Acute Respiratory Depression Research Articles

The Effect of GP683, an Adenosine Kinase Inhibitor, on the Desflurane Anesthetic Requirement in Dogs

The availability of an analgesic compound devoid of the side effects associated with the commonly used opioid and nonsteroidal antiinflammatory drugs would be useful during the perioperative period. Although adenosine has analgesic and anesthetic-sparing properties, it also produces dose-dependent cardiovascular depression. Inhibitors of adenosine kinase may be able to provide analgesia without producing acute cardiovascular or respiratory depression. This preliminary study investigated the effects of a novel adenosine kinase-inhibiting drug, GP683, on the minimum alveolar anesthetic concentration (MAC) of desflurane in dogs. Seven mongrel dogs were administered one of three different GP683 dose regimens (or the solvent) by intravenous infusion on separate occasions according to a cross-over study design. After determining the baseline desflurane MAC value, GP683 was infused at 75, 150, or 300 microg x kg(-1) x min(-1) for 5 min as a loading dose, followed by 15, 30, or 60 microg x kg(-1) x min(-1) for an additional 85 min to maintain a stable plasma drug level. The desflurane MAC was redetermined 30-90 min after starting the study drug or vehicle infusion, and 30-90 min and 120-180 min after termination of the infusion. Cardiovascular variables and plasma concentrations of GP683 were determined at specific intervals before, during, and after the MAC determinations. The three GP683 dose regimens produced 22%, 31%, and 50% decreases in the desflurane MAC, respectively. In addition, there was good correlation between the decrease in desflurane MAC and the plasma GP683 concentration (r = -0.78). Although the mean arterial pressure (MAP) was decreased up to 25% by the highest infusion rate of GP683, adjustments in the desflurane concentration to an equi-MAC value resulted in normalization of the MAP values. Furthermore, GP683 produced no changes in heart rate. In conclusion, the adenosine kinase-inhibiting drug, GP683, produced dose-dependent decreases in the desflurane MAC of dogs without producing untoward hemodynamic changes. An investigational drug (GP683) that can increase the levels of an important endogenous substance in the body (adenosine) has been found to decrease the anesthetic requirement in dogs without producing adverse effects on the cardiovascular system.

Central opiate mu-receptor-mediated suppression of tissue protein synthesis.

We determined the dose-dependent effects of central mu-opioid receptor stimulation on rates of tissue protein synthesis. Chronically catheterized conscious rats received an intracerebroventricular injection of [D-Ala2, N-Me-Phe4,Gly5-ol]enkephalin (DAGO, 0.5, 2, or 8 nmol/rat) or water (5 microliters) 45 min before determination of protein synthesis by the flooding dose technique. DAGO produced a significant decrease in tissue protein synthesis in liver (57%), spleen (54%), gut mucosa (36%), gut serosa (23%), kidney (48%), gastrocnemius (33%), and plantaris muscle (27%), but it did not alter rates of protein synthesis in the brain, heart, and soleus muscle. DAGO produced an acute dose-dependent respiratory depression 30 min after intracerebroventricular injection; this depression resulted in acidosis, hypoxia, and hypercapnia (pH 7.19 +/- 0.04, arterial partial O2, pressure 44.2 +/- 3.4 Torr, arterial O2 saturation 65.3 +/- 5.5%, and PCO2 66.3 +/- 4.4 Torr). Intracerebroventricular DAGO increased circulating levels of catecholamines, corticosterone, and growth hormone but did not alter those of insulin and insulin-like growth factor I. Significant positive correlations between protein synthesis and pH were observed in the tissues studied (i.e., liver protein synthesis vs. pH, P < 0.0001, r = 0.902; gastrocnemius protein synthesis vs. pH, P < 0.0001, r = 0.830). Our results indicate that mu-receptor stimulation inhibits tissue protein synthesis, and this effect appears to be secondary to respiratory depression and the resulting acidosis and/or hypoxia. Furthermore, our findings suggest differential sensitivity in tissue response to alterations in pH, hypoxia, and stress hormone elevation.

An unusual complication following combined spinal-epidural anaesthesia for caesarean section

The combined spinal-epidural technique is widely used in obstetric anaesthetic practice. Epidural catheter migration through a dural hole is a theoretical but rarely described complication. We report a case of acute and life-threatening respiratory depression following administration of diamorphine through an epidural catheter after a single space combined spinal-epidural technique for caesarean section. We believe this complication occurred as a result of catheter migration through a dural hole into the subdural space and rupture of the thin arachnoid layer causing massive subarachnoid blockade.

Mortality, morbidity and drug consumption in a rural area (Spain).

A descriptive study was made of the health indicators in 5 rural municipalities of the province of Castellón (Spain), with a total of 1428 inhabitants. This population is characterized by its aging, 36.9% of all individuals being older than 65 years. A retrospective evaluation was made of the annual mortality rates between 1940 and 1990, and of morbidity and medications consumption for the period between June 1991 and May 1992. An increase in general mortality was observed during the study period, though the rates also diminished in relation to age groups, sex and cause of death. In addition, 59.45% of the study population made use of health-care services in the course of one year, an average of 2.59 drugs being prescribed per inhabitant in that same period. Morbidity in decreasing order of importance was attributed to acute respiratory disease, osteomuscular disorders, hypertension, depression and gastric pathology. Medications for the common cold and coughing were the most frequently used drugs, along with pain-killers, cardioactive agents, psycholeptics and non-sterioidal anti-inflammatory drugs (NSAIDs). Aging causes the mortality variations recorded, despite the socio-sanitary improvements observed in the zone during the study period. Aging may also be related to the important use of healthcare services and of drugs noted in the study. The highest morbidity rates and drug consumption levels corresponded to chronic diseases that deteriorate patient quality of life without actually increasing mortality.

Potentiation of acute opioid-induced respiratory depression and reversal of tolerance by the calcium antagonist nimodipine in awake rats.

The interaction between sufentanil, a mu-opioid agonist, and the Ca2+ antagonist nimodipine on respiration and on the development of opioid tolerance in awake rats has been analyzed. Our previous work demonstrated that chronic treatment with nimodipine together with sufentanil increases the analgesic potency of the opioid 50 fold. Therefore, we have investigated whether the opioid-induced respiratory depression is potentiated in parallel with the analgesia. Ventilation was measured by the whole body plethysmographic method. In naive rats, sufentanil (10-80 micrograms/kg) consistently induced a dose-dependent respiratory depression. Pretreatment with nimodipine (200 micrograms/kg) potentiated this effect but to a lesser extent than it potentiated analgesia. After chronic administration of the opioid (2 micrograms/h, 7 days) tolerance was manifested as a reduction in both the area under the time course curve and in the maximum effect. Nimodipine (1 microgram/h) administered concurrently with sufentanil for 7 days counteracted the tolerance to respiratory depression but no additional potentiation was observed. These results demonstrate that the interaction between nimodipine and sufentanil is not limited to antinociception but also extends to respiratory depression. However, compared with analgesia, the clinical relevance of a potential increase in opioid-induced respiratory depression by nimodipine may be negligible.

Comparison of non-invasive respiratory and arterial blood gas analysis. A recovery room study on acute respiratory depression

The effect on invasive and non-invasive oxygen, carbon dioxide and haemoglobin saturation measures of two repeated doses of alfentanil 0.5 microgram/kg were tested in 16 patients scheduled for elective cataract surgery under periocular anaesthesia. Alfentanil caused an acute respiratory depression, which was demonstrated as increased levels of arterial and end-tidal carbon dioxide and concomitant decrease in arterial and end-tidal oxygen levels as well as decreased arterial blood saturation and pulse oximeter readings. There was a good correlation between the non-invasive respiratory parameters and blood gas levels, as well as between pulse oximetry numbers and oxygen saturation of arterial blood. Therefore, hypoventilation and concurrent hypoxaemia can be predicted by monitoring end-tidal CO2.

Cathartic-induced magnesium toxicity during overdose management

A 39-year-old women was admitted to the hospital following a large ingestion of a tricyclic antidepressant. The administration of magnesium citrate in repeated doses with activated charcoal resulted in a striking increase in serum magnesium levels followed by acute neuromuscular deterioration and respiratory depression. The patient required dialysis for control of hypermagnesemia. Her clinical condition improved slowly without further complication and she was discharged to a rehabilitation center.

Acute poisoning due to non-steroidal anti-inflammatory drugs. Clinical features and management.

Despite the widespread use of non-steroidal anti-inflammatory drugs (NSAIDs), the current number of reported cases of poisoning is small. However, with the introduction of 'over-the-counter' preparations of NSAIDs in some countries (e.g. ibuprofen in the UK and USA) an increased incidence of acute poisoning from this group of drugs can be expected. Conventionally, NSAIDs are divided into the following groups based on their chemical structure: arylpropionic acids, indole and indene acetic acids, heteroarylacetic acids, fenamates, phenylacetic acids, pyrazolones and oxicams. Unless NSAIDs are ingested in substantial overdose, acute poisoning with these agents does not usually result in significant morbidity or mortality. In most cases the clinical features are mild and confined to the gastrointestinal and central nervous systems, though acute renal failure, hepatic dysfunction, respiratory depression, coma, convulsions, cardiovascular collapse and cardiac arrest may complicate severe poisoning. Arylpropionic acid derivatives were thought initially to have a low order of toxicity in overdose but, in addition to anticipated gastrointestinal symptoms, headache, tinnitus, hyperventilation, sinus tachycardia, hypoprothrombinaemia, haematuria, proteinuria and acute renal failure have been described. In addition, drowsiness, coma, nystagmus, diplopia, hypothermia, hypotension, respiratory depression and cardiac arrest have been reported in severe cases of poisoning. Oxyphenbutazone and phenylbutazone are considerably more toxic in overdose. Complications of severe poisoning include coma, convulsions, hepatic dysfunction, acute renal failure, sodium and water retention, haematuria, cardiovascular collapse, respiratory alkalosis, metabolic acidosis, hypoprothrombinaemia and thrombocytopenia. In contrast, indomethacin appears to be much less toxic. In addition to gastrointestinal symptoms, indomethacin taken in overdose induces headache, tinnitus, dizziness, lethargy, drowsiness, confusion, disorientation and restlessness. Only 1 case of acute sulindac poisoning has been reported in the literature. A 16-year-old boy was admitted with hypokalaemia (2.2 mmol/L), transient granulocytosis and 'scanty' haematemesis after ingesting 12 g sulindac. No case of acute tolmetin poisoning have been reported. The fenamates (flufenamic acid, meclofenamic acid, mefenamic acid, tolfenamic acid) are, with the exception of mefenamic acid, not as widely prescribed as other groups of NSAIDs. In overdose, mefenamic acid may result in nausea, vomiting, diarrhoea, muscle twitching, convulsions and coma.(ABSTRACT TRUNCATED AT 400 WORDS)

Patient-controlled analgesic therapy: clinical experience.

Fifty-six surgical patients self-administered i.v. narcotic analgesics to combat postoperative pain. Analgesic demand per h was 2.7 +/- 1.1 mg of morphine, 26 +/- 10 mg of pethidine or 2.3 +/- 0.8 mg of ketobemidone, which reflects the equianalgesic ratios. Acute respiratory depression was seen in two hypovolaemic patients as evidenced by a raised PaCO2 on air breathing. Carbon dioxide retention disappeared upon correction of hypovolaemia. Late respiratory complications of short duration were encountered in 13%. Drowsiness and dry mouth were the most frequent complaints. Self-administered analgesia was considered highly satisfactory by the patients.

THERAPY OF SALICYLATE POISONING

SALICYLATE intoxication presents as complex a metabolic disturbance as the pediatrician is likely to be called upon to treat. This disorder is frequently accompanied by a) one of several disturbances of acid-base equilibrium, b) depletion of body potassium, c) fever, d) disturbed mental state and coma, e) bleeding due to hypoprothrombinemia, thrombocytopenia or to other causes, and f) variable degrees of dehydration. In very severe cases, acute pulmonary edema, respiratory depression or acute renal failure may occur. The nature of the acid-base disturbances is considered in this issue of Pediatrics. The typical disturbance in children is a mixed state involving primary respiratory stimulation, manifested by hyperventilation, and a primary metabolic disturbance, manifested by ketosis. The sequential nature of these two disturbances has been stressed in the past but without adequate documentation. However, it is clear that many patients do present with both disturbances occurring simultaneously.

DISTURBANCES OF ACID-BASE EQUILIBRIUM IN SALICYLATE INTOXICATION

The initial disturbances in acid-base equilibrium and the pathways of recovery have been studied in 33 patients, predominantly infants and young children, with salicylate intoxication due either to accidental ingestion or to therapeutic overdosage. In nearly all patients there were significant reductions in the total content of carbon dioxide and in pCO2 of plasma; pH of the blood did not vary consistently: some patients were alkalotic, others were acidotic, while still others had no significant deviation in pH of the blood. Evidence was obtained in many of the patients for a mixed disturbance in acid-base equilibrium with primary disturbances in the metabolic and in the respiratory components. The nature of the component of metabolic acidosis has been analyzed by a detailed study of the anions in the serum of five patients with this disturbance. A variety of anions were present in excess: chloride, salicylate, and undetermined anion; in one patient the concentration of phosphate was also elevated. Reasons are presented suggesting that the undetermined anion fraction represents largely ketone bodies. The pathway of return to normal acid-base equilibrium was studied with six patients presenting with acid pH. The predominent tendency of this group was to recover through a point at which pH of the blood was normal or even alkaline, even though pCO2 was still low. In two patients initially presenting with acid pH, acute respiratory depression supervened after acute pulmonary edema. Respiratory depression was accompanied by a marked elevation of pCO2 and a marked fall in pH. One of these patients expired; the other was successfully ventilated by artificial means and made a full recovery. The basic actions of toxic amounts of salicylate—respiratory stimulation, changes in metabolic rate, and disturbances in the metabolism of carbohydrate, protein and fat—are reviewed. The pathogenesis of the acid-base disturbances is formulated in terms of these known actions of toxic amounts of salicylate. Several factors correlate with the particular type of disturbance which a given patient may develop and may be important as conditioning influences. These factors are age of the patient, duration of the intoxication, type of intoxication (i.e., whether accidental or the result of therapeutic over-dosage) and, perhaps, the amount of salicylate ingested.