Low-dose doxapram for treatment of apnoea following early weaning in very low birthweight infants: a randomized, double-blind study

The effects of low-dose doxapram (0.5 mg kg(-1)h(-1)) in combination with caffeine were evaluated on apnoea frequency following weaning from mechanical ventilation, and on blood pressure, in very low birthweight (BW) premature infants. Twenty-nine infants with BW < or=1250 g, gestational age at birth (GA) <34 weeks and postnatal age <5 d, who required minimal respiratory support, were included. Following randomization, they received a loading dose of caffeine citrate and a continuous infusion of doxapram (doxapram, n=14) or placebo (n=15) was started. They were extubated 8 h after starting the infusion, which was continued for 5 d. During this period, weaning was well tolerated in both groups, apnoeas occurred less frequently and there was a greater increase in systolic blood pressure in infants treated with doxapram than in controls. Plasma doxapram levels were also higher than expected. It is therefore suggested that doxapram, even at low doses, should not be used during the first few days of life. Careful monitoring of blood pressure is required if doxapram is used later.     

Doxapram reversal of respiratory failure in a patient refusing assisted ventilation

A 75-year-old man with severe chronic obstructive pulmonary disease and epistaxis experienced progressive respiratory failure after receiving an injection of meperidine and hydroxyzine in preparation for nasal packing. The patient and his family refused endotracheal intubation; despite aggressive medical care, he continued to deteriorate toward an expected fatal outcome. An i.v. infusion of doxapram hydrochloride at 2 mg/min rapidly reversed his downhill course and hypercarbic coma. This case illustrates the potential usefulness of doxapram in the emergency setting. The mechanism of action, indications, dosing methods, and potential side effects of this agent are discussed.     

Dyspnea sensation and chemical control of breathing]

In order to estimate the role of peripheral chemosensitivity in dyspnea sensation, we performed BH experiment under the acute or chronic hypoxic condition. The former was simulated by a given rate (0-3.2 mg/kg/hr) of doxapram infusion. The latter experiment was carried out during sojourn in Lhasa (3700 m), China. Subjects conducted BH by inhaling 7% CO2 in O2 and assessed dyspnea sensation by visual analog scale (VAS) while repeatedly measuring PCO2 at breaking point (BP). Lowering of resting PETCO2 by augmented ventilation was derived by doxapram infusion and during acclimatization at high altitude. The effect of PCO2 on VAS was enhanced by doxapram. However, altitude acclimatization resulted in attenuated effect of PCO2 on VAS despite of further development of hypocapnia. The rate of PCO2 elevation during doxapram infusion was reduced and it might be attributed to decreased body storage of CO2. On the other hand, its rate was tended to recover to sea level value after acclimatization at high altitude and it may have cancelled the mitigated dyspnea sensation. Thus, BHT almost comparable period in both acute hypoxia and during altitude acclimatization. These results suggest that CO2 storage in the body contributes to modify dyspnea sensation as well as augmented peripheral chemosensitivity.     

Doxapram improves pulmonary function after upper abdominal surgery

The effects of doxapram on postoperative pulmonary function were studied in 40 ASA I and II patients randomly allocated to receive either doxapram 1.8 mg.kg-1.h-1 or placebo for 2 h immediately after elective cholecystectomy. The two groups displayed similar reductions of carbon dioxide production at 2 h and 6 h postoperatively, whereas oxygen consumption remained at preoperative levels for 24 h. Minute ventilation was similarly reduced in the two groups at 2 h and 6 h postoperatively, with corresponding increases in PaCO2. PaO2 was similarly and significantly decreased in both groups postoperatively, whereas P(A-a)O2 remained unchanged at 2 h and 6 h in doxapram-treated patients. FRC was reduced postoperatively in both groups, significantly more so in the control group at 6 h. Various indices of intrapulmonary gas distribution, including the functional (nitrogen) dead space, underwent similar changes in the two groups. By contrast, the physiological dead space was reduced in doxapram-treated patients at 2 h, 6 h and 24 h postoperatively, whereas no significant changes were seen in the control group. The ventilatory equivalent for CO2 was significantly lower in the doxapram-treated group, implying higher ventilatory efficiency. Our findings indicate that infusion of doxapram postoperatively attenuates the impairment of pulmonary function postoperatively, chiefly via effects on V'A/Q' ratios. No side effects of doxapram were observed.     

Effect of doxapram on the action of other drugs and the hepatic drug-metabolizing system in mice

Effects of doxapram, a respiratory stimulant, on the action of other drugs and the activity of the hepatic drug-metabolizing enzyme were studied in mice. The hypothermic effect induced by aminopyrine and the muscle relaxant effect induced by meprobamate were potentiated by the pretreatment with doxapram 60 min before. Furthermore, doxapram significantly enhanced the lethalities of picrotoxin and strychnine and the analgesic actions of aminopyrine and morphine. The plasma concentration of aminopyrine or pentobarbital in doxapram-treated mice was higher than those in untreated mice, and the plasma concentration of normustard related to an active metabolite of cyclophosphamide after the administration of cyclophosphamide was lower in doxapram-treated mice. On the other hand, doxapram (50 mg/kg, i.p.) reduced remarkably the activities of aminopyrine N-demethylase and aniline hydroxylase in the hepatic 9,000xg supernatant fraction, and also reduced the cytochrome P-450 contents in hepatic microsomes. However, no significant alteration by doxapram was observed on the activities of NADH-ferricyanide reductase and NADPH-cytochrome c reductase and cytochrome b5 contents. It seems likely that the mechanisms of the interaction between doxapram and combined drugs involved the depression of the hepatic drug-metabolizing system in microsomes and a subsequent variation of drug level in the plasma.     

The use of Dopram as a respiratory stimulant following Immobilon in the pony

The effects of the analeptic agent, Dopram (doxapram hydrochloride) were investigated in 2 ponies during Immobilon - induced neuroleptanalgesia. Although Dopram was demonstrated to exert a degree of respiratory stimulation, this was concluded to provide no overall advantage. The etorphine-induced hypoxic hypoxia was only partially reversed, and there was additional cardiovascular stimulation, in contrast to the previously reported tendency for arterial blood pressure to return towards conscious control values during the course of action of Immobilon.     

Comparison of unilateral arytenoid lateralization and ventral ventriculocordectomy for the treatment of experimentally induced laryngeal paralysis in dogs

This study evaluated changes in respiratory function in dogs with experimentally induced laryngeal paralysis treated with either unilateral arytenoid lateralization or ventral ventriculocordectomy, and compared the effectiveness of these procedures. Evaluation consisted of clinical assessment and tidal breathing flow volume loop and upper airway resistance measurements. Carbon dioxide and doxapram hydrochloride were used as respiratory stimulants. Initially, all dogs improved clinically after corrective surgery. However, by the end of the study, laryngeal collapse had developed in 2 of 5 dogs corrected by ventral ventriculocordectomy. No statistical differences in upper airway mechanics testing were seen between the surgical procedures. With both groups combined, many measurements of upper airway obstruction improved after surgical correction. Based on this study, these surgical procedures yield comparable results, although additional studies are needed to evaluate both the cause of laryngeal collapse and the role of upper airway mechanics testing in the evaluation of canine laryngeal paralysis.     

Rapid roentgenologic diagnosis of acute cholecystitis

A rapid and safe method of roentgenographic evaluation of the acutely inflamed wall of the gallbladder, infusion tomography of the gallbladder, was performed 146 times, and the correlation with 67 subsequent cholecystectomies was reviewed. If the results of infusion tomogram of the gallbladder are abnormal, the gallbladder is diseased; if acute cholecystitis is present, the results of the examination will be abnormal in 96 per cent; if results of the infusion tomogram of the gallbladder are normal, the results are questionable, and oral cholecystography should be performed to evaluate the condition further. If the results of a repeat dosage oral cholecystogram are abnormal, the gallbladder probably is diseased, even if the results of an infusion tomographic examination of the gallbladder are normal.     

Effect of conditioning method and testing method on strength of lithium-induced taste aversion learning.

Here the authors evaluated the effect of the method of conditioning (bottle or intraoral [IO] infusion) on the strength of a flavor-drug association when measured in a standard 1-bottle consumption test or when measured by IO infusion in a taste reactivity test. When tested with the bottle test in Experiment 1, rats conditioned by bottle displayed stronger taste avoidance than those conditioned by IO infusion. When tested for rejection reactions with the taste reactivity test in Experiment 2, rats conditioned by infusion displayed a stronger aversion than did rats conditioned by bottle. The results suggest that when the contextual cues of conditioning are similar at conditioning and testing, a stronger association is evident regardless of the individual specifics of each method. These results may shed light on recent reports that different neural mechanisms are involved in conditioning by active consumption and passive infusion. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of intravenous infusions on laboratory results in blood specimens drawn proximal to the insertion site of an intravenous canula

BACKGROUND: Blood sampling contralateral to the insertion site of an intravenous line is always first choice. When blood must be drawn proximal to an i.v. insertion site, dilution and contamination by the infused substance can occur. To study the effects of obtaining blood specimens proximal to a discontinued intravenous line a clinical trial in a small community hospital was designed. METHODS: Ten patients received an intravenous infusion with sodium chloride 0.45%/dextrose 2.5%. Bloodsamples were taken simultaneously from the i.v.-arm and the control-arm with the infusion running and 1, 3, and 5 min after shutting off the infusion. RESULTS: Between-arm differences are significant for all analytes while the infusion is running, but not after the infusion is discontinued. Wide ranges in differences in terms of percentage exist for many analytes 1 min after shutting off the infusion, and for glucose also 3 min after shutting off the infusion. CONCLUSIONS: A three minute interval is recommended when drawing blood proximal to a shut-off infusion. Longer intervals may be advisable for analytes present in the infused substance.     

The effect of stevioside on glucose metabolism in rat

This study was conducted to determine the effect of stevioside (SVS) on glucose metabolism. The experiments were performed in male Wistar rats treated with SVS either by intravenous infusion or feeding. SVS infusion (150 mg/mL) was carried out in doses of 0.67, 1.00, and 1.33 mL.kg-1 body weight.h-1. The plasma glucose level significantly increased both during and after SVS infusion, whereas it was not affected by SVS feeding (13.3 mL.kg-1 body weight). The glucose turnover rate (GTR) of [14C(U)]glucose and [3(-3)H]glucose was not significantly different between control and SVS infusion animals. Percent glucose carbon recycling and glucose clearance were reduced from 28.7 +/- 1.3 to 23.0 +/- 1.6% (p < 0.05) and from 6.46 +/- 0.34 to 4.99 +/- 0.20 mL.min-1.kg-1 body weight (p < 0.01), respectively. The plasma insulin level did not change, whereas the plasma glucose level significantly increased from 120.3 +/- 5.9 to 176.8 +/- 10.8 mg% (p < 0.01) during SVS infusion. Animals pretreated with angiotensin II and arginine vasopressin showed no significant effect, while animals pretreated with prazosin had an attenuated hyperglycemic effect of SVS infusion. Pretreatment with indomethacin or N omega-nitro-L-arginine methyl ester (L-NAME) alleviated the plasma glucose level during the second period of SVS infusion. Pretreatment with the combination infusion of indomethacin and L-NAME reduced the plasma glucose level from 117.0 +/- 1.8 to 109.0 +/- 1.7 mg% (p < 0.001), and normalized the plasma glucose level in the second period of SVS infusion. Insulin infusion inhibited the hyperglycemic effect of SVS infusion. The present results show that the elevation of the plasma glucose level during SVS infusion is not due to the reduction of the insulin level. It is probably the effect of SVS on glucose transport across the cell. Insulin response to a high plasma glucose level is suppressed during SVS infusion. Several interactions among norepinephrine, prostaglandin, and nitric oxide are involved in modulating the hyperglycemia during SVS infusion.     

Hyperkalemia associated with rapid infusion of conventional and lipid complex formulations of amphotericin B

A child developed hyperkalemia and cardiac arrest with infusion of an amphotericin B lipid complex 5.0 mg/kg over 1 hour. Another child, with chronic renal failure, developed hyperkalemia after infusion of conventional amphotericin B deoxycholate 1.0 mg/kg over 2 hours. Rapid infusion of the agent causes hyperkalemia in dogs and humans that is exacerbated in the setting of renal failure. A lipid formulation of amphotericin B is commercially available, and no reports of hyperkalemia are associated with its administration.     

Continuous infusion of chemotherapy: focus on 5-fluorouracil and fluorodeoxyuridine

Continuous infusion of chemotherapy is one of the developments to try to improve the treatment of metastatic cancer. There is a sound theoretical rationale to deliver cytotoxic drugs as a continuous infusion. Furthermore, the development of reliable venous access devices and portable infusion pumps enables patients to be treated in an ambulatory setting. This review focuses on the continuous infusion of the most frequently used drugs: 5-fluorouracil (5-FU) and fluorodeoxyuridine (FUDR). An overview is given of both preclinical studies and studies in humans. Continuous infusion of 5-FU and FUDR has proven to be feasible in all studies. However, the results (response rate and especially survival) are rather disappointing. So far, continuous infusion of cytostatic drugs can still be considered as an experimental procedure. Whether protracted, intermittent of circadian modulated continuous infusion is the optimal treatment schedule has still to be proven in future studies. Furthermore, studies are needed to demonstrate whether dose intensity for most tumours is important for treatment outcome. Also, studies are needed to investigate quality of life and economic issues.     

Pre- and posttraining infusion of N-methyl-D-aspartate receptor antagonists into the amygdala impair memory in an inhibitory avoidance task

Involvement of amygdaloid N-methyl-D-aspartate (NMDA) receptors in memory processes was investigated. Rats with cannulas implanted in the basolateral amygdala were trained on a 1 trial step-through inhibitory avoidance task and tested for 24-hr retention. Pretraining infusion of 2-amino-5-phosphonovaleric acid (APV) into the amygdala, but not striatum or hippocampus, produced a dose-dependent retention deficit, which was attenuated by immediate posttraining intra-amygdala infusion of NMDA. Posttraining APV infusion also caused a dose- and time-dependent retention deficit. Pretest APV infusion had no effect on performance in the retention test. Further, pre- or posttraining infusion of 5.0 micrograms APV failed to affect acquisition and retention in the Morris water maze task. These findings suggest that amygdala NMDA receptors are normally activated by aversive training and play a critical role in memory formation for affective experience.     

The effects of large volume intravenous fluid infusion on neonatal renal function

Twenty healthy infants weighing less than 2,000 gm were studied at low (3.6 ml/kg/hr) or high (10.3 ml/kg/hr) rates of intravenous infusion. Inulin clearance determined by the constant infusion method was greater at the high rate of infusion (p = less than 0.05). Inulin clearance in two groups of infants over 2,000 gm studies at the same low or high rates of infusion did not increase at the higher rate of infusion. Since the GFR in infants less than 2,000 gm depends partially on the rate of intravenous infusion, small, healthy preterm infants may benefit from a rate of fluid administration greater than the low rate. When studies at low and high rates of infusion were compared in the 20 infants less than 2,000 gm, the fractional urinary sodium excretion increased with the increased fluid load. Delivery of fluid from the proximal tubule (CH2O =Na per dl GFR) increased (p less than 0.005). Free-water clearance and the absolute volume of urine increased at the high rate of infusion. These data indicate that the healthy preterm infant less than 2,000 gm, like the adult, compensates by increasing free-water clearance and urine volume when challenged with a large fluid load. Although fluid changes of short duration are appropriately handled, the effect of continuous rapid infusion on water and sodium balance in infants of this size remains to be determined.     

MRI and articular cartilage

There are considerable laboratory data and information from animal and continuous culture in vitro models to support continuous infusion therapy for penicillins and cephalosporins, but, as yet, the only existing clinical data relate to cephalosporins. Penicillins do not exert concentration-dependent killing in the therapeutic range but have a post-antibiotic effect (PAE) against Gram-positive cocci but not Gram-negative rods. Animal models indicate the time (T) during which the serum concentrations exceed the minimum inhibitory concentration (MIC) of the pathogen [T > MIC] determines outcomes. Pharmacokinetic studies in humans indicate that continuous infusion with penicillins is possible but there are no clinical data on efficacy. Cephalosporins have similar pharmacodynamic properties to penicillins; T > MIC determines outcome. Data related to ceftazidime indicate that the drug concentration at steady-state (Css) should exceed the pathogen MIC by > 1-fold and perhaps by 4- to 5-fold or more. Human pharmacokinetics of ceftazidime administered by continuous infusion to a wide variety of patient groups indicates that Css of > 20 mg/L can easily be achieved using conventional daily doses. Clinical data indicate increased effectiveness of a continuous regimen in neutropenic patients with Gram-negative infection. Furthermore cefuroxime administration by continuous infusion has resulted in lower doses and shorter course durations. Little is known of the pharmacodynamics of monobactams and there are few clinical data on continuous infusion therapy. Carbapenems have different pharmacodynamics to other beta-lactams as they have concentration-dependent killing and a PAE with both Gram-positive and Gram-negative bacteria. While T > MIC has a role in determining outcomes, the proportion of the dosing interval for which serum drug concentrations should exceed the pathogen MIC is less than for other beta-lactams. In vitro models have shown that continuous infusion is effective, as is less frequent dosing. There are few data on continuous infusion of carbapenems but some patients have been treated with once-daily dosing. Clinically, continuous infusion therapy with penicillins and cephalosporins should be considered in patients infected with susceptible Gram-negative rods not responding to conventional therapy. As an approximation, the same total daily dose should be given but a bolus intravenous injection should be give at the start of continuous infusion to ensure Css is reached rapidly. The Css may be difficult to predict and determination of serum drug concentrations may be indicated. Ideally, the Css should be calculated based on the MIC of the potential pathogen and may be higher or lower than the Css achieved by a conventional daily dose.     

A novel method for efficient drug delivery

Local delivery of anti-thrombotic and anti-restenotic drugs is desired to achieve high concentrations of agents which may be rapidly degraded systemically or which exhibit very short half-lives in vivo. In this article, the operating characteristics of a novel local drug delivery method are described and its effectiveness demonstrated computationally and experimentally. Computational models used a finite volume method to determine the concentration field. Optical dye density measurements of Evans blue in saline were performed in an in vitro steady flow system. Modeling parameters were kept in the physiologic range. Experimental flow visualization studies demonstrated high concentrations of infusate near the vessel wall. Computational studies predicted high, clinically significant drug concentrations along the wall downstream of the infusion device. When the radial infusion velocity is large (infusion flow rate, Qinf>0.5% of the main flow rate, Q), the wall concentration of the infused drug remains high, e.g., levels are greater than 80% of the infusate concentration 5 cm downstream of the infusion device. At lower infusion rates (Qinf<0.001Q), the drug concentration at the wall decreases exponentially with axial distance to less than 25% of the infusate concentration 5 cm downstream of the infusion device, although therapeutic drug levels are still readily maintained. The near wall drug concentration is a function of flow conditions, infusion rate, and the drug diffusivity. Good agreement was obtained between computational and experimental concentration measurements. Flow simulation and experimental results indicate that the technique can effectively sustain high local drug concentrations for inhibition of thrombosis and vascular lesion formation.     

Fos-like immunoreactivity in the medulla after acute and chronic angiotensin II infusion

Acute and chronic angiotensin (Ang) II hypertension are reported to have different mechanisms that involve differential contributions of the peripheral vasculature and the nervous system. Acute Ang II hypertension is mediated primarily by Ang acting at vascular smooth muscle, whereas chronic Ang II hypertension appears to have a neural component. In our experiments, the transition from a peripheral to a neural effect occurs over 10 hr of Ang II infusion in rats. To identify the role of the central nervous system in this transition, we measured Fos immunoreactivity, an indicator of neural activity, in the nucleus of the solitary tract (NTS), caudal ventrolateral medulla (CVL) and rostral ventrolateral medulla (RVL) in normal, sinoaortic denervated (SAD) and sham SAD rats after 2- or 18-hr Ang II infusion (50 ng/kg/min intravenously). Vehicle (5% dextrose) was infused in normal rats as control. Comparable increases in arterial pressure were produced by 2- and 18-hr Ang II infusion in all groups. Fos was increased in the NTS in sham SAD rats by 2- and 18-hr Ang II infusion (P < .05 vs. vehicle control). In the CVL, only 2-hr Ang II infusion was associated with increased Fos in normal and sham SAD rats (P < .05 vs. vehicle control) but not in SAD rats. In the RVL, 18-hr Ang II infusion elevated Fos in all groups (P < .05 vs. vehicle control). Activation of NTS during Ang II infusion is baroreceptor mediated and independent of infusion duration. Acute Ang II infusion produced a baroreceptor-mediated activation of the CVL, a region associated with baroreflex sympathoinhibition. Chronic Ang II infusion produced a baroreceptor-independent activation of the RVL, a brain area associated with sympathoexcitation, suggesting a centrally mediated increase in sympathetic outflow that may be associated with chronically infused Ang II.     

Quality of life assessment in reflux disease

It has been suggested that inhibitors of nitric oxide synthesis are of value in the treatment of hypotension during sepsis. In this pilot study, we examined the effects of inhibition of nitric oxide synthesis by continuous infusion of N(omega)-nitro-L-arginine methyl ester (L-NAME) at 1.5 mg/kg/h in a patient with severe septic shock. L-NAME produced a rise in mean arterial blood pressure and systemic vascular resistance; catecholamine infusion could be reduced. Parallel to these findings, there was a 50% reduction in cardiac output and a 5-fold rise in pulmonary vascular resistance, which resulted in severe pulmonary hypertension after 3 h of L-NAME infusion, for which the infusion had to be stopped. Following the termination of L-NAME infusion, pulmonary artery pressure and blood pressure returned to baseline values, although pulmonary and systemic vascular resistance remained elevated for several hours. We conclude that nitric oxide appears to play a role in the cardiovascular derangements during human sepsis. Inhibition of nitric oxide synthesis with L-NAME can increase blood pressure and systemic vascular resistance. However, reduced cardiac output and pulmonary hypertension are possible side effects of continuous NO synthase inhibition. These side effects necessitate careful monitoring and may hinder the clinical application of NO synthase inhibitors.     

Liver stem cells: a two compartment system

STUDY OBJECTIVE: To develop management guidelines for the treatment of anaphylactoid reactions to intravenous N-acetylcysteine (NAC) and to assess the safety of restarting the infusion after a reaction. METHODS: In phased 1, we used a 6-year retrospective case series of hospitalized patients and a review of the literature to develop the management guidelines for anaphylactoid reactions to intravenous NAC. In phase 2, these guidelines were evaluated prospectively in our poison-control center. RESULTS: In phase 1, the charts of 11 patients with anaphylactoid reactions (9 cutaneous and 2 systemic) were reviewed. In most cases, no treatment or treatment with diphenhydramine alone or with salbutamol was sufficient to continue or restart NAC infusion safely. On the basis of our findings in those patients and on published experience, we concluded that anaphylactoid reactions to intravenous NAC are dose-related and the antihistamines are useful in controlling and in preventing recurrence of anaphylactoid symptoms. We developed the following guidelines: flushing requires no treatment, urticaria should be treated with diphenhydramine, and NAC infusion should be continued in both cases. Angioedema and respiratory symptoms each require the administration of diphenhydramine and symptomatic therapy. In these cases, NAC infusion should be stopped but, when necessary, can be started 1 hour after the administration of diphenhydramine in the absence of symptoms. In phase 2, 50 patients (31 cutaneous and 19 systemic reactions) were treated prospectively with the use of these guidelines. Recurrence of symptoms occurred in only one case involving a deviation from the guidelines. The NAC infusion was restarted immediately after the administration of diphenhydramine in a patient who sustained a systemic reaction. CONCLUSION: Non-life-threatening anaphylactoid reactions to intravenous NAC are treated easily and the infusion may be continued or restarted safely after the administration of diphenhydramine.