Cost and outcome of mechanical ventilation for life-threatening stroke.

BACKGROUND AND PURPOSE: Hospital mortality rates of 50% to 90% have been reported for stroke patients treated with mechanical ventilation. These data have raised serious questions about the cost-effectiveness of this intervention. We sought to determine how often stroke patients are mechanically ventilated, identify predictors of 30-day survival among ventilated patients, and evaluate the cost-effectiveness of this intervention. METHODS: We identified mechanically ventilated patients in a population-based multiethnic cohort of 510 incidence stroke patients who were hospitalized between July 1993 and June 1996. Factors affecting 30-day survival were identified in a multiple logistic regression analysis. We calculated the cost per patient discharged alive, life-year saved, and quality-adjusted life-year saved using a zero-cost, zero-life assumption. RESULTS: Ten percent of patients (n=52) were mechanically ventilated. Thirty-day mortality was 65% overall and did not differ significantly by stroke subtype. Glasgow Coma Scale score on the day of intubation (P:<0.01) and subsequent neurological deterioration (P:=0.02) were identified as predictors of 30-day mortality. The cost (1996 US dollars) of hospitalization per patient discharged alive was $89 400; the cost per year of life saved was $37 600; and the cost per quality-adjusted life-year saved was $174 200. Functional status of most survivors was poor; at 6 months, half were severely disabled and completely dependent. In a worst-case scenario of quality of life preferences, mechanical ventilation resulted in a net deficit of meaningful survival. CONCLUSIONS: Two thirds of mechanically ventilated stroke patients die during their hospitalization, and most survivors are severely disabled. Survival is particularly unlikely if patients are deeply comatose or clinically deteriorate after intubation. In our multiethnic urban population, mechanical ventilation for stroke was relatively cost-effective for extending life but not for preserving quality of life.

Effect of cisternal and ventricular blood on risk of delayed cerebral ischemia after subarachnoid hemorrhage: the Fisher scale revisited.

BACKGROUND AND PURPOSE: Thick cisternal clot on CT is a well-recognized risk factor for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH). Whether intraventricular hemorrhage (IVH) or intracerebral hemorrhage (ICH) predisposes to DCI is unclear. The Fisher CT grading scale identifies thick SAH but does not separately account for IVH or ICH. METHODS: We studied 276 consecutively admitted patients with an available admission CT scan performed within 72 hours of onset. Demographic, clinical, laboratory, and neuroimaging data were recorded, and the amount and location of SAH, IVH, and ICH on admission CT scans were quantified. The relationship between these variables and DCI was analyzed separately and in combination with multiple logistic regression. RESULTS: DCI developed in 20% of patients (54 of 276). Among SAH variables, thick clot completely filling any cistern or fissure was the best predictor of DCI (P=0.008), and among IVH variables, blood in both lateral ventricles was most predictive (P=0.001). These variables had independent predictive value for DCI in a multivariate analysis of CT findings, and both were included in a final multivariate model when evaluated in conjunction with other clinical risk factors: IVH (OR 4.1, 95% CI 1.7 to 9.8), SAH (OR 2.3, 95% CI 1.5 to 9.5), mean arterial pressure >112 mm Hg (OR 4.9, 95% CI 2.1 to 11.4), and transcranial Doppler mean velocity >140 cm/s within 5 days of hemorrhage (OR 3.8, 95% CI 1.5 to 9.5). Similar results were obtained in a repeat analysis with infarction due to vasospasm as the dependent variable. CONCLUSIONS: SAH completely filling any cistern or fissure and IVH in the lateral ventricles are both risk factors for DCI, and their risk is additive. We propose a new SAH rating scale that accounts for the independent predictive value of subarachnoid and ventricular blood for DCI.

Delirium from nicotine withdrawal in neuro-ICU patients.

Five cases of presumed nicotine withdrawal delirium among brain-injured patients treated in a neurologic intensive care unit are presented. Each patient had a history of heavy tobacco use and experienced dramatic and sustained clinical improvement within hours of transdermal nicotine replacement. These preliminary observations suggest that nicotine withdrawal may be an under-recognized cause of delirium in patients with acute brain injury.

Global and domain-specific cognitive impairment and outcome after subarachnoid hemorrhage.

BACKGROUND: Cognitive dysfunction is the most common form of neurologic impairment after subarachnoid hemorrhage (SAH). OBJECTIVE: To evaluate the impact of global and domain-specific cognitive impairment on functional recovery and quality of life (QOL) after SAH. METHODS: One hundred thirteen patients (mean age 49 years; 68% women) were evaluated 3 months after SAH. Three simple tests of global mental status and neuropsychological tests to assess seven specific cognitive domains were administered. Four aspects of outcome (global handicap, disability, emotional status, and QOL) were compared between cognitively impaired and unimpaired patients with analysis-of-covariance models controlling for age, race/ethnicity, and education. Multiple linear regression was used to evaluate the relative contribution of global and domain-specific cognitive status for predicting concurrent modified Rankin Scale (mRS) and Sickness Impact Profile (SIP) scores. RESULTS: Impairment of global mental status on the Telephone Interview of Cognitive Status (TICS) was associated with poor performance in all seven cognitive domains (all p < 0.0005) and was the only cognitive measure associated with poor recovery in all four aspects of outcome (all p < or = 0.005). Cognitive impairment in four specific domains was also associated with functional disability or reduced QOL. After accounting for global cognitive impairment with the TICS, however, neuropsychological testing did not contribute additional predictive value for concurrent mRS or SIP total scores. CONCLUSIONS: Cognitive impairment impacts broadly on functional status, emotional health, and QOL after SAH. The TICS may be a useful alternative to more detailed neuropsychological testing for detecting clinically relevant global cognitive impairment after SAH.

beta-Endorphin-induced hyperthermia in the cat.

beta-Endorphin was injected into the third cerebral ventricle (ICV) of conscious, unrestrained cats. Hyperthermic response to 50 microgram of this peptide were reduced by 20-100 microgram naloxone given ICV 1 hr later. A dose of 40 microgram beta-endorphin increased body temperature at ambient temperature of 4, 22 and 34 degrees C, with the response being greater the warmer the environment. These results indicate that beta-endorphin acts on a central naloxone-sensitive receptor which is probably the v2 receptor that is activated by low doses of D-Ala2-Met-enkephalinamide to evoke a similar pattern of change in body temperature over a comparable range of ambient temperatures.

Intracerebroventricular and septal injections of arginine vasopressin are not antipyretic in the rabbit.

Arginine vasopressin (AVP) has been reported to have an antipyretic effect in the ewe and guinea pig near term. Perfusions with AVP of sites in the septal region also reduced fever in non-pregnant sheep. In the present experiments adult rabbits with third cerebral ventricular or septal cannulas were restrained in a 23 degree C environment, and rectal temperature was recorded every 10 min. Fever induced by IV administration of leukocytic pyrogen was not reduced by AVP (25-100 ng) given intraventricularly 20 min later. Doses of 1-5 micrograms AVP injected into the septum likewise were not antipyretic but actually caused an increase in fever. This augmentation of the febrile response is consistent with results of previous studies in this laboratory in which AVP increased hyperthermia in a hot environment and enhanced hyperthermic responses to PGE2. The data from these experiments provide no evidence that central AVP is an endogenous antipyretic in rabbits; rather, it may be that central AVP augments fever in this species.

alpha-MSH injected into the septal region reduces fever in rabbits.

In previous research the concentration of alpha-MSH within the septal region of rabbits increased with fever. This finding raises the possibility that the septal concentration of this peptide, which reduces fever when given both peripherally and intracerebroventricularly, is important to limitation of fever. To test this idea, rabbits with cannulas in the septal region were made febrile by IV injections of leukocytic pyrogen (LP). Injection of alpha-MSH (1 microgram bilaterally) into the septal region did reduce fever, consistent with the idea that the increase in septal alpha-MSH concentration which occurs naturally in fever limits the febrile response. We also noted late rises in body temperature when experimental and control septal injections were given close together in time. These increases in temperature were similar to those known to occur after injections into the primary temperature control in the PO/AH region. This commonality further strengthens the possibility that septal neurons are important to central modulation of body temperature.

Antipyretic effect of centrally administered CRF.

CRF injected into the third cerebral ventricle (0.5-2.5 micrograms) caused dose-related reductions in fever induced in rabbits by IV administration of leukocytic pyrogen. Control injections of CRF when the same animals were afebrile did not alter normal body temperature. Intravenous injections of 5 and 20 micrograms CRF, doses known to release ACTH and corticosteroids into the bloodstream in other species, did not reduce fever. CRF injected into the cerebral ventricles may be antipyretic per se, or it may reduce fever by virtue of central release of the antipyretic peptides ACTH and alpha-MSH.

Applications of piezoelectric fluid jetting devices to neuroscience research.

Piezoelectric pumps or "jets" are used in industry for precise dispensing of small volumes of fluids. In the present work we have tested the feasibility of using these piezoelectric devices for dispensing fluids in neurobiological research. In one experiment, 70 picoliter (pl) droplets of histochemical reagent were jetted onto discrete targets of frozen tissue sections, and qualitative and quantitative histochemical studies were done on the small (170 microns diameter) circle of tissue wet by the droplets. In the second experiment, 70 pl droplets of neuroactive drugs were jetted onto brain tissue slices while recording single neurons extracellularly in vitro, and the effects of the drugs were found to vary systematically as a function of the number of drops and the distance between drop application and the recorded neuron. The results indicate that piezoelectric jets could have wide application for dispensing fluids in neurobiological research.

Increased midbrain dopaminergic cell activity following 2'CH3-MPTP-induced dopaminergic cell loss: an in vitro electrophysiological study.

Several days after the administration of 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'CH3-MPTP) to the BALB/cJ mouse there is a loss of midbrain dopaminergic neurons, a reduction of forebrain dopamine (DA) content, and an elevation in forebrain DA turnover. The purpose of the present study was to determine whether the increase in forebrain DA turnover is related to an increase in dopaminergic neuronal activity. In vitro extracellular single unit recordings were made from midbrain dopaminergic neurons in the substantia nigra pars compacta (nucleus A9) and ventral tegmental area (nucleus A10) of BALB/cJ mice. The experimental animals were treated intraperitoneally with 40, 50 or 55 mg/kg 2'CH3-MPTP and killed 7-15 days later. Forebrain DA concentrations were decreased below control values by the two higher toxin doses in the caudate-putamen (67% and 78%, respectively), but not in the nucleus accumbens. DA turnover increased more than 2-fold in the caudate-putamen, but was unchanged in the nucleus accumbens. Nucleus A9 cells, in the 2'CH3-MPTP-treated animals, exhibited a 3-fold increase in the number of spontaneously active cells, and an 84% increase in basal firing rates. There was also a positive correlation between the A9 cell firing rates, and the DA turnover in the striatum of the toxin-treated mice. Nucleus A10 cells, in the 2'CH3-MPTP-treated animals, exhibited neither changes in number of spontaneously active cells nor changes in firing rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Nucleus A10 dopaminergic neurons in inbred mouse strains: firing rate and autoreceptor sensitivity are independent of the number of cells in the nucleus.

Inbred mouse strains have different numbers of midbrain dopaminergic neurons; for example, BALB/cJ mice have 20-25% more neurons than CBA/J mice. As the number of cells decrease, for example in Parkinson's disease and in animals with midbrain dopaminergic cell lesions, the activity of their remaining cells increases. The purpose of the present experiment was to determine whether the functional properties of dopaminergic neurons in the ventral tegmental area (nucleus A10) differ in inbred mouse strains which possess different numbers of cells. The firing rate and autoreceptor sensitivity of A10 dopaminergic cells were examined in the in vitro slice preparation in BALB/cJ, C3H/HeJ, CBA/J, and DBA/2J mouse strains. It was observed that the autoreceptors on mouse dopaminergic neurons exhibit pharmacological properties of dopamine autoreceptors; activation of the autoreceptor produced a marked inhibition (50-70%) in cell firing rate by quinpirole (10(-8) M), LY-141865 (10(-7) M), (+)-3-(3-hydroxyphenyl)-N-n-propyl-piperidine (10(-6) M), propyl-norapomorphine (10(-5) M) and dopamine (10(-4) M), and this inhibition was blocked or reversed by specific dopamine D2 receptor antagonists [(-) sulpiride and spiroperidol, 10(-6) M]. The baseline firing rates of the A10 cells did not differ among the four inbred strains [range 2.5 +/- 0.2 (C3H/HeJ)-3.4 +/- 0.3 (CBA/J) spikes/s +/- SEM], and there was no significant difference in autoreceptor sensitivity among the mouse strains as assessed either by superfused dopamine (inhibitory dose 50% approximately 150 microM), or by superfused quinpirole (inhibitory dose 50% approximately 10 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperthermic response of the cat to intraventricular injection of the opioid delta-receptor agonist D-Ala2-D-Leu5-enkephalin.

The delta opioid receptor agonist D-Ala2-D-Leu5-enkephalin was injected into the third cerebral ventricle of cats to determine its effects on core temperature for comparison with other peptide and non-peptide opioids that act on a variety of receptors to alter thermoregulation. Like other opioid peptides that have been studied in this species, D-Ala2-D-Leu5-enkephalin (5-25 micrograms) induced a dose-related hyperthermia. This response was undiminished in cats tolerant to morphine and was found to consist of two components. One component of the hyperthermic response was inhibited by pretreatment with low doses of opioid antagonists (25 micrograms naloxone; 5-15 micrograms naltrexone) and may be mediated by the v2-receptor that mediates this response to D-Ala2-Met-enkephalinamide. The other component, which was prevented by 100 micrograms naltrexone but still only partially inhibited by 250 micrograms naloxone, is attributed to delta-receptor stimulation. In tests over a range of environmental temperatures, the hyperthermic response to 10 micrograms D-Ala2-D-Leu5-enkephalin was less in a 4 degrees C environment than at the usual laboratory temperature of 22 degrees C. Responses in 22 and 34 degrees C environments were similar. No increase in respiratory rate occurred to indicate activation of compensatory heat-loss mechanisms so that the hyperthermia was indicative of an increase in the level about which body temperature is regulated.

Central injection of a sigma opioid receptor agonist alters body temperature of cats.

The prototype sigma opioid receptor agonist N-allyl-normetazocine (SKF 10,047) was injected into the third cerebral ventricle of conscious, unrestrained cats, and their temperature was monitored automatically from the retroperitoneal space. In a cold environment (0 degrees C) a small, but not dose-related, hypothermia occurred after doses of 100-500 micrograms. This response was not antagonized by naloxone given intraventricularly either 15 min before or 1 hr after the opioid. A smaller hypothermia resulted after 250 micrograms SKF 10,047 when the environmental temperature was 22 degrees C, whereas hyperthermia developed in a hot environment (34 degrees C). Thus SKF 10,047 appears to allow body temperature to drift, upward in the heat and downward in the cold, a pattern indicative of thermoregulatory depression. These results are similar to those obtained in the first 2-3 hr after pentazocine administration, and they support a previous classification of the initial temperature response to centrally injected pentazocine as due to stimulation of sigma opioid receptors.

Depression of learned thermoregulatory behavior by central injection of opioids in cats.

Third cerebral ventricular administration of morphine (20 microgram), pentazocine (1 mg) or the synthetic opioid peptides D-Ala2-Met-enkephalinamide (25 microgram) and D-Ala2-D-Leu5-enkephalin (10 microgram) decreased heat-reinforcement activity and either reduced or did not increase heat-escape activity of cats trained to control thermal stimuli through behavior. If the behavioral changes had been coupled to the primary effects of these opioids on thermoregulation, one would have expected an inverse relationship between changes in heat-reinforcement and heat-escape activity. Motor incapacitation appeared not to have contributed to the reduction in responding except briefly after pentazocine injection. The opioids may have distracted the animals or otherwise reduced their reaction to thermal stimuli until body temperature increased to a potentially dangerous level.

Evidence against involvement of beta-endorphin in thermoregulation in the cat.

In the cat naloxone has little, if any, effect on temperature under usual laboratory conditions and does not reduce febrile responses to leukocytic pyrogen. Hence, endogenous opioid peptides that are antagonized by naloxone are not essential for induction of fever or for maintenance of normal temperature in the absence of appreciable thermal stress. The purpose of this study was to assess the contribution of such endogenous opioids to thermoregulation in cats exposed to more severe thermal and non-thermal stresses. Changes in temperature of unanesthetized cats were determined after third cerebral ventricular injections of large doses (100, 250 micrograms) of naloxone or saline vehicle. Naloxone had no appreciable effect on the temperature of cats acutely exposed to hot (34 degrees C) or cold (4 degrees C) environments, either before or after tolerance to morphine had been induced by progressively greater daily or twice-daily intraventricular doses of 10-70 micrograms morphine sulfate. Naloxone also did not significantly affect the temperature of cats subjected to neck-restraint or forced to stand on a small platform if they were to avoid contact with ice water. These results provide no indication that an endogenous opioid peptide, such as beta-endorphin, that is antagonized by naloxone contributes appreciably to thermoregulation in cats. They do not rule out the possibility that endogenous opioids, such as Met-enkephalin, that are not readily antagonized by naloxone are important for normal thermoregulation.

Extreme hyperthermia induced in cats by the enkephalin analog FK 33-824.

FK 33-824 [H2N-Tyr-D-Ala-Gly-MePhe-Met(O)-OH] was injected into the third cerebral ventricle of unrestrained cats. Doses of 0.25-4 microgram induced dose-related increases in body temperature. Hyperthermic responses to 1 microgram of the peptide were greater the warmer the environment. Naloxone given intraventricularly 1 hr after FK 33-824 (1 microgram) reduced the hyperthermia. In 12 tests with six cats FK 33-824 (1-25 microgram) increased temperature 4.2-4.7 degrees C. These marked responses were also inhibited by naloxone, but two cats died when administration of antagonist was delayed for 80 min to 3 hr after attainment of maximal body temperature. Larger doses of FK 33-824 (50-250 microgram) evoked little increase in temperature, indicative of a separate action to depress thermoregulation. Although responses to FK 33-824 were antagonized by naloxone, this peptide, like another enkephalin analog D-Ala2-Met-enkephalinamide, must act on receptors which are not affected by morphine since (1) the hyperthermic response to FK 33-824 varied with environmental temperature, whereas the response to morphine does not, and (2) high doses of FK 33-824 depressed thermoregulation, an activity not shared by morphine in the cat. Furthermore, the maximal increases in temperature after FK 33-824 injection were greater than those evoked by either morphine or D-Ala2-Met-enkephalinamide. This observation provides evidence for an additional subset of naloxone-sensitive, v, receptors, stimulation of which can influence thermoregulation in the cat.

Critical care of intracerebral and subarachnoid hemorrhage.

The acute management of primary intracerebral or aneurysmal subarachnoid hemorrhage requires a comprehensive approach involving stabilization of the patient, surgical intervention, and continued intensive care treatment of medical and neurologic complications. The are several causes of intracerebral hemorrhage (ICH), including hypertension, cerebral amyloid angiopathy, sympathomimetic drugs, and coagulopathies. More recently, use of thrombolytic agents in the treatment of acute ischemic stroke has increased the risk of ICH. Treatment of intracerebral hemorrhage is based on blood pressure control, and, in selected cases, surgical evacuation of clot. Patients with aneurysmal subarachnoid hemorrhage may experience rebleeding, symptomatic vasospasm, or hydrocephalus. Medical management in the intensive care unit with careful attention to fluid and electrolyte balance, nutrition, cardiopulmonary monitoring, and close observation for changes in the neurologic exam is vital. This review examines the diagnosis and intensive care management of patients with intracerebral or subarachnoid hemorrhage, and reviews some of the newer therapies for treatment of these disorders.