the armodafinil group compared with −0.3 min for the placebo group (P < 0.05).
Effects on memory and attention
Compared with placebo, armodafinil significantly improved the quality of episodic secondary memory across the first four tests (09:30, 11:30, 13:30, 15:30) at all study visits (P < 0.05; Fig. 3a). The mean (SD) change from baseline in quality of episodic secondary memory at final visit was 10.2 (31.7) U for the armodafinil group compared with −0.7 (46.3) U for the placebo group (P < 0.01). Differences between the treatment groups did not achieve statistical significance at the final visit for speed of memory, power of attention, or continuity of attention across the first four tests.
Fig. 3Mean (SEM) change from baseline in quality of episodic secondary memory. a Scores averaged across the first four tests (09:30–15:30). b Scores averaged across last three tests (15:30–19:30)
Across the later three tests of the day (15:30, 17:30, 19:30), the difference in the quality of episodic secondary memory was statistically significant at week 8 for armodafinil compared with placebo (P = 0.011; Fig. 3b), with a trend toward significance at week 12 (P = 0.081). The difference between treatment groups was not statistically significant at the final visit for the quality of episodic secondary memory. There were no significant changes from baseline to final visit between the armodafinil and placebo groups for speed of memory, power of attention, or continuity of attention across the last three tests.
Effects on patients’ ability to engage in activities
The mean (SD) ESS scores were high at baseline (15.4 [3.5] and 15.9 [3.5] for the armodafinil and placebo groups, respectively), despite the high nCPAP use as shown in Table 1. Compared with placebo, treatment with armodafinil significantly improved patients’ ability to engage in activities of daily living (ESS) at all visits (P < 0.0001; Fig. 4). Nearly half of all patients (49%) in the armodafinil group responded to treatment (total ESS score less than 10 at final visit) compared with 26% in the placebo group.
Fig. 4Mean (SEM) change from baseline in Epworth Sleepiness Scale total score
Effects on fatigue
The mean (SD) scores for global fatigue from the BFI at baseline were 4.8 (1.9) and 4.9 (1.9) for the armodafinil and placebo groups, respectively. Armodafinil significantly improved global fatigue at all visits compared with placebo (P < 0.01; Fig. 5a). Mean scores for worst fatigue in the past 24 h from the BFI at baseline were nearly identical for the armodafinil and placebo groups (7.2 [2.0] and 7.3 [2.0], respectively) and indicated severe fatigue (score greater than or equal to 7). Armodafinil significantly improved scores for worst fatigue in the past 24 h at weeks 4 and 12 and at the final visit (P < 0.05 vs placebo; Fig. 5b), with a trend toward significance at week 8 (P = 0.056 vs placebo).
Fig. 5Mean (SEM) change from baseline in fatigue. a Global fatigue. b Worst fatigue in the past 24 h. BFI Brief Fatigue Inventory
Safety and tolerability
Armodafinil was well tolerated, with a low incidence of adverse events, most of which were mild to moderate in nature. Headache was the most commonly reported adverse event, defined as occurring in greater than or equal to 5% in either group (Table 2). Serious adverse events were considered by the investigator unlikely to be or not related to armodafinil (ulcerative colitis, n = 1; migraine, n = 1; worsening of Axis II disorder and mood disorder, n = 1; duodenal ulcer hemorrhage, n = 1). One serious adverse event was reported in the placebo group (gastroesophageal reflux disease). The most frequently occurring adverse events that led to discontinuation among patients receiving armodafinil were headache (n = 5) and nausea (n = 4).
Table 2Adverse events occurring in ≥5% of patientsAdverse event, n (%)Armodafinil (n = 391)Placebo (n = 260)Headache65 (17)20 (8)Nausea22 (6)10 (4)Insomnia22 (6)3 (1)Dizziness19 (5)4 (2)Anxiety20 (5)2 (<1)
There were no clinically significant changes from baseline to final visit in either the armodafinil group or the placebo group for laboratory values, electrocardiogram parameters, or physical examinations. There were also no meaningful changes (clinical or statistical) from baseline to final visit for systolic blood pressure (0.2 [14.2] mmHg for armodafinil vs −1.0 [14.6] mmHg for placebo), diastolic blood pressure (0.3 [9.3] mmHg for armodafinil vs −1.0 [10.0] mmHg for placebo), and heart rate (2.3 [9.6] bpm for armodafinil vs 1.4 [9.6] bpm for placebo).
The incidence of patients with newly diagnosed hypertension was less than 1% in the armodafinil group and less than 1% in the placebo group. The proportion of patients at risk for hypertension was similar for both treatment groups (18% of 391 patients, armodafinil group; 16% of 260 patients, placebo group). The incidence of patients with worsening hypertension was 3% of 391 patients in the armodafinil group and 2% of 260 patients in the placebo group.
nCPAP use remained high (approximately 7 h/night) throughout both of the studies. The duration of nCPAP use at final visit was reduced from baseline by a mean (SD) of −0.3 (0.7) h with armodafinil compared with −0.1 (0.6) h with placebo (a between-group difference of about 12 min; P < 0.0001). At final visit, AHI values remained low and were comparable between the armodafinil and placebo groups (P > 0.05 vs placebo). In addition, there were no significant changes from baseline in nocturnal PSG sleep variables between the armodafinil and placebo groups (P > 0.05; Table 3).
Table 3Nocturnal polysomnography parametersaVariable (units), mean (SD)Armodafinil (n = 391)Placebo (n = 260)BaselineFinal VisitBaselineFinal VisitLatency to persistent sleep (min)22.3 (26.9)19.6 (20.5)21.3 (24.0)20.8 (21.4)Number of arousals, n20.0 (11.3)18.5 (10.2)18.7 (9.7)18.4 (10.4)Number of awakenings, n8.8 (4.7)9.2 (5.3)8.7 (5.1)9.6 (5.4)Sleep efficiency (%)82.4 (10.9)82.0 (12.0)82.0 (12.1)81.4 (11.2)Wake after sleep onset (min)66.6 (43.9)69.1 (48.5)68.7 (50.3)70.2 (46.5)Stage 1 (%)11.2 (6.4)10.5 (5.5)10.9 (6.1)10.6 (6.2)Stage 2 (%)59.3 (9.8)58.8 (11.2)58.8 (10.1)57.7 (11.2)Stage 3/4 (%)10.6 (9.0)10.3 (9.0)10.8 (9.6)10.9 (10.2)REM (%)18.9 (6.9)19.8 (7.1)19.5 (7.2)20.7 (8.0)REM Rapid eye movementaNo significant differences between baseline and final visit were observed.
Discussion
Recognizing and effectively managing ES in patients with OSA is essential for clinicians because of the profound impact that ES has on the patients, their families and coworkers, and the general public (e.g., increased risk of traffic accidents) [4–6]. Without appropriate treatment, ES adversely affects cognitive [15, 17], occupational [6], and social functioning [8]. Several studies evaluated in a comprehensive review [11] have shown that there is general improvement in wakefulness with nCPAP therapy, especially in patients with more severe OSA. Nonetheless, residual ES can persist even after effective nCPAP treatment [18], suggesting that there is need for adjunctive therapy to treat ES in these patients.
The present study re-evaluates the findings from two separate studies on the effects of armodafinil in patients with refractory ES associated with OSA and provides additional information regarding secondary analyses, for which the individual studies may not have had adequate statistical power. In the individual studies [26, 27], armodafinil was shown to significantly improve daytime mean sleep latency across the first four tests on the MWT and overall clinical condition as assessed by the CGI-C. In the pooled analysis, armodafinil significantly improved patients’ ability to sustain wakefulness as objectively assessed by the MWT. Improvements in mean sleep latency were observed at the first visit at week 4 and were maintained throughout the remainder of the study. The lack of a consistent effect of armodafinil on wakefulness across the last three MWTs (15:00, 17:00, 19:00) likely reflects the high mean sleep latency (approximately 24.5 min) at these times. Behavioral effects, causing poorer performance on the last test of the day, and high intertest variability in sleep latency may have also contributed to this finding [38].
The individual studies also included the clinician’s subjective assessment of treatment effect on ES, the CGI-C. Data for the CGI-C, however, were not poolable for this analysis because of substantial differences in the proportion of patients considered responders to placebo between the two studies. In the individual studies, the proportion of patients considered responders to armodafinil and placebo was 71 and 53%, respectively, in one study [26] and 72 and 37%, respectively, in the other study [27].
Cognitive impairment is common in patients with OSA [17]. Although the etiology has not been definitively determined, decreased cortical activity because of impaired arousal or neuronal damage because of chronic intermittent hypoxia are possible causes [16, 39–41]. It is not yet clear what additional interventions may be effective in restoring cognitive function in patients with OSA. Findings from studies evaluating the effects of nCPAP therapy on memory and attention have yielded inconsistent results [15, 16, 40, 42, 43]. Unlike the findings from the individual armodafinil OSA studies [26, 27], the pooled analysis showed that adjunct armodafinil significantly improves long-term memory (i.e., quality of episodic secondary memory) at all study visits compared with placebo, indicating that treatment was associated with a greater ability to recall verbal and visual information. Interestingly, the long-term memory benefit occurred independent of a consistent benefit on attention and concentration. It is important to note that the CDR composite factors in both of the individual armodafinil OSA studies were secondary efficacy variables. Thus, although results from the pooled analysis provide a more precise estimate of the effects on long-term memory, further studies are needed to determine the potential role of armodafinil in improving cognitive function in nCPAP-adherent patients with OSA and associated ES.
Armodafinil significantly improved patients’ ability to engage in activities of daily living at all visits as measured by the ESS. The patient population studied in this pooled analysis had severe ES (mean ESS score greater than 15) despite effective and regular nCPAP therapy. At the final visit, 49 and 26% of patients receiving armodafinil and placebo, respectively, had ESS scores less than 10, indicating that nearly half of patients no longer had pathological sleepiness with adjunct armodafinil treatment.
Fatigue may be the presenting complaint of patients with ES [44] and is a common associated symptom [45, 46]. Armodafinil significantly reduced fatigue, a result similar to findings from the individual studies [26, 27]. Armodafinil reduced global fatigue from a baseline value of 4.8 to a final visit value of 3.6. Similarly, worst fatigue in the past 24 h was reduced from a baseline of 7.2 to 5.8 at final visit. These findings indicate that armodafinil significantly reduced the severity of global fatigue and worst fatigue in the past 24 h to the mild-to-moderate range of fatigue (BFI score less than 7 [37]).
This pooled analysis shows that armodafinil does not adversely affect nighttime sleep in patients with OSA even with its longer-lasting duration of action compared with modafinil on a milligram-to-milligram basis [24]. Armodafinil was well tolerated; in general, adverse events were rated as mild to moderate in nature, although some patients discontinued because of adverse events. There were some minor changes in vital signs; however, these effects were not considered to be clinically significant. The patient population selected for both studies was verified to be adherent to nCPAP therapy; thus, the primary pathology of OSA was being treated in an appropriate and effective manner throughout the course of the two studies. At the final visit, the duration of nCPAP use had decreased minimally from baseline compared with placebo. Average nCPAP use remained high (approximately 7 h/night) and was effective (i.e., low AHI values). Adjunct armodafinil treatment did not affect arousals.
Findings from the present pooled analysis are limited to patients with OSA who have residual ES despite regular and effective nCPAP therapy and should not be generalized to patients with OSA who are not receiving adequate nCPAP therapy or are not using it regularly. Additionally, the 12-week duration of treatment in these studies limits the applicability of observed results to a longer period of treatment. It should be recognized that armodafinil does not treat the underlying airway obstruction and should not be considered a replacement for nCPAP therapy in patients with OSA. Further research is needed to determine the role armodafinil may have in improving cognitive function and whether the significant reduction in fatigue observed in the pooled analysis will contribute toward improved quality of life in this patient population.
In conclusion, pooled data from two 12-week, double-blind, placebo-controlled studies showed that once-daily administration of armodafinil significantly improved wakefulness when used as adjunct therapy in nCPAP-adherent patients with residual ES associated with OSA. The effect on wakefulness with armodafinil was maintained throughout the day. Importantly, adjunctive treatment with armodafinil was associated with significant improvements in long-term memory and patients’ ability to engage in daily activities. Armodafinil significantly reduced fatigue in the studied population and was well tolerated.

armodafinil
wakefulness
sleepiness
fatigue
obstructive sleep apnea syndrome


Paradigm shift in hydrocephalus research in legacy of Dandy’s pioneering work: rationale for third ventriculostomy in communicating hydrocephalus

Objective This study aims to question the generally accepted cerebrospinal fluid (CSF) bulk flow theory suggesting that the CSF is exclusively absorbed by the arachnoid villi and that the cause of hydrocephalus is a CSF absorption deficit. In addition, this study aims to briefly describe the new hydrodynamic concept of hydrocephalus and the rationale for endoscopic third ventriculostomy (ETV) in communicating hydrocephalus.
Introduction
The modern era of hydrocephalus research began with the experimental studies of Dandy and Blackfan [3] in 1914, which, until today constitutes an unsurpassed contribution to this field. By plugging the aqueduct, they produced hydrocephalus in dogs. The division of hydrocephalus into the obstructive and communicating type originates from their work. The bulk flow theory and the concept of cerebrospinal fluid (CSF) malabsorption as the cause of hydrocephalus are also based on their experiment [3]. However, Dandy strongly opposed the view that idiopathic communicating hydrocephalus is caused by an obstruction at the arachnoid villi. Such an obstruction cannot cause a higher pressure in the ventricles than in the subarachnoid space but would rather dilate the subarachnoid space. He also objected to the view that the CSF is absorbed by the arachnoid villi and instead proved that the CSF is absorbed by the capillaries [3, 4]. If this is true, the modern era of CSF and hydrocephalus research started and ended with Dandy, who left the pathophysiology of idiopathic communicating hydrocephalus unexplained for future exploration.
By going back to Dandy and following his lead of a capillary CSF absorption, a new understanding of hydrocephalus may be found. O’Connel [19] and Bering [1] suggested that increased pulse pressure in the ventricles is the cause of communicating hydrocephalus. In 1978, Di Rocco and Pettorossi [5] verified that an intraventricular pulsating balloon causes communicating hydrocephalus in sheep. In 1993, Greitz re-valuated the physiology of the CSF circulation and hydrocephalus by using flow sensitive magnetic resonance imaging (MRI) and radionuclide cisternography [9]. He suggested that the capillaries absorb the CSF and that the distending force in the production of chronic hydrocephalus is an increased systolic pulse pressure in brain tissue [14].
The hydrodynamic concept of hydrocephalus
Classification of hydrocephalus The classification is based on capillary absorption of the CSF [9–14]. Hydrocephalus is divided into two main groups, acute hydrocephalus and chronic hydrocephalus [14]. Acute hydrocephalus is caused by an intraventricular CSF obstruction in accordance with the conventional view. As opposed to that view, it is suggested that chronic hydrocephalus is caused by decreased intracranial compliance.
Causes of decreased intracranial compliance Although the etiology of the decreased intracranial compliance such as CSF obstructions at the foramen magnum and adhesions in the subarachnoid space after intracranial bleedings, trauma, operations and infections is well known, the etiology remains unknown in many idiopathic and congenital cases of hydrocephalus. However, the final stage of chronic hydrocephalus, independent of its etiology, is uniform. The final stage is characterised by narrow capacitance vessels and reduced cerebral blood volume. This reduces cerebral blood flow, reduces intracranial compliance and enhances the intracerebral pulse pressure.
Intracerebral pulse pressure theory of chronic hydrocephalus Chronic hydrocephalus consists of two subtypes, communicating hydrocephalus and chronic obstructive hydrocephalus [14]. The associated malabsorption of CSF is not involved as a causative factor in chronic hydrocephalus. The theory is based on one basic mechanism, i.e. that chronic hydrocephalus is caused by decreased intracranial compliance increasing the systolic pressure transmission into the brain parenchyma [9, 10, 12–14]. The increased systolic pressure in the brain is the cause of the distension of the brain and ventricles. The systolic expansion of the brain distends the brain towards the skull and simultaneously compresses the periventricular region of the brain. The rationale result is the predominant enlargement of the ventricles and a narrowing of the subarachnoid space.
Rationale for ETV in communicating hydrocephalus As described above, communicating hydrocephalus is caused by decreased compliance increasing the systolic pressure transmission into the brain. The systolic force compresses the brain including the intracranial capacitance vessels, i.e. the cerebral veins and capillaries. This results in a vicious cycle with narrow capacitance vessels and significantly reduced cerebral blood volume that causes further decrease in intracranial compliance and further increase in intra-cranial pulse pressure. It is obvious that an endoscopic third ventriculostomy (ETV) may interrupt the vicious cycle and reduce the systolic pressure in the brain simply by venting ventricular CSF through the stoma. The patent aqueduct in communicating hydrocephalus is too narrow to vent the ventricular CSF sufficiently. By reducing the pulse pressure, the ETV also reduces the compression of the capacitance vessels thereby restoring some degree of venous compliance, which in turn reduces the intracerebral pulse pressure further.
ETV versus shunting The proposed concept opens a new avenue in that ETV may be an effective treatment also in communicating hydrocephalus [8, 16–18]. It thus constitutes an interchangeable alternative to shunting. The primary aim of the treatment of chronic hydrocephalus is to restore intracranial compliance, which is achieved by both treatments [14]. Effective shunting is based on a slight over-drainage of CSF that ultimately causes a direct and forced dilation of the compressed veins [14]. Therefore, shunting is more effective in increasing intracranial compliance than ETV where the dilating effect on the veins works indirectly by reducing the systolic compressing force on the veins. Because ETV provides a more physiological treatment and has less late complications than shunting, it may be of benefit to increase the number of patients finally treated by ETV [2, 6–8, 15, 17, 18, 20]. In patients shunted under 1 year of age, ETV should be considered as an alternative treatment when they grow older. However, the final answer as to which is the optimal treatment must be based on randomized clinical studies.
Discussion
The aim of this paper is to briefly describe the hydrodynamic concept of hydrocephalus, which is based on Dandy’s observation of capillary absorption of the CSF. Oi and Di Rocco [20] recently suggested that a minor CSF pathway through the brain parenchyma is the dominant CSF absorption site in the embryo, foetus and infant. The theory described here suggests that the minor pathway in the developing immature brain as well as the major pathway in adults are through the brain capillaries. It is beyond the scope of this brief communication to present the numerous physiological (and self-evident) evidences that the brain capillaries have the capacity to absorb fluids such as the CSF and its constituencies [3, 4, 9, 11, 12, 14]. This contrasts to the total lack of physiological evidence that the arachnoid villi can absorb the CSF. The CSF dynamics has been described in earlier published papers [9, 11, 12, 14].
The proposed concept indicates a paradigm shift in our view on hydrocephalus. It is suggested that chronic hydrocephalus is caused by decreased intracranial compliance rather than a CSF absorption deficit [14]. The associated CSF malabsorption is a secondary phenomenon to the decreased intracranial compliance. The only residue of the conventional view is acute hydrocephalus, which is caused by a CSF absorption deficit (of the periventricular capillaries). Normal-pressure hydrocephalus, aqueductal stenosis as well as communicating hydrocephalus in infants and adults are typical manifestations within the spectrum of chronic hydrocephalus. It should be emphasised that chronic hydrocephalus is an unstable hemodynamic disorder occurring at normal or slightly increased mean intracranial pressure with superimposed vascular pressure waves that can be fatal.
The theory may thus have identified decreased intra-cranial compliance as a new and potential universal cause of chronic hydrocephalus. Decreased compliance is common to all different types of chronic hydrocephalus whatever their etiology. If the theory is correct, there is hope for improved treatment of chronic hydrocephalus of unknown etiology. How come then that treatment failure rather is the rule than the exception of this devastating condition? The reason may be that shunting and ETV essentially represents symptomatic treatments of hydrocephalus. To improve therapy, we have to find treatments that are more effective in increasing compliance in cases with unknown etiology or are directed against the cause of the decreased compliance in cases with known etiology.

hydrocephalus
cerebrospinal fluid
etv
pathophysiology
pulse pressure
compliance
normal-pressure hydrocephalus


BioMagResBank (BMRB) as a partner in the Worldwide Protein Data Bank (wwPDB): new policies affecting biomolecular NMR depositions

We describe the role of the BioMagResBank (BMRB) within the Worldwide Protein Data Bank (wwPDB) and recent policies affecting the deposition of biomolecular NMR data. All PDB depositions of structures based on NMR data must now be accompanied by experimental restraints. A scheme has been devised that allows depositors to specify a representative structure and to define residues within that structure found experimentally to be largely unstructured. The BMRB now accepts coordinate sets representing three-dimensional structural models based on experimental NMR data of molecules of biological interest that fall outside the guidelines of the Protein Data Bank (i.e., the molecule is a peptide with 23 or fewer residues, a polynucleotide with 3 or fewer residues, a polysaccharide with 3 or fewer sugar residues, or a natural product), provided that the coordinates are accompanied by representation of the covalent structure of the molecule (atom connectivity), assigned NMR chemical shifts, and the structural restraints used in generating model. The BMRB now contains an archive of NMR data for metabolites and other small molecules found in biological systems.
Organization. The BioMagResBank (BMRB, http://www.bmrb.wisc.edu/), the repository for experimental and derived data gathered from NMR spectroscopic studies of biological molecules (Ulrich et al. 2008), has been a member of the Worldwide Protein Data Bank (wwPDB, http://www.wwpdb.org/) since 2006 (Berman et al. 2003). Other wwPDB partners include the Research Collaboratory for Structural Biology (RCSB PDB, http://www.pdb.org/), the Protein Data Bank Japan (PDBj, http://www.pdbj.org/), and the Macromolecular Structure Database at the European Bioinformatics Institute (MSD EBI, http://www.ebi.ac.uk/msd/). These four groups work closely together with the goal of maintaining a single Protein Data Bank archive of macromolecular structural data that is freely and publicly available to the global community.
The wwPDB Advisory Committee (wwPDBAC), which provides oversight and advice, meets yearly and currently is chaired by Stephen K. Burley. This committee consists of the leaders of the four sites plus two scientists nominated by each of the four partner sites. Additional ex officio members include scientists representing various stakeholder communities (e.g., International Union of Crystallography, International Council on Magnetic Resonance in Biological Systems, electron microscopy, structural genomics) and representatives of the international funding agencies that support the wwPDB member sites.
On matters pertaining to NMR spectroscopy, the wwPDB is advised by members of the wwPDB NMR Task Force (NMR TF), which is chaired by Robert Kaptein (a wwPDBAC member). Historically, members of this TF have been nominated by the wwPDB leadership. Additional interested persons are welcome to join and participate. The wwPDB NMR TF meets periodically (usually more than once each year) at international NMR conferences.
Data remediation. Together with other wwPDB partners, the BMRB participated in the recently completed remediation of the full PDB archive (Henrick et al. 2008). Among the changes was adoption of uniform atom nomenclature in accordance with longstanding IUPAC recommendations (Markley et al. 1998). BMRB’s major contribution to the remediation was to parse and organize restraints for NMR structures into the NMR Restraints Grid (http://tang.bmrb.wisc.edu:8080/WebModule/MRGridServlet) (Doreleijers et al. 2005).
Requirement for structure factors and constraints. Over the past 2 years, the wwPDB organization, in consultation with other members of the crystallographic and NMR communities, reviewed policies concerning data deposition. These deliberations led to the decision, supported by the wwPDBAC and wwPDB NMR TF at their most recent meetings, that all PDB depositions must be accompanied by structure factors (for X-ray structures) and restraints (for NMR structures). These requirements, listed below, were formally announced on November 30, 2007, and are scheduled to go into effect on February 1, 2008.The wwPDB shall require deposition of structure factor amplitudes/intensities (for crystal structure depositions) and/or NMR restraints (for NMR structure depositions) in addition to atomic coordinates as a prerequisite for receiving a PDB ID.The wwPDB leadership shall inform the relevant journals of this new policy, and will suggest that Instructions to the Authors read as follows:“For papers describing structures of biological macromolecules, atomic coordinates and the associated experimental data (structure factor amplitudes/intensities and/or NMR restraints) must be deposited at a member site of the Worldwide Protein Data Bank (www.wwpdb.org): RCSB PDB (www.pdb.org), MSD-EBI (www.ebi.ac.uk/msd), PDBj (www.pdbj.org), or BMRB (www.bmrb.wisc.edu). The PDB ID should be included in the manuscript. Authors must agree to release the atomic coordinates and deposited experimental data when the associated article is published. Questions relating to depositions should be sent to info@wwpdb.org.”
Chemical shift depositions remain optional. These bodies also considered a proposal by members of the community that NMR structure depositions be accompanied by a BMRB deposition of assigned chemical shifts. Although it was decided that this requirement should not be made mandatory at present, the wwPDB NMR TF strongly recommend that these valuable data be deposited.
Small molecule NMR structures. At its 2006 meeting, the wwPDBAC discussed the question of small molecule NMR structures that do not comply with PDB guidelines. X-ray structures of such compounds are commonly deposited in the Cambridge Structural Database (CSD, http://www.ccdc.cam.ac.uk/products/csd/), but no such archive is available for NMR structures. Subsequently, the wwPDBAC approached BMRB with a request that it consider supporting this effort. BMRB developed the following proposal, which was brought before its External Advisory Board in May 2007.
BMRB will consider accepting coordinate sets representing three-dimensional structural models provided that the following criteria are met:The molecule falls outside the guidelines of the Protein Data Bank (i.e., the molecule is a peptide with 23 or fewer residues, a polynucleotide with 3 or fewer residues, a polysaccharide with 3 or fewer sugar residues, or a natural product)The molecule is of biological interestThe structural model(s) are based on experimental NMR dataThe coordinates are accompanied by:
A representation of the covalent structure of the molecule (atom connectivity)Assigned NMR chemical shifts for the moleculeStructural restraints used in generating the structural model
For depositions meeting these criteria, BMRB encourages that authors submit their primary (time-domain) data, tables of NOEs, and other relevant information
This policy was announced at the most recent meetings of the wwPDBAC and wwPDB NMR TF.
Small molecule NMR structures meeting the above criteria can be deposited at the SMSDep website developed by BMRB and PDBj-BMRB (http://smsdep.bmrb.wisc.edu/bmrb-adit/). With small molecule structure depositions, the BMRB accession code serves to identify the structure as well as the supporting NMR data (questions about small molecule NMR structure depositions should be addressed to bmrbhelp@bmrb.wisc.edu).
Depositor defined regions of local disorder in structures. At the request of the wwPDB NMR TF, BMRB created tags, enumerations, and formal PDBx dictionary (Westbrook et al. 2005) entries for the following purposes: To separately specify the single structural model chosen by the authors to best represent the solution structure and to describe how it was derived.To describe uncertainty in the structural model (on a per-residue basis) and to denote residues found experimentally to be largely unstructured.To describe uncertainty in the structural model (on a per-atom basis) both qualitatively and quantitatively depending on the available data.
A detailed draft was refined by RCSB PDB and circulated to the wwPDB NMR TF. These specifications make it possible for an author to clearly define those regions that are experimentally determined to be structured and those that are not. This information will be available in the mmCIF version of the PDB entry and can be used by software developers in displaying structures.
Metabolomics data at BMRB. In collaboration with the Madison Metabolomics Consortium and the Human Metabolome Database (HMDB, http://www.hmdb.ca/), BMRB has developed an archive of NMR data for metabolites and other small molecules found in biological systems (Ulrich et al. 2008). A metabolomics deposition tool under construction at BMRB will enable others to submit data to add to this collection. Compounds are cross-referenced to PDB ligands, and the spectral information should be of interest to scientists studying macromolecule:ligand complexes. The site is mirrored by PDBj and CERM in Florence, Italy.

structural restraints
nmr structure
metabolomics
archived nmr data
unstructured regions


Preoperative Chemoradiotherapy with Capecitabine and Oxaliplatin in Locally Advanced Rectal Cancer. A Phase I–II Multicenter Study of the Dutch Colorectal Cancer Group

Background We studied the maximum tolerated dose (MTD) and efficacy of oxaliplatin added to capecitabine and radiotherapy (Capox-RT) as neoadjuvant therapy for rectal cancer.
Colorectal cancer is a major public health problem in the Western world and ranks as the third leading cause of death in both males and females. In 2000, more than 9000 new colorectal cancer patients were registered in the Netherlands, of whom 25% had rectal cancer.1 Surgical resection is the only curative treatment. However, following potentially curative resection, local recurrence rate varies between 5 and 40%.2–4 Total mesorectal excision (TME) is now the standard technique for primary resectable rectal cancer and has significantly improved local control.4–6 The cornerstone of the TME technique is the complete removal of the rectum and mesorectum to realize free circumferential resection margins. Adam showed in 1994 that the incidence of local recurrence 5 years after resection will rise from 10–78% in case of circumferential margin (CRM) involvement.7 So downstaging before the TME procedure may decrease the incidence of CRM involvement and local recurrence. In the Dutch TME trial, no tumor downstaging was detected in the week after 5 × 5 Gy.8 A recent Polish trial demonstrated that a radiotherapy schedule of 50.4 Gy combined with chemotherapy (5-FU/Leucovorin) followed after 4–6 weeks by surgery resulted in a significant higher percentage of downstaging compared with short-term preoperative radiotherapy of 5 × 5 Gy followed by surgery within 7 days.9 So downstaging is dependent on both the total radiotherapy dose and the interval between the end of the radiotherapy and the surgery. In general, to achieve downstaging this interval needs to be at least 6 weeks and the dose needs to be at least 45 Gy.9 Although the obtained downstaging after neoadjuvant radiochemotherapy did result in a favorable prognosis,10 it was not clear until recently whether the addition of chemotherapy to preoperative radiotherapy could increase the amount of downstaging and thus improve local control. The evidence that the addition of chemotherapy to preoperative radiotherapy improves local control rates has recently been shown by two separate trials. The EORTC 22921 trial has a two by two factorial design and randomized between preoperative radiotherapy (45 Gy) versus preoperative chemoradiotherapy (45 Gy combined with 5-FU/Leucovorin). The results demonstrated an increased local control rate for the chemoradiation arm: 91% versus 83%.11,12 A similar result was found in the French FFCD 9203 study, which randomized between preoperative radiotherapy (45 Gy) and preoperative chemoradiotherapy (45 Gy and 5-FU/Leucovorin) and which showed local recurrence rates of 16.5% and 8%, respectively.13 Based on these studies, prolonged preoperative chemoradiation is considered the standard treatment for resectable locally advanced rectal cancers. The EORTC study and the French study employed 5FU bolus injection modulated with leucovorin. However 5FU administered by continuous infusion or orally (capecitabine/ UFT) may be more effective and less toxic than 5FU administered by bolus injection.14–16 In parallel, the results of palliative chemotherapy in advanced colorectal cancer have been substantially improved by the combination of 5FU with oxaliplatin or irinotecan (reviewed by Punt17). Both in vivo and in vitro, oxaliplatin has been shown to have at least an additive interaction with radiotherapy in the management of digestive tract tumors.18–20 Incorporation of those drugs in combined treatment strategies could substantially improve the results obtained with bolus 5FU alone in downstaging and R0 resection rates in patients with locally advanced rectal cancer.
We investigated the combination of capecitabine and oxaliplatin given concomitantly with radiotherapy in patients with locally advanced rectal cancer. The optimal dose of oxaliplatin was first established in a phase I study, and in the following phase II study the efficacy of this regimen was tested.
PATIENTS AND METHODS
Objectives
The objective of the phase I study was to determine the maximum tolerated dose (MTD) of oxaliplatin in combination with a fixed dose of capecitabine and radiotherapy, and the objective of the phase II study was to determine the R0 resection rate and pathological complete response rate (pCR).
Eligibility Criteria
Eligibility criteria included histologically documented adenocarcinoma of the rectum within 15 cm from the anal sphincter, locally advanced stage T3 (distance to the endopelvic fascia < 2 mm) or T4 tumors based on computed tomography (CT) or magnetic resonance imaging (MRI) findings, performance status (Eastern Cooperative Oncology Group) 0–2, age >18 years old, adequate hematological, liver function, and other laboratory parameters (white blood cells 3.0 × 109/L, platelets >100 × 109/L, creatinin clearance > 50 mL/min, bilirubin < 1.5 times the upper limit of the normal range (ULN), and written informed consent. Patients with reproductive potential should use adequate contraceptive measures. Patients were excluded in case of prior chemotherapy and/or pelvic radiotherapy, acute bowel obstruction without colostomy, uncontrolled ischemic heart disease, peripheral neuropathy, or any uncontrolled serious systemic disease. The protocol was approved by the local ethics committees of all four participating hospitals. The study was performed within the framework of the Dutch Colorectal Cancer Group (DCCG).
TREATMENT
Radiotherapy
All patients received radiation delivered by an isocentric three- or four-field technique, using a linear accelerator of at least 10 MV. The patients were treated in either supine or prone position with a full bladder. The radiation field extended superiorly to the L5/S1 junction and covered inferiorly the obturator foramina. The minimal inferior border extended 4–5 cm below the tumor. In case the tumor was located in the lower third of the rectum, the perineum was encompassed in the treatment field. The width of the AP-PA portals had to cover the lateral pelvic inlet with a margin of 1.5 cm. The entire sacrum was included with a dorsal margin of 1.5 cm. Anteriorly, the lateral fields had to encompass the tumor as determined by barium enema (optional) and pelvic CT scan. If there was clinical evidence of involvement of the bladder, the prostate, the cervix or the uterine body, not only the internal iliac nodes but also the external iliac nodes were included in the radiation field. Computerized dosimetry was routinely performed. Irradiation was delivered 5 days per week at a dose of 1.8 Gy/day to a total dose of 45 Gy with a boost to the tumor in 3 fractions of 1.8 Gy to a total of 50.4 Gy.
Chemotherapy
Capecitabine was administered orally twice daily at 1000 mg/ m2 on days 1–14 and 25–38.
Oxaliplatin was given twice by intravenous infusion over 2 h, on the first day of radiotherapy and on day 29. Oxaliplatin doses were planned at 85, 100, and 135 mg/m2. Each dose level was to be administered to at least three patients. If a dose-limiting toxicity (DLT) was observed in ≥1 patient, a total of 6 patients had to be treated at that dose level. The maximum-tolerated dose (MTD) was defined as the level at which ≤2 out of 6 patients experienced DLTs without compromizing radiotherapy and surgery and was the recommended dose in the phase II study.
Surgery
Surgical resection was performed 6–8 weeks after completion of the chemoradiation therapy. The resection was performed according to the principles of total mesorectal excision as described by Heald2 and Enker.21 These principles include sharp dissection under direct vision following the lipoma-like surface of the mesorectum. Proximal transection of the inferior mesenteric artery was in general performed distal to the collateral between the left colic artery and branches of the sigmoid artery. Anterior dissection in male patients was carried out in front of Denonvilliers’ fascia. If tumor extended into the prostate a total exenteration was performed. In female patients, resection of the posterior vaginal wall was performed if necessary. A distal mesorectal margin of 2 cm was considered adequate if bowel continuity was to be restored.
Pathology
Pathology evaluation was standardized according to national guideliness. The CRM was assessed according to the method of Quirke et al.,7 and a margin of <1 mm from the primary tumor to the endopelvic fascia is considered positive.
Statistics
Twenty patients were to be included at the MTD to detect with a power of 80% a R0 resectability rate of >80% (with a 95% CI of 56–94%).
Monitoring and Management During Treatment
Physical examination and evaluation of toxicity was performed weekly. Complete blood count, electrolytes, creatinine, and total protein were determined weekly. Standard antiemetic prophylaxis with 5HT3 antagonist prior to oxaliplatin infusion was used. Adverse events were classified according to the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Version 2.0. Global quality of life (QOL) assessment was evaluated weekly during the chemoradiotherapy using a visual analogue scale (VASQOL) in which in a single 10 cm line anchored on the left with “worst” and on the right with “best” for QOL.22 Dose-limiting toxicities were defined as white blood cell (WBC) and platelets < 3.0 and < 100 × 109/L, respectively, before start of the next treatment cycle with oxaliplatin after a maximum delay of one week; diarrhea grade > 2; oral mucositis grade >1; skin toxicity grade > 2 before start of next treatment cycle with capecitabine, despite a delay of dosing for 1 week; neurosensory toxicity grade > 2 despite a delay in dosing for 1 week; occurrence of any grade 4 toxicity; and any event that would compromise the administration of radiotherapy.
RESULTS
Patients Characteristics
Between June 2003 and December 2004, 22 patients with T3/T4 rectal cancer from four different centers were enrolled in the study. Patient characteristics are shown in Table 1. All patients were evaluable for toxicity during chemoradiation. One patient was lost to follow-up after chemoradiation (surgery was performed abroad). Therefore, 21 patients were evaluable for clinical outcome after surgery. Twenty patients (91%) received the planned dose of chemotherapy. All patients received the planned dose of radiotherapy. The median follow-up was 14 months.
TABLE 1.Patient characteristics (n = 22)CharacteristicsNo.Median age (years)58Range (years)45–70Men/Women12/10Performance status  03  119Distance of tumor to anal verge (cm)  0–511  5–107  10–153  Unknown1T status  T3a17  T4b5a T3 beyond the fascia recti.b T4: into pelvic organs (1 ureter, 2 vagina, 2 prostate)
Toxicity
At the first oxaliplatin dose level of 85 mg/m2, one patient experienced DLT (hospitalization for grade 3 nausea and grade 2 diarrhea). This dose level was then expanded to six patients, and DLT was observed in another patient (hospitalization for grade 3 diarrhea). Therefore, a dose of 85 mg/m2 oxaliplatin was considered the MTD. In the additional 16 patients, two more patients experienced grade 3 diarrhea. Hand-foot syndrome, myelosuppression, and neurotoxicity were observed only in a minority of patients and were of mild severity. The grade 3/4 toxicity data are shown in Table 2.
TABLE 2.Toxicity in the study population (n = 22)StudyPhase IPhase IIDose oxaliplatin (number of patients)85 mg/m2 (3)85 mg/m2 (3)(22)Toxicity grade (NCI CTCV2.0)Toxicity grade (NCI CTCV2.0)Toxicity grade (NCI CTCV2.0)343434Leukopenia––––––Neutropenia––––––Thrombopenia––––––Anemia––––––Diarrhea––1–4–Abdominal pain––––––Nausea1–––––Mucositis––––––Neurotoxicity––––––
Surgery
TME surgery was performed after a median of 47 days (range 4–8 weeks range in days) following the completion of chemoradiation. Mean hospitalization time was 14 days (range 9–95; 70% < 21 days). The main surgical complications were: major bleeding (1), rectal perforation (1), ureter lesion (1). Postsurgery treatment related complications were seen in 12 patients with mild wound infections (6), wound dehiscences (2), (sub)ileus (4), rhabdomyolysis (1), and in one patient a life-threatening multiorgan failure after a perforation in an abcess located near the anus praeter. Rhabdomyolysis is an unusual complication. In this patient it was probably caused by the operation procedure and not by this specific procedure as there were no other postoperative complications. Three patients (15%) needed reoperation for perforation (1) and pelvic abscesses (2). The 60-day mortality rate was nil.
Efficacy
Twenty-one patients with a T3–T4 tumor based on CT or MRI underwent surgery with 10 abdominoperineal resections (APRs) and 10 low anterior resections (LARs); in one patient the tumor was not resectable. A R0 resection was achieved in 17 patients (81%, 95% CI 58–95%). A pCR was observed in 2 patients (10%, 95% CI 1–30%), and in one patient (5%) the surgical specimen only showed minimal microscopic disease. The postradiotherapeutic pathologic staging yielded in seven patients (33%; 95% CI 15–57%) a downstaging to pT0–T2. After a median follow-up of 14 months, four patients have died due to metastatic disease and one patient has experienced a local recurrence.
Quality of Life
The VASQOL score was measured weekly during chemoradiotherapy. The QOL decreased after 4 weeks treatment from 80% in week 4 to 60% in week 6 (p < .002, student-t test).
DISCUSSION
Based on the EORTC 22921 and FFCD 9203 phase III studies,11,13,23 preoperative chemoradiation with 5FU and 45 Gy or higher is now considered to be the standard of care for locally advanced rectal cancer. In these studies, 5FU was given as a daily bolus infusion in week 1 and 5. To improve on these results, we tested the feasibility and efficacy of the addition of oxaliplatin to capecitabine in this combined treatment strategy. Our recommended dose for the phase II study was oxaliplatin 85 mg/m2 on day 1 and 29 plus capecitabine 1000 mg/m2 twice daily during 14 days starting on day 1 and 25 in combination with radiotherapy at a total dose of 50.4 Gy. In our phase I/II study, we found grade III diarrhea in 19%, a R0 resection in 81%, downstaging to T0–2 in 33%, and a pCR in 10% of patients. Table 3 summarizes the studies with the addition of oxaliplatin to a fluoropyrimidine (IV or orally) and radiotherapy. These studies show a toxicity and efficacy profile comparable to the results from our study.
TABLE 3.Locally advanced rectal cancer, recent neoadjuvant studies with fluoropyrimidines and oxaliplatin in combination with radiotherapyStudyDesign (phase)StageNEBRT (Gy)CTR0 (%)pCR (%)Toxicity grade 3–4 (%)TotalDiarrheaMyelotoxicPreoperative radiotherapy vs. chemoradiotherapy (with 5 FU)EORTC 2292111,23IIIT3/T4 101145––538a17–1–455FU pre–1454–34–9–FFCD 920313IIIT3/T476245–9043––455FU pre911215––Bujko9IIIT3/T43165 × 5–8713––50.45FU pre961718––Preoperative CRT with capecitabineKim30IIT3/T4/N+4550.4 Cap 3–31174–Dunst31/Glynne- Jones32IIT3/T4/N+9850.4 + 5.4Cap 1–422410Chau33IIT3+, low T3, N27754Cap 1b99244 deathsYerushalmi16IIT3/T4 (T2 10%)4650.4 5FU vs Cap 2–17443–302Preoperative CRT with 5 FU based chemotherapy and oxaliplatinGambacorta34IIT33050Tomox–3013310Gerard26IIT2/T3/T44050.4FU + Ox 1–151853Rodel35IIT3–43250.4Capox 479191680Carraro36IIT3/T42250.4FU + Ox 2–14–2714Aschele25I/IIT3/T4/N+2550.4FU + Ox 3892824164Glynne-Jones32I/IIUnresectable9445Capox 278281310–Machiels24IIT3/T4/N+4045Capox 18314–30–Hospers (2006) This studyI/IIT3/T42250.4Capox8110–18–Cap 1: 825 mg/m22× daily, 7 daysCapox 1: Cap 825 2× daily, Monday–Friday, oxali 50 weeklyTomox: raltitrexed 3, oxali 130, day 1, 19, 38Cap 2: 825 mg/m2 2× daily, Monday–FridayCapox 2: Cap 650 2× daily, 7 days, oxali 130 per 2 weeksFU + Ox 1: 5FU 350 daily, Oxali 130 weekly, week 1 and 5Cap 3: 825 mg/m2 2× daily,14 days (2×)Capox 3: Cap 825 2× daily, 7 days, oxali 60 per 2 weeksFU + Ox 2: 5FU 375/4 days, Oxali 25/4 days, week 1 and 5Capox 4: Cap 825 2× daily, 2 × 14 days, oxali 50, day 1, 8, 22, 29FU + Ox 3: 5FU 225 daily, Oxali 60 weeklya ≥Grade 2 toxicity.b 12 weeks neoadjuvant CAPO.
Diarrhea generally occurred during the last 2 weeks of chemoradiation, which was accompanied by a significant decrease in QOL. As shown in Table 2, the addition of oxaliplatin increases the incidence of toxicities when compared with the use of 5FU alone. The observed postsurgical morbidity (mild wound infections excluded), the reoperations and the median hospitalization time in our study were 30%, 15%, and 14 days, respectively, and are comparable with other studies.24–26
We found a similar efficacy in pCR and R0 compared to other studies (Table 3). However, comparing the efficacy of these regimes is hampered by a number of technicalities. These comprise differences in 1) staging techniques, 2) the determination of distance of the tumor to the endopelvic fascia, 3) pathology techniques, and 4) the difference in interval between neoadjuvant treatment and surgery. The staging techniques used to define the locally advanced stage of the primary tumor and lymph nodes are clinical examination, CT, MRI, endoultrasound or combinations, the use of ultrasmall particles of iron oxide (USPIOs).27 These different staging techniques may lead to variabilities in pretreatment staging and therefore compromise the quantitation of downstaging. Moreover, the tumor might be still visible on posttreatment imaging, but it may have become nonvital. The distance of the tumor to the endopelvic fascia will influence the local recurrence rate. The determination of a pCR and an R0 resection depends on the sophistication of the pathology techniques used, and the definition of a R0 resection (distance tumor to resection or to CRM) is not uniform. In the various clinical protocols, the time interval between chemoradiotherapy and surgery is not standardized, which may influence the degree of downstaging but also the ultimate results of local cure. Therefore, cross-study comparison should be interpreted with caution. The end points used in this study are known to have a different impact on clinical outcome: a pCR is associated with a low local recurrence rate, and prolonged DFS and is not significantly related to the cT and cN categories.28 R0 resection is known to be a highly relevant prognostic factor.29 Comparing our results on pCR and R0 to other oxaliplatin-containing studies, we found similar results; however, these were also observed using monotherapy with 5FU or capecitabine (Table 2). Therefore, it is yet unknown whether the increased toxicity of adding oxaliplatin to a fluoropyrimidine in neoadjuvant chemoradiation schedules results in a clinical benefit for patients with rectal cancer.
In conclusion, this multicenter study demonstrated a neoadjuvant regimen with Capox-RT with an acceptable acute toxicity profile. Randomized phase III studies with in the standard arm 5FU will be necessary to show the true benefit of this approach. In such prospective studies, the standardization of the staging technique (i.e., the distance of the tumor to the endopelvic fascia), TME surgery, radiotherapy, and pathology should minimize the influence of these factors on the outcome.

chemoradiation
radiotherapy
capecitabine
oxaliplatin
rectal cancer
phase i–ii study


Reduced brain perfusion and cognitive performance due to constitutional hypotension

This review article includes a systematic evaluation of the empirical data concerning deficits in mental ability, brain perfusion, and cerebral functioning due to chronically low blood pressure. A number of studies have provided strong evidence for reduced cognitive performance in hypotension, particularly in the domains of attention and memory. EEG studies have demonstrated that the hypotension-related poorer mental ability is also reflected in diminished cortical activity. Contrary to convention, more recent research has suggested a deficient regulation of cerebral blood flow in persons with low blood pressure. In addition to reduced tonic brain perfusion, studies demonstrated insufficient adjustment of blood flow to cognitive requirements. Altogether, these findings suggest that more attention should be allocated to chronic hypotension in both research and clinical practice.
Introduction
Chronically low blood pressure is accompanied by a variety of complaints including fatigue, reduced drive, faintness, dizziness, headaches, palpitations, and increased pain sensitivity [1–4]. In addition, hypotensive individuals report cognitive impairment, above all deficits in attention and memory. Nevertheless, it is generally the case that in research, as well as in clinical practice, relatively little importance is ascribed to hypotension. One reason for this is that, despite mental symptoms, cerebral dysfunction generally is not taken into account [1]. This is a consequence of the current doctrine that low systemic blood pressure is compensated by autoregulatory processes which prevent reduced blood perfusion of the brain [5, 6].
Some recent findings challenge this doctrine: reduced cognitive performance in hypotension has been demonstrated by neuropsychological testing, and EEG studies have revealed diminished cortical activity. Moreover, the assumption of unimpaired brain perfusion in hypotension no longer holds. In the present review the necessity of a reappraisal concerning hypotension is discussed in light of the relationship between blood pressure and cerebral functioning.
Constitutional hypotension
Hypotension has been defined by the World Health Organization (WHO) [4] as a low blood pressure with a systolic reading below 110 mmHg in males and below 100 mmHg in females, regardless of diastolic blood pressure. The concept of constitutional hypotension refers to a chronic condition of inappropriately reduced blood pressure independent of the presence of further pathological factors. Both secondary hypotension (e.g. due to blood loss or medication) and orthostatic hypotension (caused by circulatory problems when assuming an upright position) are distinguished from the constitutional form [1, 6].
Constitutional hypotension is relatively widespread in the general population. In a representative German sample of more than 7,000 subjects approximately 3% fulfilled the criteria of the WHO [c.f. 1]. In contrast to elevated blood pressure, which constitutes a significant risk factor for cardiovascular disease, hypotension is commonly not regarded as a severe condition. Nevertheless, its impact on personal well-being and quality of life has been shown in several epidemiological studies. For instance, Wessely et al. [7], as well as Pilgrim et al. [3] demonstrated impaired physical and mental health in the case of low blood pressure. Reduced health-related quality of life [8] and a heightened degree of depressiveness [9] were also reported by hypotensive individuals.
Chronic hypotension has been identified as a major risk factor in pregnancy [10]. Moreover, several studies focusing on the elderly population have reported associations between low blood pressure and the prevalence and incidence of Alzheimer’s and vascular dementia [c.f. 11–14]. Whilst a few longitudinal studies examining this relationship have been published [15, 16], the causal role of low blood pressure in degenerative brain disorders has thus far not been proven [e.g. 13].1
Concerning the etiology of hypotension, reduced liquid intake and low body weight may be considered [c.f. 1, 17]. A dysregulation of the autonomous nervous system may additionally be of significance. Various findings on reduced electrodermal activity [18] and increased heart rate variability [19] reflect diminished sympathetic tone and habitually heightened parasympathetic activity in persons with low blood pressure values. This is corroborated by findings on the effects of sympathomimetic drugs [20, 21]. In mixed samples of persons with constitutional and orthostatic hypotension, α and β adrenergic substances were shown to lead to blood pressure elevation accompanied by a reduction of subjective symptoms. A malfunction of the arterial baroreceptor system was postulated as a further etiological factor [22]. Responding to mechanical stretch of the vessel walls, the baroreceptors form part of a negative feedback loop (“baroreflex”) compensating phasic blood pressure fluctuations [23]. Increased sensitivity of the baroreceptor system may result in stabilizing blood pressure at a lower level. In addition to findings in animals [24], this hypothesis is supported by a still unpublished study of our own group which yielded increased baroreflex sensitivity in the case of low blood pressure.
Cognitive deficits in constitutional hypotension
Table 1 presents the most relevant studies devoted to cognitive functioning in hypotension. In addition to the main results, the table includes information concerning the respective samples and assessment instruments.
Table 1Studies on cognitive performance in hypotension (SBP, systolic blood pressure; DBP, diastolic blood pressure)AuthorsMain focusSamplesAssessment instrumentsMain resultsRichter-Heinrich  et al. [18]Attentional performance in  hypotension and hypertension30 hypotensives (SBP < 106 mmHg);  40 hypertensives (SBP > 140 mmHg);  31 normotensive controls; age 16–40 yearsKonzentrations-Verlaufs-Test (course  of concentration test) [25]Reduced attentional performance in the  case of both lowered and elevated  blood pressureStegagno et al. [26]Attentional, memory and  arithmetic performance  in hypotension17 female hypotensives (SBP < 100 mmHg);  19 normotensive controls; mean  age 23 yearsReaction times to acoustic stimuli;  digit span [27]; recall of word  lists [28]; serial subtractionsProlonged reaction times, poorer  performance on the verbal memory  and arithmetic tasks in hypotension,  no effect for digit spanCosta et al. [29]Attentional and memory  performance in hypotension26 female hypotensives (SBP < 105,  DBP < 65 mmHg), 22 normotensive  controls; mean age 29 yearsAufmerksamkeits-Belastungs-Test  (attentional strain test) [30];  Zahlen-Verbindungs-Test (trail making  test) [31]; recall of word lists [28]Poorer attentional and memory  performance on each of the three  tests in hypotensionMorris et al. [32]Relationship between blood  pressure and cognitive  performance in elderly  personsRepresentative population sample covering  the total spectrum of blood pressure  (n = 5,816; age over 64 years)East Boston Memory Test [33]; Symbol  Digit Modalities Test [34]; Mini-Mental  State Examination [35]Weak U-shaped relationship between  blood pressure and cognitive  performanceWeisz et al. [22]Attentional performance in  hypotension25 female hypotensives (mean  SBP = 102 mmHg); 25 normotensive  controls; age 19–44 yearsAttentional and Cognitive  Efficiency Battery [36]Reduced performance on a subtest  assessing cognitive flexibility  in hypotensionDuschek et al. [37]Attentional performance in  moderate hypotension26 borderline hypotensives (mean  SBP = 112 mmHg); 29 normotensive  controls; mean age 26 yearsReaction times to acoustic stimuli;  Aufmerksamkeits-Belastungs-Test (attentional  strain test) [30]; Zahlen-Verbindungs-Test  (trail making test) [31]Prolonged reaction times and poorer  performance on the  “Aufmerksamkeits-Belastungs-Test” in  moderate hypotension, no effects  for the “Zahlen-Verbindungs-Test”Duschek et al. [38]Attentional and working  memory performance in  hypotension with motor  performance and  mood controlled40 hypotensives (SBP < 105 mmHg in  women, SBP < 110 mmHg in men);  40 normotensive controls; age  19–45 yearsTestbatterie zur Aufmerksamkeitsprüfung  (battery for the assessment of attention)  [39]; Motorische Leistungsserie (motor  performance series) [40]; Befindlichkeitsskala  (mood scale) [41]Poorer performance on six tests  assessing tonic and phasic alertness,  selective, divided and sustained  attention as well as working memory  in hypotensives with fine motor  performance and mood controlled
A pioneering study investigating the relationship between blood pressure and cognitive abilities was conducted by Richter-Heinrich et al. [18]. They showed reduced performance of individuals with both lowered and elevated blood pressure on a test of concentration. A more comprehensive assessment was carried out by Stegagno et al. [26], in which poorer performances of hypotensive subjects on a verbal memory test and on an arithmetic task, as well as prolonged reaction times to acoustic stimuli were observed. Costa et al. [29] found reduced scores on two standard German paper–pencil tests assessing selective attention and cognitive speed. Moreover, as in the Stegagno et al. [26] study, impaired verbal memory performance was documented.
Weisz et al. [22] reported that female hypotensive subjects performed significantly worse than controls on a computer-based test measuring attentional flexibility [36]. Subjects with only a moderately decreased blood pressure were assessed by Duschek et al. [37]. In this sample, reduced attentional performance and prolonged reaction times were again found as compared to normotensive controls.
Duschek et al. [38] investigated the relationship between low blood pressure and attentional abilities through the application of a multidimensional diagnostic approach. They presented their subjects with a battery of six computer-based tasks [39] focusing on tonic and phasic alertness, selective, divided and sustained attention, as well as working memory. Additionally, in order to control for possible confounders, a test battery examining fine motor abilities [40] and a mood questionnaire [41] were presented. Reduced performance of hypotensives was evident in each of the six cognitive tests. The significant differences between hypotensive and control subjects persisted even when the effects of motor performance and mood were controlled.
Altogether, the existing data provide strong evidence for cognitive deficits related to constitutional hypotension, especially in the domains of attention and memory. The reduced performance seems to be a direct consequence of low blood pressure rather than an effect of impaired well-being related to this state. Up to now there have been no empirical data concerning specific effects of hypotension-related deficits on everyday life. Nonetheless, these findings raise concern regarding the impact of the deficits on attention-demanding activities (e.g. professional or academic), including public health-related functions (e.g. traffic safety) [42].
It would appear that both extremes of the blood pressure spectrum are accompanied by a decrease in cognitive ability. A number of studies concerned with elevated blood pressure showed reduced performance on various cognitive tests [43, 44]. This is in line with epidemiological studies reporting an inverted U-shaped relationship between blood pressure and cognitive performance in elderly persons [c.f. 11, 13, 32, 45, 46]. Therefore, it may further be hypothesized that there is a relatively small range of normal blood pressure in which the brain exerts its optimal function.
Neuroelectrophysiological correlates of hypotension-related cognitive deficits
Cognitive deficits in low blood pressure states are also reflected in decreased cortical activity. In accordance with earlier results [22, 29], Duschek et al. [47] found the amplitude of the contingent negative variation (CNV) to be reduced in a hypotensive sample defined according to the WHO criteria [4] (c.f. Fig. 1).
Fig. 1The CNV occurs during the period between a warning signal (S1) and a second stimulus (S2) demanding a motor, verbal or cognitive response. As can be seen in the figure, its amplitude was found to be reduced in hypotensive subjects (N = 40) as compared to normotensive controls (N = 40); modified from [47]
The CNV is an evoked potential which is generally viewed as a neuroelectrophysiological correlative of attentional processing [48]. This is supported by pharmacological studies showing that the effects of various stimulant and sedative drugs on attention involve an increase or decrease, respectively, of the CNV amplitude [49, 50]. Moreover, attentional deficits due to brain lesions and psychiatric diseases are associated with a reduced CNV [51, 52]. In the Duschek et al. [47] study, the amplitude of the CNV proved to be negatively correlated with reaction time, which in turn was prolonged in the hypotensive group. This highlights that the CNV constitutes a brain electrical correlate of an aspect of cognitive functioning which is affected in hypotension.
The relationship between blood pressure and cortical activity is also reflected in a negative correlation between blood pressure and α wave activity in the spontaneous EEG [47]. This suggests that low blood pressure is associated with a reduced tonic cortical arousal [53]. On the behavioral level, higher degrees of α activity are known to be associated with generally diminished vigilance and preparedness to react [54].
Considering the physiological processes mediating the relationship between blood pressure and brain function, it must be taken into account that blood pressure can influence cortical activation processes via afferent projections [47, 55–57]. The brain continuously receives information about the state of the cardiovascular system by means of viscero-afferent fibers [23]. These afferent signals enter the brain via brainstem nuclei. From there, ascending pathways continue via hypothalamic and thalamic regions to cortical areas such as the anterior cingulate, the insula and the prefrontal lobe [58]. The latter areas, in particular the prefrontal cortex and the anterior cingulate are of crucial importance in the regulation of cortical arousal, as well as for attentional processes [59, 60]. Thus, these brain structures may represent functional interfaces between cardiovascular activity and attention [42].
Also neurochemical mediators should be regarded in the relationship between blood pressure and cortical activity. Noradrenaline is involved in the control of cortical arousal and attentional processes, as well as in the genesis of the CNV [59, 61]. Catecholamines are also of great influence in the regulation of blood pressure [62]. Bearing this in mind, one could speculate on the neurochemical level about a specific role of noradrenaline linking cardiovascular and cortical activation.
Cerebral blood perfusion in constitutional hypotension
It is generally assumed that in healthy individuals processes of autoregulation keep the cerebral blood flow constant within a wide range of arterial pressure. In order to ensure stable perfusion, cerebral resistance vessels constrict during increases and dilate during reductions in systemic blood pressure [5]. Autoregulation is considered to be a protective mechanism which prevents brain ischemia during blood pressure decrease, and guards against capillary damage and edema formation during periods of elevated blood pressure.
Under normal conditions the limits within which cerebral blood flow is assumed to be constant are approximately between a mean arterial pressure (MAP) of 60 and 150 mmHg [5, 63, 64]. If blood pressure is outside of this range, cerebral blood flow rises or falls with respective increases or decreases in blood pressure. Slight reductions of blood pressure below the lower limit of autoregulation can be compensated by an increase of the extraction coefficient of oxygen from the blood. Further reductions are accompanied by symptoms such as pallor and dizziness and ultimately lead to irreversible brain damage [5].
MAP in individuals with constitutional hypotension usually does not decrease beyond the assumed lower MAP limit of autoregulation (60 mmHg). In light of this, low blood pressure in these subjects should be compensated, and cerebral blood flow should not be affected. This assumption was challenged by Duschek and Schandry [65]. They recorded blood flow velocities by means of transcranial Doppler sonography in both middle cerebral arteries (MCA) in hypotensive individuals, defined according to the WHO [4], and in normotensive control subjects. Contrary to the current doctrine, MCA blood flow at rest was found to be substantially bilaterally reduced in hypotensives (c.f. Fig. 2).
Fig. 2Mean flow velocities in the left and right middle cerebral arteries under resting conditions in hypotensive (N = 40) and control subjects (N = 40); bars represent standard errors [65]
The perfusion territory of the MCA includes subcortical areas, large fractions of the frontal and parietal lobes, as well as the temporal lobes [66]. Thus, the latter finding demonstrated that, despite autoregulation, blood pressure in subjects with constitutional hypotension is not sufficient in maintaining the perfusion of a large part of the brain at the level of normotensive individuals [see also 67].
In explaining this unexpected result, it must be noted that the determination of the lower limit of autoregulation was exclusively based on the experimental manipulation of blood pressure employing pharmacological methods, as well as head up-tilt [68–71]. However, such a transient reduction of blood pressure is most certainly not comparable to conditions of chronic hypotension. Additionally, in all of these studies global cerebral blood flow was assessed by means of the oxygen difference method according to Lennox and Gibbs [72], which may be less sensitive to perfusion changes than Doppler sonography.
Nevertheless, more recent findings suggest values for the lower MAP limit of autoregulation to be considerably higher than 60 mmHg [73–75]. In a critical review of the literature, Drummond [76] postulated an average lower limit of no less than 70 mmHg. Moreover, the limit seems to vary strongly across individuals. Waldemar et al. [77], for instance, reported an inter-individual range between 53 and 103 mmHg. In accordance with Duschek and Schandry’s [65] data, the doctrine of stable cerebral perfusion down to the limit of a MAP of 60 mmHg can no longer be supported by the current state of research.
A further important aspect of cerebral hemodynamics concerns the continuous adjustment of brain perfusion to current requirements. Due to the close coupling of neural activity and brain metabolism, cerebral activation processes are accompanied by changes in cerebral blood flow [78]. Neurovascular coupling is based on the contraction and dilation of small resistance vessels, resulting from the changing metabolic demands of neuron populations in the vicinity [64].
With regards to hypotension-related cognitive deficits, the extent of blood flow adjustment to mental activity was also tested in the Duschek and Schandry [65] study. Subjects were presented with a simple attentional task (motor reactions to visual stimuli cued by acoustic signals). During task execution blood flow velocities in the MCA of both hemispheres were recorded by means of functional transcranial Doppler sonography (for technical details see [66]).
As expected, mental activity was accompanied by a substantial increase of MCA perfusion. In control subjects, however, this increase was approximately 70% stronger than in hypotensives (c.f. Fig. 3). It would seem that blood pressure in the latter group was not sufficient to enable adjustment of brain perfusion to cognitive demands, as seen in normotensives. Moreover, hypotensive participants showed prolonged reaction times, and a positive correlation was found between reaction speed and the extent of blood flow increase. This finding corroborates the significance of hemodynamic adjustment for optimal cognitive functioning.
Fig. 3Changes of blood flow velocities in the left and right MCA during the execution of an attentional task in hypotensives (N = 40) and controls (N = 40). The subjects had to press a key in response to a visual imperative stimulus which was announced by a cuing tone. In both MCA the rise in flow velocity which occurred during the anticipation of the imperative stimulus was substantially less pronounced in hypotensives. A second flow velocity maximum visible after the motor reaction was also slightly reduced in hypotensives [65]
Final comments
There is strong evidence suggesting that chronically low blood pressure is accompanied by diminished cognitive performance, primarily involving attention and memory [26, 29, 38]. Recent research has provided an insight into the psychophysiological mechanisms of action underlying these deficits: EEG studies have demonstrated that the weaker cognitive performance is associated with reduced cortical activity [22, 29, 47]. Furthermore, deficient regulation of cerebral blood flow must be assumed in hypotension. In addition to diminished tonic brain perfusion, reduced adjustment of brain perfusion to cognitive demands was documented [65]. It stands to reason that, as a consequence of this situation, a diminished metabolic supply of the brain tissue accounts for the cognitive deficits.
The cognitive deficits can widely affect the every day life of hypotensive persons, and more attention should therefore be allocated to this topic within basic and clinical research, as well as in clinical practice [1, 17]. This finally leads to the issue of the treatment of hypotension. Empirical knowledge concerning the effectiveness of antihypotensive therapy continues to be scant. A variety of treatment strategies such as physical training, increase of liquid intake and pharmacological measures have been suggested [1]. In two clinical trials the administration of sympathomimetics was found to result in a reduction of subjective hypotensive symptoms [20, 21]. Recent data of our own group suggest that cognitive performance may also be enhanced by pharmacological blood pressure elevation [79]. Based on a placebo controlled design, the vasopressor agent midodrine was shown to raise cerebral blood perfusion as well as performance on a test assessing selective attention [30] in hypotensive subjects, defined according to the WHO [4]. The results of these pioneering studies are promising. Further research would appear worthwhile and should aim to establish precise guidelines which enable chronic hypotension to be efficiently and effectively dealt with in practice.

cognitive
hypotension
blood pressure
cerebral blood flow
autonomic nervous system