Sleep-disordered breathing and coronary artery disease: long-term prognosis.

The evidence linking sleep-disordered breathing to increased mortality and cardiovascular morbidity has been conflicting and inconclusive. We hypothesized that a potential adverse effect of disordered breathing would be more obvious in patients with established vascular disease. In a prospective cohort study 408 patients aged 70 yr or younger with verified coronary disease were followed for a median period of 5.1 yr. An apnea-hypopnea index (AHI) of > or = 10 and an oxygen desaturation index (ODI) of > or = 5 were used as the diagnostic criteria for sleep-disordered breathing. The primary end point was a composite of death, cerebrovascular events, and myocardial infarction. There was a 70% relative increase and a 10.7% absolute increase in the primary composite end point in patients with disordered breathing defined as an ODI of > or = 5 (risk ratio 1.70, 95% confidence interval [CI] 1.15-2.52, p = 0.008). Similarly, patients with an AHI of > or = 10 had a 62% relative increase and a 10.1% absolute increase in the composite endpoint (risk ratio 1.62, 95% CI 1.09-2.41, p = 0.017). An ODI of > or = 5 and an AHI of > or = 10 were both independently associated with cerebrovascular events (hazard ratio 2.62, 95% CI 1.26-5.46, p = 0.01, and hazard ratio 2.98, 95% CI 1.43-6.20, p = 0.004, respectively). We conclude that sleep-disordered breathing in patients with coronary artery disease is associated with a worse long-term prognosis and has an independent association with cerebrovascular events.

Interindividual differences in the analgesic response to ketamine in chronic orofacial pain.

The analgesic effect of the N-methyl-D-aspartate (NMDA) receptor blocker ketamine in 17 patients (13 females and four males, age 32-88 years) who had suffered neuropathic orofacial pain for time periods ranging from 6 months to 28 years was examined. The patients were given an i.m. test-dose of 0.4 mg/kg ketamine combined with 0.05 mg/kg midazolam. Four patients did not experience any analgesic effect of the i.m. test dose. The remaining 13 patients experienced an analgesic effect which lasted for less than 1 h (transient effect) in seven and for several hours (long-term effect) in six. One week later they were given 4 mg/kg ketamine to be taken orally in combination with a hypnotic drug for three consecutive nights. All patients who reported a long-term analgesic effect after i.m. ketamine also reported reduced pain intensity on days after taking ketamine at night. The findings of this open study are in accord with the results from a previous double-blind randomized investigation. In order to evaluate the role of age and pain duration for the analgesic effect of ketamine, we pooled the data from the two studies and performed a correlation analysis of 43 patients. We found a positive correlation between a long pain-history and lack of analgesic effect and also between a short pain-history and a long-term analgesic effect of low-dose ketamine. The apparent relationship between patient age and ketamine response was, however, not statistically significant. Further, patients with pain following a nerve lesion and patients without a known lesion of peripheral nerves were equally distributed between the three response groups. These results indicate that pain mechanisms are subject to alterations with time and that these alterations involve transition from NMDA to non-NMDA receptor mediated transmission in central pain pathways.

Cardiac rhythm in patients with sleep-disordered breathing and coronary artery disease.

We examined the effect of sleep-disordered breathing on heart rates and arrhythmias in men and women with disabling angina pectoris and verified coronary artery disease by an overnight sleep study and Holter recording. The number of oxyhaemoglobin desaturations > or =4% (ODI) and number of apnoea-hypopnoeas per hour of sleep (AHI) were recorded. ODI > or =5 and AHI > or =10 were used as measures of disordered breathing and patients below these limits formed the control groups. One-hundred and forty-one men and 98 women < or =70 years of age were randomly included. Thirty-eight percent of the men and 36% of the women had an ODI > or =5. No serious ventricular arrhythmias occurred. Women with disordered breathing (ODI > or =5) had higher heart rates (mean 63.3 vs 59.1, p < 0.05) and a higher occurrence of ventricular premature contractions (VPCs) during sleep (75th percentiles 2.5 vs 0.5 per hour, p < 0.01). In men, however, no significant association between disordered breathing and heart rates or arrhythmias was found. We conclude that serious arrhythmias are infrequent in unselected patients with coronary artery disease and mild to moderate sleep-disordered breathing. Disordered breathing in women is associated with higher heart rates and a higher occurrence of VPCs during sleep.

Effects of the NMDA receptor antagonist ketamine in electrically induced A delta-fiber pain.

OBJECTIVES: Both ketamine and pethidine have previously been found to have analgesic effects in experimentally induced C-fiber pain. The aim of the present study was to examine the effects of ketamine and pethidine in A delta-fiber-mediated pain induced by electrical tooth stimulation. METHODS: In this double-blind crossover study, an upper right central incisor was stimulated by a Bofors electrical stimulator before and after the intravenous administration of drugs. According to a randomized protocol and with a one-week wash-out period, 9 healthy female volunteers were given either racemic ketamine 0.3 mg/kg or pethidine 0.7 mg/kg, and 11 participants were given (R)-ketamine 0.5 mg/kg or (S)-ketamine 0.15 mg/kg. Pain thresholds were registered by an amperemeter on the stimulator. Drug-induced side effects were registered by use of a standardized questionnaire and visual analog scales. RESULTS: Both ketamine and pethidine gave significant but short-lasting increases in pain thresholds compared to no medication. The participants reported more pronounced mental side effects after ketamine injection. A comparison of (R)- and (S)-ketamine revealed no statistical difference in the effect on pain thresholds of the two enantiomers at the present doses, but 7 out of 11 participants reported to have fewer and less pronounced side effects from (R)-ketamine than from (S)-ketamine. CONCLUSIONS: Ketamine and pethidine have only a marginal effect on pain thresholds in electrically induced A delta-fiber-mediated tooth pulp pain, in contrast to the analgesic effects previously found in experimental and postoperative C-fiber-mediated pain. The ketamine enantiomers at the doses used in this study showed equal analgesic properties but different side effect profiles.

Sleep-disordered breathing and myocardial ischemia in patients with coronary artery disease.

STUDY OBJECTIVES: To examine the occurrence of nocturnal myocardial ischemia and its relationship to sleep-disordered breathing (apneas and oxygen desaturations) in randomly selected men and women undergoing coronary angiography because of angina pectoris. DESIGN: An observational study using an overnight sleep study and Holter recording to examine disordered breathing (oxyhemoglobin desaturations > or = 4% and apnea-hypopneas), heart rates, and ST-segment depressions (> or = 1 mm, > or = 1 min). SETTING: University Hospital, Umeå, a teaching hospital in northern Sweden. PATIENTS: One hundred thirty-two men and 94 women referred for consideration of coronary intervention were randomly included, by lot. RESULTS: ST-segment depressions occurred in 59% (134 of 226) of the patients, and nocturnal ST-segment depressions occurred in 31% (69 of 226). A ST-segment depression occurred within 2 min after an apnea-hypopnea or desaturation in 12% (27 of 226) of patients. This temporal association was seen in 19% of nocturnal ST-segment depressions (71 of 366), more frequently in men (p < 0.01) and in more severely disordered breathing (p < 0.001). Most of these ST-segment depressions were preceded by a series of breathing events: three or more apnea-hypopneas or desaturations or both in 70% (50 of 71). CONCLUSION: Episodes of nocturnal myocardial ischemia are common in patients with angina pectoris. However, a temporal relationship between sleep-disordered breathing and myocardial ischemia is present only in a minority of the patients, but occurs more frequently in men and in more severely disordered breathing.

Prolonged analgesic effect of ketamine, an N-methyl-D-aspartate receptor inhibitor, in patients with chronic pain.

We examined the role of N-methyl-D-aspartate (NMDA) receptors in chronic (pathological) pain in humans by using the NMDA receptor antagonist ketamine as a probe. Thirty patients with neuropathic pain in the trigeminal area were given an i.m. injection of ketamine 0.4 mg/kg combined with midazolam 0.05 mg/kg. Pethidine 1.0 mg/kg served as a control. Three different response patterns were observed. Ketamine caused a long-term (6-24 h) analgesic effect partly dissociated from the mental side effects in 8 of the 26 patients who completed the study; these patients also had a slight analgesic effect of pethidine. In nine patients, ketamine caused a short-lasting (<2 h) analgesic effect closely associated with the mental side effects, whereas pethidine caused little or no analgesia. The remaining nine patients did not experience any reduction of pain after either drug in spite of characteristic side effects. One week after the i.m. challenge the patients received either 4.0 mg/kg ketamine hydrochloride or placebo capsules to be taken orally as a nightly dose for three consecutive nights. Five of the eight patients who had a long-term analgesic effect of the i.m. challenge reported decreased pain on days after ketamine. None of the others reported an analgesic effect. The phenomenon of long-term depression of pain in a subgroup of patients was thus confirmed when ketamine was given p.o. These findings indicate that NMDA receptors are involved in the perception and maintenance of pathological pain in some patients. In others, pain appears to be mediated by NMDA receptor-independent mechanisms. We suggest that NMDA receptor-independent transmission in central pain pathways may contribute to the reduced efficiency of analgesic drugs often seen in chronic pain states.

Trigeminal neuropathic pain: pathophysiological mechanisms examined by quantitative assessment of abnormal pain and sensory perception.

OBJECTIVE: This study was undertaken to examine the pathophysiological characteristics of trigeminal neuropathic pain. METHODS: The study included 23 consecutive patients with trigeminal neuropathic pain (15 patients with pain after nerve injury and 8 patients with pain of spontaneous origin). For each patient, quantitative examination of sensory and pain perception was performed in the painful facial skin area, and results were compared with the findings for the contralateral nonpainful facial skin area. RESULTS: In the painful facial skin area of patients with neuropathic pain after nerve injury, we demonstrated increased temperature and tactile thresholds, as well as abnormal temporal summation of pain (i.e., repetitive nonpainful skin stimulation produced an abnormal progressive increase of pain intensity, with abnormal radiation of pain and aftersensation). In the painful skin area of patients with pain of spontaneous origin, temperature and tactile thresholds were not increased, but heat pain and cold pain thresholds were significantly reduced, indicating heat and cold hyperalgesia. The characteristics of temporal summation of pain were not significantly altered in the painful facial skin area in this group of patients. CONCLUSION: This clinical study provides evidence that the pathophysiological mechanisms of trigeminal neuropathic pain after nerve injury involve impaired function of both small unmyelinated fibers and large myelinated fibers. An explanation for the finding of abnormal temporal summation of pain may involve hyperexcitability of central wide-dynamic range neurons. The results suggest that other mechanisms are involved in trigeminal neuropathic pain of spontaneous origin. Reduced heat and cold pain thresholds indicate heat and cold hyperalgesia, which possibly may be explained by sensitization of peripheral C nociceptors.

Effects of transient and persistent cerebrospinal fluid drainage on sleep disordered breathing in patients with idiopathic adult hydrocephalus syndrome.

OBJECTIVES: To examine sleep disordered breathing including obstructive sleep apnoea in patients with idiopathic adult hydrocephalus syndrome (IAHS) and to study the effects of CSF drainage and shunting procedure on sleep disordered breathing. METHODS: In 17 patients with IAHS polysomnographic investigations were performed before and after lumbar CSF drainage and after shunt operation. RESULTS: Baseline investigations documented a high prevalence of sleep related obstructive respiratory events (respiratory disturbance index >10 in 65% of the patients) and impaired sleep structure. There was no correlation between respiratory disturbance index and CSF pressure. Minimum oxygen saturation was highly correlated with cognitive function. Neither lumbar CSF drainage nor shunting alleviated the respiratory disturbance index. REM and delta sleep increased initially after shunting but there was no sustained effect on sleep quality. CONCLUSIONS: Sleep disordered breathing is a prevalent finding in patients with IAHS. The shortcoming of CSF drainage to improve sleep disordered breathing either transiently or permanently implies that sleep disordered breathing is a coexistent condition, or an irreversible consequence of the hydrocephalus, with a potential of causing additional dysfunction in IAHS.

The effect of peripheral glycerol on trigeminal neuropathic pain examined by quantitative assessment of abnormal pain and sensory perception.

In nine patients with trigeminal neuropathic pain after nerve injury, we examined prospectively the effect of peripheral glycerol neurolysis on abnormal pain and sensory perception. In the painful facial skin area of these patients, we found increased temperature and tactile thresholds and the presence of abnormal temporal summation of pain. In seven patients, neuropathic pain was peripheral and disappeared after application of local anaesthesia at or proximal to the site of nerve injury. Neuropathic pain was central in two patients, and unresponsive to local anaesthesia applied proximal to the site of nerve injury. Six weeks after injection of glycerol proximal to the site of nerve injury, no or marginal pain relief was found in 8 patients with peripheral or central trigeminal neuropathic pain. On the other hand, in one of the patients with peripheral trigeminal neuropathic pain, glycerol was given at the site of nerve injury, and produced total pain relief for the whole observation period of 7 months. In this patient, pain relief was associated with normalisation of abnormal temporal summation of pain, which was not observed in the 8 patients with no or marginal pain relief. No further changes in temperature or tactile thresholds were found in any of the 9 patients after a single injection of absolute glycerol. Total pain relief in one of the patients probably is related to the ability of glycerol to inhibit ongoing ectopic impulse generation at the site of nerve injury. We suggest that glycerol-induced reduction of primary afferent hyperactivity may secondarily result in down-regulation of central neuronal hyperexcitability. The efficacy of application of glycerol at the site of nerve injury in patients with peripheral trigeminal neuropathic pain may warrant further investigation. However, this prospective study does not provide evidence that application of glycerol proximal to the site of nerve injury has a place in the treatment of trigeminal neuropathic pain.

[Analgesic effect of ketamine in a patient with neuropathic pain]. / Analgetisk effekt av ketamin hos en pasient med neuropatiske smerter.

We report the effect of a single daily dose of ketamine in a 54 year old woman with fibromyalgia and severe post-traumatic neuropathic pain. A number of different approaches for pain relief had been tried with little effect. An intramuscular test dose of 0.4 mg/kg ketamine combined with 0.05 mg/kg midazolam lead to analgesia which lasted for almost two days. Long-term analgesia was also obtained by 250 mg/kg ketamine hydrochloride taken orally in the form of capsules every night at bedtime. The patient has now used this dose for nine months. Ketamine is an NMDA receptor antagonist. A single sub-anaesthetic dose of ketamine causes a long-term depression of pain intensity in some, but not in all, patients suffering chronic pain. This effect is distinctly different from the short-lasting (10-30 min) analgesic effect in cases of acute nociceptive pain. The long-term depression of the intensity of chronic pain states may be due to a reversal of NMDA receptor-dependent long-term potentiation of synapses in central pain pathways. By giving ketamine as a single dose at night the mental side-effects are reduced or avoided.

Sleep-disordered breathing in women: occurrence and association with coronary artery disease.

PURPOSE: To examine the occurrence of sleep apnea and nocturnal hypoxemia in women with and without coronary artery disease (CAD) and to investigate the relationship between sleep-disordered breathing and coronary artery disease. PATIENTS AND METHODS: In a case-control study, 102 cases were randomly selected among women with angina pectoris and angiographically verified coronary disease. Fifty age-matched controls without known heart disease were selected from the population registry. Pulse oximetry, oronasal thermistors, body position indicator, and recording of body and respiratory movements were used to quantify oxygen desaturations (the number of desaturations > or = 4% per hour of sleep, oxygen desaturation index [ODI]) and apneas (the number of apneas or hypopneas per hour of sleep, apnea-hypopnea index [AHI]). RESULTS: Women with CAD had a high occurrence of disordered breathing measured as AHI > or = 5, 54% (n = 54), AHI > or = 10, 30% (n = 30) or ODI > or = 5, 34% (n = 35) while the same proportions in controls were 20% (n = 10, P < 0.0001), 10% (n = 5, P < 0.01) and 18% (n = 9, P < 0.05), respectively. In a multiple logistic regression model, sleep apnea (AHI > or = 5), hypertension, and smoking habits were independent predictors of CAD with odds ratios of 4.1 (95% confidence interval [CI] 1.7 to 9.7, P < 0.01), 3.4 (CI 1.3 to 8.9, P < 0.05) and 2.4 (CI 1.0 to 5.7, P < 0.05), respectively. CONCLUSION: Sleep apnea is common in women with CAD and remains as a significant predictor of coronary disease after adjustment for age, body mass index, hypertension, smoking habits, and diabetes.

Sleep-disordered breathing: a novel predictor of atrial fibrillation after coronary artery bypass surgery.

BACKGROUND: Sleep-disordered breathing is a common condition associated with nocturnal hypoxaemia, sympathetic activation and haemodynamic stress that can trigger arrhythmias. We examined whether preoperatively diagnosed disordered breathing was associated with an increased incidence of atrial fibrillation after coronary artery bypass surgery. METHODS: A sleep study was performed in 121 consecutive patients, who were monitored prospectively until discharge from hospital after surgery. Disordered breathing was defined as an apnoea-hypopnoea index (AHI) > or = 5 or an oxygen desaturation index (ODI) > or = 5. All episodes of atrial fibrillation requiring pharmacological intervention or cardioversion were included in the analysis. RESULTS: Atrial fibrillation was diagnosed in 32% of patient with AHI > or = 5 (25 of 78) and in 18% patients with AHI < 5 (7 of 39, P = 0.11). Similarly, atrial fibrillation was diagnosed in 39% of patients with ODI > or = 5 (19 of 49) and in 18% of patients with ODI < 5 (13 of 72, P = 0.02). In a multiple-logistic regression model including age, left ventricular function, aortic cross clamp time, maximum postoperative level of lactate dehydrogenase and disordered breathing (ODI > or = 5), greater age and disordered breathing were independent predictors of postoperative atrial fibrillation. The relative risk of atrial fibrillation was 2.0 (95% confidence interval 1.1-3.8) for a 10-year increase in age and 2.8 (95% confidence interval 1.2-6.8) for disordered breathing (ODI > or = 5). CONCLUSIONS: Pre-operatively diagnosed sleep-disordered breathing with nocturnal hypoxaemia is an independent predictor of atrial fibrillation after coronary bypass surgery.

Sleep-disordered breathing in men with coronary artery disease.

OBJECTIVE: To examine the occurrence of sleep apnea and nocturnal hypoxemia in men with symptomatic coronary artery disease (CAD) and to evaluate the relationship between disordered breathing and coronary artery disease. DESIGN: Case-control study. Cases were randomly selected from men undergoing coronary angiography because of angina pectoris. Controls were age matched and selected from the population registry. Pulse oximetry, oronasal thermistors, body position indicator, and recording of body and respiratory movements were used to quantify desaturations and apneas. SETTING: Norrland University Hospital, a referral center for northern Sweden. SUBJECTS: One hundred forty-two men with angina pectoris and angiographically verified CAD and 50 controls without known heart disease. MAIN OUTCOME MEASURES: The number of arterial oxygen desaturations of 4% or more per hour of sleep, oxygen desaturation index (ODI), and the number of apneas or hypopneas per hour of sleep, apnea-hypopnea index (AHI). RESULTS: Men with CAD had a high occurrence of sleep-disordered breathing measured as ODI of 5 or more, 39% (n=55), or AHI of 10 or more, 37% (n=50), while, the same proportions in controls were 22% (n=11, p<0.05) and 20% (n=10, p<0.05). Mean values of ODI in cases and controls were 6.4 and 2.7, respectively (p<0.001). Multiple logistic regression analysis identified ODI, AHI, body mass index, and hypertension as significant predictors of CAD (p<0.05). CONCLUSION: Sleep- disordered breathing is common in men with CAD. A significant association between sleep apnea with nocturnal hypoxemia and CAD remains after adjustment for age, hypertension, body mass index, diabetes, and smoking.

[Nasal CPAP--treatment of choice in obstructive sleep apnea]. / Näs-CPAP--ett förstahandsval vid behandling av obstruktiv sömnapné.

There is no doubt about the effectiveness of nasal-CPAP (continuous positive airway pressure) in treatment on obstructive sleep apnea syndrome (OSAS), however there has been doubts about the tolerance and compliance rate. Seventy-two (88 percent) out of 82 patients evaluated for CPAP tolerated and accepted treatment for home use. Five patients did not tolerate CPAP at all, of them four were former operated with Uvulopalatopharyngoplasty. Five patients refused home CPAP therapy. According to a questionnaire 42 (91 percent) out of 46 patients with home CPAP therapy used their CPAP five to seven nights/week. We suggest CPAP as the treatment of choice at AHI greater than 20, since the treatment is highly effective and well tolerated by the patients.