Effect of vehicle on the nasal absorption of epinephrine during cardiopulmonary resuscitation.

STUDY OBJECTIVES: We have shown in previous studies that epinephrine administered intranasally is a feasible route of administration during cardiopulmonary resuscitation (CPR). To promote the absorption of epinephrine we administered phentolamine prior to epinephrine and used a bile salt as a vehicle to dissolve the epinephrine. The purpose of this study was to compare the effect of two different vehicles (bile salt vs surfactant) in promoting the absorption of nasally administered epinephrine during CPR and to determine their effects on the nasal mucosa. STUDY DESIGN: A randomized, blinded study. SETTING: A controlled laboratory environment. SUBJECTS: Eleven mongrel dogs. INTERVENTIONS: Each dog underwent 3 minutes of unassisted ventricular fibrillation (VF) followed by 7 minutes of VF with CPR. Five minutes after the start of VF, 10 dogs received intranasal phentolamine 0.25 mg/kg/nostril followed 1 minute later by intranasal epinephrine 7.5 mg/kg/nostril. The epinephrine was dissolved in a randomly assigned vehicle consisting of either taurodeoxycholic acid (group A, bile salt) or polyoxyethylene-9-lauryl ether (group B, surfactant). One animal acted as a control and received 0.9% sodium chloride nasally. MEASUREMENTS AND MAIN RESULTS: Data from eight dogs (one control) were included for analysis. Histology of the nasal cavity demonstrated severe multifocal erosion and ulceration of the respiratory epithelium for groups A and B compared with the control. The severity was similar between the two groups. In addition, no significant differences in plasma epinephrine concentrations or blood pressure responses were seen between the groups. CONCLUSION: Based on histology, polyoxyethylene-9-lauryl ether offered no advantage over taurodeoxycholic acid in its effect on the nasal mucosa. The data available for changes in epinephrine concentration and pressure also suggest no difference between the two vehicles in promoting the absorption of epinephrine during CPR in an animal model.

Effect of dose on the nasal absorption of epinephrine during cardiopulmonary resuscitation.

Delay in epinephrine administration during cardiopulmonary resuscitation (CPR) due to technical difficulties in obtaining an access site may be detrimental. To avoid this potential delay, we have previously shown that intranasal administration of phentolamine and epinephrine is a rapidly obtainable and feasible route of administration during CPR. A randomized blinded dose ranging study was performed in a controlled laboratory environment. Thirty mongrel dogs were randomized to one of the following dosage regimens: phentolamine, 0.25 or 2.5 mg/kg/nostril; epinephrine, 0.075, 0.75, or 7.5 mg/kg/nostril. Phentolamine was administered intranasally 1 minute before the intranasal administration of epinephrine to improve absorption. Each dog underwent 3 minutes of ventricular fibrillation followed by 7 minutes of closed chest CPR. Epinephrine was administered was administered at 3 minutes of CPR. Data from 26 dogs were included for analysis. Treatment B (0.25 and 7.5 mg/kg/nostril of phentolamine and epinephrine, respectively) produced the greatest elevation in coronary perfusion pressure (17 +/- 11 vs. 4 +/- 3 mm Hg for the next highest group, P < .003) and in epinephrine plasma concentrations (1,403 +/- 1,400 vs 290 +/- 182 ng/mL for the next highest group, P > .05). In addition, treatment B had the highest resuscitation rate, 100% (5/5) versus 0% to 50% for the other groups (P < .05). These data show that there is a dose response effect, with 0.25 and 7.5 mg/kg/nostril of phentolamine and epinephrine being the optimal dose studied. In addition, when administered in appropriate doses, intranasal epinephrine reaches the systemic circulation and increases coronary perfusion pressure and successful resuscitation during CPR in this canine model.

Variations in prothrombin time and international normalized ratio over 24 hours in warfarin-treated patients.

STUDY OBJECTIVE: To determine the variation of prothrombin times and international normalized ratio (INR) over 24 hours in humans. DESIGN: Prospective, parallel study. SETTING: University-affiliated general clinical research center. PATIENTS: Six patients receiving long-term warfarin therapy and six sex-matched controls. INTERVENTIONS: Warfarin was administered to the patients at 6:00 P.M. MEASUREMENTS AND MAIN RESULTS: Prothrombin times and INR were determined every 2 hours over 24 hours. Time of study entry, meals, and sleep cycles were controlled. A significant cosinor rhythm for prothrombin times and INR (p < or = 0.03) occurred in warfarin-treated patients, suggesting that diurnal variation occurs. The mean difference between the peak and trough prothrombin times was 1.8 +/- 0.9 seconds (range 0.8-3 sec) with a mean change of 9.3% +/- 3.7%. The peak prothrombin time and INR values occurred between 4:00 A.M. and 8:00 A.M. in five patients, and trough values between 6:00 P.M. and midnight in five. No significant cosinor rhythm was noted for controls (p > 0.5). CONCLUSION: Significant variations in prothrombin time and INR occurred in patients receiving warfarin therapy, with the highest values occurring in the morning and the lowest in the evening. These results may have clinical implications for patients receiving either high- or low-intensity warfarin therapy.

Effect of high-dose sodium bicarbonate on the vasopressor effects of epinephrine during cardiopulmonary resuscitation.

We attempted to determine the effect of extreme alkalemia induced by highdose sodium bicarbonate on the vasopressor effects of epinephrine during cardiopulmonary resuscitation (CPR). Subjects in this randomized, blinded study performed in a controlled laboratory environment were 12 mongrel dogs that had had a previous episode of CPR. Each dog underwent 3 minutes of ventricular fibrillation (VF) followed by 7 minutes of closed-chest CPR. Animals were assigned to receive either sodium bicarbonate 3 mEq/kg and epinephrine 0.1 mg/kg, or normal saline 3 ml/kg and epinephrine 0.1 mg/kg. The sodium bicarbonate or normal saline was infused over 2 minutes beginning at 4 minutes of VF (1 min of CPR) followed by bolus epinephrine. Arterial pH in the sodium bicarbonate group was significantly higher at each sampling point (7.7 +/- 0.1 vs 7.29 +/- 0.06 at 1 min after drug, p < 0.001). However, there were no statistically or clinically significant differences in coronary perfusion pressure between the groups at any time: 29 +/- 13 versus 32 +/- 21 mm Hg 1 minute, and 22 +/- 12 versus 26 +/- 19 mm Hg 4 minutes after epinephrine for sodium bicarbonate and normal saline, respectively (p > 0.7). Increased arterial pH (alkalemia) induced by high-dose sodium bicarbonate administration did not improve the vasopressor effects of epinephrine during CPR in this canine model. These results suggest the limited value of administering sodium bicarbonate during CPR to improve the responsiveness to epinephrine.

An alternative sodium bicarbonate regimen during cardiac arrest and cardiopulmonary resuscitation in a canine model.

We evaluated the effect of frequent, early bolus administration of low-dose sodium bicarbonate (NaHCO3) on blood gas values during ventricular fibrillation and cardiopulmonary resuscitation (CPR) compared with normal saline and standard bolus doses of NaHCO3. This was a randomized laboratory investigation involving 13 mongrel dogs and 18 experiments (5 dogs were used in a crossover manner). Each dog underwent 3 minutes of ventricular fibrillation, followed by 15 minutes of CPR. Animals were randomly assigned to one of three treatments administered early in the resuscitation effort: NaHCO3 0.5 mEq/kg at 5, 10, and 15 minutes of ventricular fibrillation (SB); NaHCO3 1 mEq/kg at 5 minutes and 0.5 mEq/kg at 15 minutes of fibrillation (SB); or 0.9% NaCl 1 ml/kg at 5 minutes and 0.5 ml/kg at 15 minutes of fibrillation (P). A total of 15 experiments were included for analysis. Arterial and venous blood gases were sampled at 4, 8, 13, and 18 minutes of fibrillation. The SB group demonstrated the highest arterial partial pressures of carbon dioxide (pCO2) at each sampling point after NaHCO3, including the 18-minute sample: 42 +/- 12, 29 +/- 11, and 35 +/- 10 torr for SB, P, and B, respectively. In addition, SB produced arterial alkalemia (pH > 7.45) after NaHCO3 administration. The arterial pH at 18 minutes of fibrillation for SB, P, and B was 7.46 +/- 0.14, 7.29 +/- 0.07, and 7.41 +/- 0.1, respectively. Similar trends for pCO2 and pH were observed for venous samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Flumazenil: a benzodiazepine antagonist.

The mechanism of action, pharmacokinetics, and use of flumazenil in benzodiazepine overdose, as well as in the management of other disease states, are reviewed. Flumazenil interacts at the central benzodiazepine receptor to antagonize or reverse the behavioral, neurologic, and electrophysiologic effects of benzodiazepine agonists and inverse agonists. Flumazenil has been studied for a variety of indications, including as an antidote to benzodiazepine overdose and for awakening of comatose patients, reversal of sedation after surgery and in critically ill patients, and management of hepatic encephalopathy. It improves the level of consciousness in patients with benzodiazepine overdose; however, resedation may occur within one to two hours after administration, so repeated doses or a continuous infusion may be required to maintain therapeutic efficacy. It appears to be effective in reversing sedation induced by midazolam or diazepam, and case reports suggest that it is useful in awakening comatose patients, although its clinical utility is questionable. Flumazenil has proved useful in reversing conscious sedation in critically ill patients, although response may be dose dependent. Animal models indicate that flumazenil is of some benefit in hepatic encephalopathy, but until well-designed clinical trials are conducted, hepatic encephalopathy must be considered an investigational indication for flumazenil. Adverse reactions include CNS manifestations, resedation, cardiovascular effects, seizures, and alterations in intracranial pressure and cerebral perfusion pressure. Hepatic dysfunction results in a substantial change in the pharmacokinetic profile of flumazenil; therefore, dosage adjustment may be necessary in patients with hepatic dysfunction or in those receiving medications that alter flumazenil metabolism. Flumazenil has been shown to reverse sedation caused by intoxication with benzodiazepines alone or benzodiazepines in combination with other agents, but it should not be used when cyclic antidepressant intoxication is suspected. It may be beneficial after surgery when benzodiazepines have been used as part of anesthesia and after a diagnostic or surgical procedure when assessment of CNS function is necessary.

The effect of sodium bicarbonate administration on the vasopressor effect of high-dose epinephrine during cardiopulmonary resuscitation in swine.

Sodium bicarbonate is administered during cardiopulmonary resuscitation (CPR) for the treatment of systemic acidemia. However, the effect of administering standard-dose sodium bicarbonate on the vasopressor effect of epinephrine is unknown. This study compared the effects of sodium bicarbonate or normal saline on the vasopressor effect of epinephrine in 18 pigs. After 10 minutes of unassisted ventricular fibrillation, CPR was started using a pneumatic chest compression device. Two minutes after the start of CPR, sodium bicarbonate (1 mEq/kg) or normal saline (1 mL/kg) was administered into the right ventricule followed 1 minute later by epinephrine (0.2 mg/kg). Defibrillation was attempted at 8 minutes of CPR (18 minutes of ventricular fibrillation). Results demonstrated no significant differences in aortic systolic, aortic diastolic, or coronary perfusion pressure (CPP) between the two groups (1 minute after epinephrine, CPP was 22.6 +/- 13.3 mm Hg versus 21.1 +/- 20.7 mm Hg for the sodium bicarbonate and normal saline groups, respectively). However, when the data were stratified according to pH < 7.4 and pH > 7.4, the peak change in CPP was 12.7 +/- 21 mm Hg when pH < 7.4 and was 5.2 +/- 7.4 when pH > 7.4 (P = .33). Resuscitation was also similar between the two groups (two of nine for sodium bicarbonate and one of nine for normal saline). In conclusion, the standard recommended dose of sodium bicarbonate did not alter the vasopressor effect of epinephrine or resuscitation compared with normal saline in this closed chest model of ventricular fibrillation and CPR.

Comparison of intravenous and intranasal administration of epinephrine during CPR in a canine model.

STUDY OBJECTIVES: Epinephrine improves coronary perfusion pressure during CPR. However, administration of epinephrine during CPR may be delayed or omitted if IV or endotracheal access is not established. Therefore, the objective of this study was to determine if intranasal administration of epinephrine during CPR would provide an alternate route of drug administration that is readily accessible and requires no special technical skills. DESIGN AND SETTING: Randomized blinded study performed in a controlled laboratory environment. TYPE OF PARTICIPANTS: Twenty mongrel dogs weighing 19.5 +/- 4.6 kg. INTERVENTIONS: All dogs received either IV epinephrine 0.015 mg/kg or intranasal epinephrine 14 mg per nostril. Phentolamine (5 mg per nostril) was administered intranasally one minute before nasal administration of epinephrine to improve absorption. Each dog underwent three minutes of ventricular fibrillation followed by seven minutes of CPR with a pneumatic chest compression device. Epinephrine was administered at two minutes into CPR. MEASUREMENTS AND MAIN RESULTS: Seven dogs were excluded because of inadequate baseline coronary perfusion pressure or compression device displacement, leaving a total of 13 dogs for analysis (six IV epinephrine, seven intranasal epinephrine). Baseline coronary perfusion pressure (mean +/- SD) was similar for IV epinephrine and intranasal epinephrine (16.9 +/- 7.1 mm Hg versus 18.2 +/- 13.8 mm Hg, respectively, P = .84). For IV and intranasal epinephrine, coronary perfusion pressure increased to 21.4 +/- 9.2 mm Hg and 24.4 +/- 18.7 mm Hg one minute after epinephrine, respectively (P = .73). Five minutes after epinephrine coronary perfusion pressure was 18.2 +/- 8.7 mm Hg and 24.3 +/- 13.9 mm Hg for IV epinephrine and intranasal epinephrine, respectively (P = .38). The rate of successful resuscitation was similar for both groups, five of seven dogs for intranasal epinephrine and four of six dogs for IV epinephrine (P = .66). CONCLUSION: Intranasal epinephrine has similar effects on coronary perfusion pressure and resuscitation compared with standard-dose IV epinephrine. Therefore, the nasal route for administration of epinephrine appears to be an acceptable alternate method of drug delivery during CPR and compares favorably with standard IV therapy in the canine model. Because of the obvious benefits to human patients, these observations suggest further investigation.

Use of retinoids in the treatment of psoriasis.

The limitations of conventional therapy for psoriasis are reviewed, and the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, dosing and therapeutic monitoring of etretinate and other retinoids are described. Traditional treatments for psoriasis include topical application of anthralin and coal tar ointments; systemic therapy with corticosteroids or methotrexate; and systemic or methotrexate; and systemic psoralens combined with exposure to ultraviolet light (PUVA). The topical therapies are beneficial but aesthetically displeasing to patients; the systemic treatments are associated with severe adverse reactions. Etretinate provides another option in the treatment of psoriasis. Etretinate and acitretin, an investigational retinoid, appear to be effective oral therapies for severe variants of psoriasis, especially pustular psoriasis. Retinoids generally do not offer substantial therapeutic advantages over other treatments for chronic-plaque psoriasis. The most common adverse effects of etretinate are cheilitis, alopecia, desquamation of the skin, drying of mucous membranes, and pruritus. Use of low-dose etretinae in combination with other forms of therapy, such as corticosteroids or PUVA, may minimize the frequency of adverse effects. Etretinate is a known teratogen. Its elimination half-life is prolonged to 100-120 days with long-term use. Acitretin, the carboxylic acid derivative of etretinate, has a much shorter elimination half-life than etretinate (50 hours after multiple doses). Its adverse-effect profile is similar to that of etretinate. Etretinate and acitretin appear to be clinically effective for therapy of severe variants of psoriasis. Etretinate should not be used to treat mild psoriasis because of the high incidence of serious adverse effects.

Memory test performance under three different waveforms of ECT for depression.

Thirty-eight patients suffering from severe depression were given a course of ECT (Electroconvulsive therapy) in one of three waveforms. These were high-energy sine wave (HS), high-energy pulse (HP), and low-energy pulse (LP). Patients were assigned to one of these treatments on a double-blind basis. The patients were given a battery of memory tests before ECT commenced, after three treatments, at the termination of treatment, and two weeks after the last treatment. The marked improvement in both verbal and nonverbal memory scores was attributed to the lifting of depression. No significant differences were found between the memory scores of the three treatment groups at any point during the treatment period.

The effect of memory impairment on verbal recognition scores and the marking of acoustic and semantic distractors.

A test of verbal recognition, yielding separate scores for semantic and acoustic distractor errors as well as a simple recognition score, successfully discriminated between various groups of brain-damaged, depressive, and normal subjects in a sequence predictable from their pathology. However, the profile of distractor errors was similar for all groups tested, with a consistent tendency for subjects to make more semantic errors than acoustic errors in all cases. It was concluded that the failure to find qualitative coding differences was probably a consequence of the procedure used and did not necessarily contradict previous findings that amnesics were less effective than normal subjects in coding semantically.

No apology for geriatrics.

A geriatric department is described where turnover has more than kept pace with demand over a period of 17 years. The department provides two basic services-a hospital service to the pensionable population in the community, and support to other hospital departments that care for the elderly.Community emphasis is on a high turnover of patients, enabling early contract and treatment. Over the years a fall in the proportion of "chronic" to "acute" beds has occurred and this has been achieved by having the majority of beds in the general hospital, where it is possible to provide a comprehensive medical service. The hospital role has been to prevent overloading acute resources with potential long-stay cases, and this has been possible without compromising our community obligations.