Pharmacologic interventions for the therapy of postanesthetic shivering in adults: a systematic review and network meta-analysis.

INTRODUCTION: Shivering is a common side effect after general anesthesia. Risk factors are hypothermia, young age and postoperative pain. Severe complications of shivering are rare but can occur due to increased oxygen consumption. Previous systematic reviews are outdated and have summarized the evidence on the topic using only pairwise comparisons. The objective of this manuscript was a quantitative synthesis of evidence on pharmacological interventions to treat postanesthetic shivering. EVIDENCE ACQUSITION: Systematic review and frequentist network meta-analysis using the R package netmeta. Endpoints were the risk ratio (RR) of persistent shivering at one, five and 10 minutes after treatment with saline/placebo as the comparator. Data were retrieved from Medline, Embase, Central and Web of Science up to January 2022. Eligibility criteria were: randomized, controlled, and blinded trials comparing pharmacological interventions to treat shivering after general anesthesia. Studies on shivering during or after any type of regional anesthesia were excluded as well as sedated patients after cardiac surgery. EVIDENCE SYNTHESIS: Thirty-two trials were eligible for data synthesis, including 28 pharmacological interventions. The largest network included 1431 patients. The network geometry was two-centered with most comparisons linked to saline/placebo or pethidine. The best interventions were after one minute: doxapram 2 mg/kg, tramadol 2 mg/kg and nefopam 10 mg, after 5 minutes: tramadol 2 mg/kg, nefopam 10 mg and clonidine 150 µg and after 10 minutes: nefopam 10 mg, methylphenidate 20 mg and tramadol 1 mg/kg, all reaching statistical significance. Pethidine 25 mg and clonidine 75 µg also performed well and with statistical significance in all networks. CONCLUSIONS: Nefopam, tramadol, pethidine and clonidine are the most effective treatments to stop postanesthetic shivering. The efficacy of doxapram is uncertain since different doses showed contradictory effects and the evidence for methylphenidate is based on a single comparison in only one network. Furthermore, both lack data on side effects. Further studies are needed to clarify the efficacy of dexmedetomidine to treat postanesthetic shivering.

Effect of doxapram on the electrical activity of the diaphragm waveform pattern of preterm infants.

OBJECTIVE: This study aimed to evaluate the change in the waveform pattern of the electrical activity of the diaphragm (Edi) following the administration of doxapram in extremely preterm infants ventilated with neurally adjusted ventilatory assist (NAVA). STUDY DESIGN: We conducted this retrospective cohort study in our neonatal intensive care unit between November 2019 and September 2021. The study participants were extremely preterm infants under the gestational age of 28 weeks who were ventilated with NAVA and administered doxapram. We collected the data of the Edi waveform pattern and calculated the proportion. To analyze the change in the proportion of the Edi waveform pattern, we compared the proportion of the data for 1 h before and after doxapram administration. RESULTS: Ten extremely preterm infants were included. Almost all the patients' respiratory condition improved after doxapram administration. The ventilatory parameters-Edi peak, Edi minimum, peak inspiratory pressure, time in backup ventilation, and number of switches to backup ventilation-did not change significantly. However, the proportion of phasic pattern significantly increased (before: 46% vs. after: 72%; p < 0.05), whereas the central apnea pattern significantly decreased after doxapram administration (before: 31% vs. after: 8.3%; p < 0.05). The proportion of irregular low-voltage patterns tended to decrease, albeit with no significant changes. CONCLUSION: Our results indicated that the proportion of Edi waveform patterns changed following doxapram administration. Edi waveform pattern analysis could be a sensitive indicator of effect with other intervention for respiratory conditions.

Influence of doxapram and intermittent 10% carbon dioxide inspiration on cardiovascular and laryngeal functions in anesthetized dogs.

OBJECTIVE: To compare the effects of two doses of doxapram intravenous injection and carbon dioxide inhalation on the cardiovascular and laryngeal functions of anesthetized hounds. STUDY DESIGN: Experimental study. ANIMALS: Six healthy adult dogs. METHODS: In a Latin-square design, the mean arterial blood pressure (MABP) and heart rate (HR) were recorded continuously. The inspiratory normalized glottic gap areas (iNGGA) were measured before and after each stimulation with 0.55 mg/kg of doxapram (L-DOX), 2.2 mg/kg of doxapram (H-DOX), or 90 s of inhalation of 10% carbon dioxide in oxygen (I-CO2 ). The stimulations were tested in duplicate or triplicate. Video clips of the laryngeal movement were scored by board-certified surgeons masked to the treatment. RESULTS: The MABP increased with L-DOX and H-DOX up to 81% (both p < .001 compared to I-CO2 ), and persisted during the other stimulations (both p < .001). An intermittent tachycardic effect of up to 79% increase in HR was observed with doxapram. The HR following H-DOX was higher than L-DOX and I-CO2 (both p < .016). Neither hypertension nor tachycardia was observed with I-CO2 . The iNGGA increased with all treatments (p < .001). The iNGGA was greater with H-DOX than L-DOX and I-CO2 (both p < .007). All treatments received higher scores (all p < .001) with acceptable inter- and intra-observers Krippendorff's alphas. CONCLUSION: All treatments were effective respiratory stimulants in anesthetized dogs; however, doxapram caused hypertension and tachycardia. CLINICAL SIGNIFICANCE: Carbon dioxide inhalation might improve arytenoid motion without cardiovascular effects in dogs during clinical airway examinations.

Intravenous doxapram administration as a potential model of panic attacks in rats.

Panic disorder can be categorized into the nonrespiratory or the respiratory subtypes, the latter comprising dyspnea, shortness of breath, chest pain, feelings of suffocation, and paresthesias. Doxapram is an analeptic capable of inducing panic attacks with respiratory symptoms in individuals diagnosed with the disorder; however, its neuroanatomical targets and its effects on experimental animals remain uncharacterized. One of the brain regions proposed to trigger panic attacks is the midbrain periaqueductal gray (PAG). Therefore, in this study, we evaluated the effects of doxapram in Fos (c-Fos) protein expression in the PAG and characterized its cardiorespiratory and behavioral effects on the elevated T maze and in the conditioned place aversion (CPA) paradigms. Doxapram increased Fos expression in different columns of the PAG, increased respiratory frequency, decreased heart rate, and increased arterial pressure when injected via intravenous route. Alprazolam, a panicolytic benzodiazepine, injected via intraperitoneal route, decreased respiratory frequency, whereas URB597, an anandamide hydrolysis inhibitor injected via intraperitoneal route, was ineffective. Doxapram injected via intraperitoneal route induced an anxiogenic-like effect in the elevated T-maze model; however, it failed to induce CPA. This study suggests that the cardiorespiratory and behavioral effects of doxapram in rodents serve as an experimental model that can provide insights into the neurobiology of panic attacks.

Comparison of methohexital and propofol as induction agents for evaluation of laryngeal function in healthy dogs.

OBJECTIVE: To determine the influence of propofol or methohexital, with and without doxapram, on the examination of laryngeal function in dogs. STUDY DESIGN: Experimental study. ANIMALS: Forty healthy dogs randomly assigned to 4 groups: propofol with saline (n = 10), propofol with doxapram (n = 10), methohexital with saline (n = 10), or methohexital with doxapram (n = 10). METHODS: Propofol and methohexital were administered to effect. Investigators examined laryngeal function (initial) simultaneously with video laryngoscopy. Doxapram or saline was administered, and laryngeal function was reevaluated (second). Laryngeal motion, quality of laryngeal exposure, and the degree of swallowing, laryngospasm, and jaw tone were scored at each evaluation. Adverse events were recorded. Initial and second videos were evaluated by a masked observer, and still images obtained from both evaluations were evaluated for change in rima glottidis size by 2 masked observers. RESULTS: Administration of doxapram and saline was delayed with propofol (P = .001). Laryngeal function did not differ between dogs receiving propofol or methohexital, irrespective of doxapram administration. Doxapram improved breathing scores in both groups (P < .001). Jaw tone increased with propofol during the second evaluation (P = .049). Swallowing was more prevalent at initial examination (P = .020). Methohexital resulted in an increased heart rate (P < .001) compared with propofol. Twenty-five percent of dogs receiving methohexital developed seizure-like activity (n = 5/20). CONCLUSION: Evaluation of laryngeal function did not differ between healthy dogs anesthetized with propofol or methohexital. Methohexital provided shorter examination times with less jaw tone but was associated with adverse events. CLINICAL SIGNIFICANCE: This study provides evidence to recommend propofol over methohexital as an induction agent for laryngeal function examination.

Comparison of the effects of alfaxalone and propofol with acepromazine, butorphanol and/or doxapram on laryngeal motion and quality of examination in dogs.

OBJECTIVE: To compare the effects of alfaxalone and propofol, with and without acepromazine and butorphanol followed by doxapram, on laryngeal motion and quality of laryngeal examination in dogs. STUDY DESIGN: Randomized, crossover, blinded study. ANIMALS: Ten female Beagle dogs, aged 11-13 months and weighing 7.2-8.6 kg. METHODS: The dogs were administered four intravenous (IV) treatments: alfaxalone (ALF), alfaxalone+acepromazine and butorphanol (ALF-AB), propofol (PRO) and propofol+AB (PRO-AB). AB doses were standardized. Dogs were anesthetized 5 minutes later by administration of alfaxalone or propofol IV to effect. Arytenoid motion during maximal inspiration and expiration was captured on video before and after IV doxapram (0.25 mg kg-1). The change in rima glottidis surface area (RGSA) was calculated to measure arytenoid motion. An investigator blinded to the treatment scored laryngeal examination quality. RESULTS: A 20% increase in RGSA was the minimal arytenoid motion that was detectable. RGSA was significantly less in ALF before doxapram compared with all other treatments. A <20% increase in RGSA was measured in eight of 10 dogs in PRO and in all dogs in ALF before doxapram. After doxapram, RGSA was significantly increased for PRO and ALF; however, 20% of dogs in PRO and 50% of dogs in ALF still had <20% increase in RGSA. A <20% increase in RGSA was measured in five of 10 dogs in PRO-AB and ALF-AB before doxapram. All dogs in PRO-AB and ALF-AB with <20% increase in RGSA before doxapram had ≥20% increase in RGSA after doxapram. Examination quality was significantly better in PRO-AB and ALF-AB. CONCLUSIONS AND CLINICAL RELEVANCE: The use of acepromazine and butorphanol improved the quality of laryngeal examination. Any negative impact on arytenoid motion caused by these premedications was overcome with doxapram. Using either propofol or alfaxalone alone is not recommended for the evaluation of arytenoid motion.

Combating Multidrug-Resistant Pathogens with Host-Directed Nonantibiotic Therapeutics.

Earlier, we reported that three Food and Drug Administration-approved drugs, trifluoperazine (TFP; an antipsychotic), amoxapine (AXPN; an antidepressant), and doxapram (DXP; a breathing stimulant), identified from an in vitro murine macrophage cytotoxicity screen, provided mice with 40 to 60% protection against pneumonic plague when administered at the time of infection for 1 to 3 days. In the present study, the therapeutic potential of these drugs against pneumonic plague in mice was further evaluated when they were administered at up to 48 h postinfection. While the efficacy of TFP was somewhat diminished as treatment was delayed to 24 h, the protection of mice with AXPN and DXP increased as treatment was progressively delayed to 24 h. At 48 h postinfection, these drugs provided the animals with significant protection (up to 100%) against challenge with the agent of pneumonic or bubonic plague when they were administered in combination with levofloxacin. Likewise, when they were used in combination with vancomycin, all three drugs provided mice with 80 to 100% protection from fatal oral Clostridium difficile infection when they were administered at 24 h postinfection. Furthermore, AXPN provided 40 to 60% protection against respiratory infection with Klebsiella pneumoniae when it was administered at the time of infection or at 24 h postinfection. Using the same in vitro cytotoxicity assay, we identified an additional 76/780 nonantibiotic drugs effective against K. pneumoniae For Acinetobacter baumannii, 121 nonantibiotic drugs were identified to inhibit bacterium-induced cytotoxicity in murine macrophages. Of these 121 drugs, 13 inhibited the macrophage cytotoxicity induced by two additional multiple-antibiotic-resistant strains. Six of these drugs decreased the intracellular survival of all three A. baumannii strains in macrophages. These results provided further evidence of the broad applicability and utilization of drug repurposing screening to identify new therapeutics to combat multidrug-resistant pathogens of public health concern.

Effects of Neuroactive Drugs in the Discharge Patterns of Microsternarchus (Hypopomidae: Gymnotiformes) Electric Organ.

Considering the conserved nature of synaptic physiology among vertebrates, we tested the effects of three psychotropics (diazepam, doxapram, and nicotine) on Microsternarchus cf. bilineatus, measuring 10 parameters associated to the electric organ discharges rhythm and waveform before and after the administration of each drug and a control group. There were statistically significant differences (p < 0.005) among all the experimental groups, F (70, 22619.25) = 77.7, between the two experimental phases within their respective drug treatment, F (80, 24604.51) = 16.0, and among the six experimental hours within their respective phases and groups, F (320, 37124.15) = 4.1. We observed a common general trend of reduction in the electric organ's (EO) firing rate, regardless of the expected stimulant or depressor effect of the drugs on the central nervous system (CNS). The intensity of the response changed with the treatment. The observed changes in the fishes' behavior may be a result of the drugs' direct action on the CNS or a combination of this with systemic effects of each substance tested, also in the EO.

New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria.

Antibiotic resistance in medically relevant bacterial pathogens, coupled with a paucity of novel antimicrobial discoveries, represents a pressing global crisis. Traditional drug discovery is an inefficient and costly process; however, systematic screening of Food and Drug Administration (FDA)-approved therapeutics for other indications in humans offers a rapid alternative approach. In this study, we screened a library of 780 FDA-approved drugs to identify molecules that rendered RAW 264.7 murine macrophages resistant to cytotoxicity induced by the highly virulent Yersinia pestis CO92 strain. Of these compounds, we identified 94 not classified as antibiotics as being effective at preventing Y. pestis-induced cytotoxicity. A total of 17 prioritized drugs, based on efficacy in in vitro screens, were chosen for further evaluation in a murine model of pneumonic plague to delineate if in vitro efficacy could be translated in vivo Three drugs, doxapram (DXP), amoxapine (AXPN), and trifluoperazine (TFP), increased animal survivability despite not exhibiting any direct bacteriostatic or bactericidal effect on Y. pestis and having no modulating effect on crucial Y. pestis virulence factors. These findings suggested that DXP, AXPN, and TFP may modulate host cell pathways necessary for disease pathogenesis. Finally, to further assess the broad applicability of drugs identified from in vitro screens, the therapeutic potential of TFP, the most efficacious drug in vivo, was evaluated in murine models of Salmonella enterica serovar Typhimurium and Clostridium difficile infections. In both models, TFP treatment resulted in increased survivability of infected animals. Taken together, these results demonstrate the broad applicability and potential use of nonantibiotic FDA-approved drugs to combat respiratory and gastrointestinal bacterial pathogens.

The effects of doxapram on medullary respiratory neurones in brainstem-spinal cord preparations from newborn rats.

Doxapram is the only dedicated respiratory stimulant used to aid recovery of breathing after major surgery. Doxapram acts on peripheral chemoreceptors and although the central action of doxapram has been suggested, its detailed neuronal mechanism is unknown. We assessed doxapram-induced changes in spontaneous cervical nerve (C4) inspiratory activity and the firing of action potentials in pre-inspiratory and inspiratory neurones in the medulla. Experiments were performed in neonatal rat brainstem-spinal cord preparations, which can produce respiratory rhythm for several hours under in vitro conditions. Doxapram application (for 15 min) increased the frequency and amplitude of C4 activity dose-dependently. Doxapram induced changes in the electrophysiological properties of pre-inspiratory and inspiratory neurones. Our results suggest that respiratory activity enhancement was likely to be induced via effects on the potassium channels of pre-inspiratory and inspiratory neurones and indicate the central actions of doxapram.

Effects of doxapram, prethcamide and lobeline on spirometric, blood gas and acid-base variables in healthy new-born calves.

A number of drugs have been used to treat asphyxia in new-born calves and the aim of the current study was to investigate the effect of commonly-used stimulant drugs on ventilation, arterial blood gas and acid base variables. A group (n=18) of new-born (3-15 h old) calves were treated in a randomised sequence with doxapram (40 mg, IV), lobeline (5mg, IV) or prethcamide (5 mL, consisting of 375 mg crotethamide and 375 mg cropropamide, buccally). Blood and spirometric measurements, using an ultrasonic spirometer, were collected prior to and 1, 5, 15, 30, 60, 90 min after administration of each drug. Doxapram caused a significant increase in the respiratory rate, peak inspiratory and expiratory flow and minute volume (V(min)) during the 90-min post-treatment study period, although maximum values occurred 1 min after treatment. The V(min) increased from 13.8 ± 5.0 L to 28.5 ± 12.3 L. Prethcamide, but not lobeline, also caused significant increases in inspiratory and expiratory volumes. The effects of doxapram on ventilation were accompanied by an increase in arterial partial pressure of oxygen (P(a)O(2)) (77.7 ± 18.8 mm Hg to 93.2 ± 23.7 mm Hg), a decrease in arterial partial pressure of carbon dioxide (P(a)CO(2)) (42.6 ± 4.9 mm Hg to 33.1 ± 6.6mm Hg), a significant increase in pH and a decrease in bicarbonate concentration and base excess 1 min after treatment. Prethcamide caused a gradual increase in P(a)O(2) and decrease in P(a)CO(2) over 90 min, whereas lobeline had no measurable effect on the investigated variables. Of the three treatments, only doxapram had a distinct stimulatory effect on respiration in healthy neonatal calves and may therefore be useful in the treatment of calf asphyxia.

Effects of doxapram HCl on laryngeal function of normal dogs and dogs with naturally occurring laryngeal paralysis.

OBJECTIVES: To compare the effects of IV doxapram on glottic size and arytenoid motion in normal dogs and in dogs with laryngeal paralysis. STUDY DESIGN: Prospective experimental and clinical trials. ANIMALS: Six healthy dogs weighing 24.5 +/- 3.9 kg and six dogs weighing 27.4 +/- 11.5 kg suspected of having laryngeal paralysis. METHODS: Dogs were pre-medicated with acepromazine and butorphanol, and a light plane of anesthesia was induced with isoflurane by mask. Videoendoscopic examination of laryngeal function was recorded before (baseline) and after IV doxapram administration. Normalized glottal gap area (NGGA) at maximal inspiration and expiration, and percentage change in height, width, area, and NGGA were calculated with measurements from digitized images of the glottal gap. RESULTS: Active arytenoid motion was present in all normal dogs at baseline. After doxapram administration, depth of respiration appeared greater, but arytenoid motion, as measured by percentage change in NGGA, and in area and width, did not significantly increase in normal dogs. No arytenoid motion was detected in dogs with laryngeal paralysis at baseline; however, rima glottidis NGGA of dogs with laryngeal paralysis was greater at inspiration and expiration than normal dogs. After doxapram administration, dogs with laryngeal paralysis developed paradoxical arytenoid motion and significant, negative percentage change in area (-61%) and NGGA (-145%) because of inward collapse of the arytenoids during inspiration. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of doxapram during laryngeal examination is useful for differentiating normal dogs from dogs with laryngeal paralysis. Dogs with laryngeal paralysis may suffer extreme glottic constriction with vigorous respirations, and may require intubation during examination.

Rodent doxapram model of panic: behavioral effects and c-Fos immunoreactivity in the amygdala.

BACKGROUND: Panic attacks, the hallmark of panic disorder, are often characterized by hyperventilation. Existing animal models of anxiety have not addressed the effects of the hyperventilation on anxiety-related behaviors. Doxapram is a respiratory stimulant that reliably evokes panic attacks in patients with panic disorder. We examined doxapram in four rodent models of anxiety and sought to identify brain regions involved in its behavioral effects. METHODS: The effects of doxapram were determined for cue and contextual fear conditioning, the open field test, and the social interaction test. The effect of doxapram on c-Fos-like immunoreactivity was examined in three brain regions. RESULTS: Doxapram at 4 mg/kg increased anxiety-related behaviors in all four anxiety models. An inverted U-shaped dose-response curve was identified for fear conditioning to cue. Doxapram induced c-Fos-like immunoreactivity in the central nucleus of the amygdala but not the lateral nucleus or the nucleus tractus solitarius. CONCLUSIONS: Doxapram enhanced anxiety-related behaviors in four animal models of anxiety that involve conditioning or spontaneous avoidance. The effect of doxapram may result from activation of neurons in the amygdala. Doxapram, by inducing hyperventilation, may be a useful adjunct to existing animal anxiety models for improving validity for panic anxiety.

Potentiation of acetaminophen hepatotoxicity by doxapram in mouse primary cultured hepatocytes.

The augmentation by doxapram (DOP) of the reduction in viability and of the apoptosis of cells induced by acetaminophen (AA) was examined in mouse primary cultured hepatocytes. Loss of viability on exposure to AA and/or DOP in cultured hepatocytes was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and the apoptosis of cultured hepatocytes was detected by nuclear morphologic observation and from a ladder-like DNA fragmentation pattern. The combination of AA (5 mM) and DOP (10, 20, 50 or 100 microM) potentiated the reduction in cell viability and increased the oxidative stress. Hepatocytes exposed for 24 h to AA (5 mM) plus DOP (100 microM), showed atrophy of nuclei, including chromatin condensation and a ladder-like DNA fragmentation pattern, characteristic of apoptosis. Benzyl-oxycarbonyl-Asp-CH2OC (O)-2,6-dichlorobenzene (Z-Asp-CH2-DCB, 50 microM), an inhibitor for caspases, improved the viability and ladder-like DNA fragmentation in cells exposed to DOP (200 or 500 microM) alone or AA ( 5 mM) plus DOP (100 microM). However, loss of viability on exposure to a high concentration of AA (10 mM) and ladder-like DNA fragmentation were not affected by Z-Asp-CH2-DCB. These results indicated that the synergistic increase in oxidative stress, activation of caspases and DNA fragmentation induced by DOP potentiated the hepatotoxicity of AA.

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.

Metabolic, ventilatory and circulatory effects of doxapram in anaesthetized pigs during normoxia and hypoxia.

BACKGROUND: In a previous clinical study doxapram was found to improve ventilatory efficacy postoperatively, presumably via effects on hypoxic pulmonary vasoconstriction (HPV). The present study was designed to see whether doxapram induced any changes of arterial oxygenation and pulmonary vascular resistance during normoxia or hypoxia and whether the changes were influenced by the anaesthetic agents. METHODS: Seventeen piglets were anaesthetized by combinations of either midazolam + fentanyl + pancuronium + pentobarbital (TIVA, n = 9), or by midazolam + fentanyl + pancuronium + halothane, 0.5% in end-tidal gas (Hal, n = 8). Analyses of expired gas and mixed venous and arterial blood in combination with determinations of central blood flow and pressures allowed for calculations of standard metabolic, ventilatory and circulatory data. Values were obtained at normoventilation using normoxic (FIO2 = 0.3) and hypoxic (FIO2 = 0.08) gas mixtures at calculated doxapram plasma concentrations of 1, 2 and 4 micrograms.ml-1. RESULTS: With few exceptions doxapram administration affected the investigated variables only moderately during normoxia. In group Hal, PVR and SVR showed a biphasic raise (P < 0.05), CO fell (P < 0.05-P > or = 0.05) and C (a-v)O2 rose (P < 0.05). In group TIVA, PaO2 fell (P < 0.01-0.05) despite unchanged PVR, CO and VD/VT. Hypoxia affected a moderate increase in PVR in group TIVA (P < 0.05), which was slightly lower at the lowest and highest plasma levels of doxapram (P < 0.05). In group Hal, the induction of hypoxia induced a more pronounced rise in PVR (P < 0.05) which showed a biphasic response to increasing dose levels of doxapram, the lowest dose affecting a further rise (P < 0.05) and the highest a reduction to values below hypoxia control levels (P < 0.05). Pronounced differences between the two groups with respect to values for metabolic and circulatory variables make the interpretation of data difficult. CONCLUSIONS: Doxapram administration to anaesthetized animals did not induce any effects indicative of augmentation of the HPV response.

The influence of alfentanil pre-treatment on ventilatory effects of doxapram following induction of anaesthesia with propofol.

BACKGROUND: Hypoventilation may occur following induction of anaesthesia with propofol and is potentiated by concurrent use of opioid drugs. This effect is undesirable in patients who will continue to maintain spontaneous respiration during anaesthesia and surgery. The analeptic drug doxapram is known to have selective respiratory stimulatory effects but its action during induction of anaesthesia has been inconsistent. METHOD: In a double-blind, placebo-controlled study, the influence of alfentanil pre-treatment on the ventilatory effects of doxapram given during induction of anaesthesia with propofol was studied in 40 patients. Four groups of ten patients (two groups pre-treated with 7 micrograms.kg-1 of alfentanil and two groups with saline) were randomly allocated to receive either 0.5 mg.kg-1 doxapram or saline following infusion of propofol to loss of verbal contact. RESULTS: In the groups that received doxapram, minute volumes were significantly increased and end-tidal carbon dioxide concentrations were significantly reduced compared to control groups, although the duration and extent of these effects were less in the group that received alfentanil. Doxapram also reversed an alfentanil-induced reduction in respiratory rate. No adverse cardiovascular or neurological stimulatory effects of doxapram were evident at any time. CONCLUSION: We conclude that doxapram 0.5 mg.kg-1 is effective in augmenting ventilation that has been obtunded following induction of anaesthesia with propofol in patients pre-treated with alfentanil.

Influence of charge and polarity on the redox potentials of high-potential iron-sulfur proteins: evidence for the existence of two groups.

We have investigated the HiPIPs from Ectothiorhodospira vacuolata (iso-1 and iso-2), Chromatium vinosum, Rhodocyclus gelatinosus, Rhodocyclus tenuis (strain 2761), Rhodopila globiformis, and Rhodospirillum salinarum (iso-2) by direct electrochemistry. Using a glassy carbon electrode with a negatively charged surface, direct, unpromoted electrochemistry is possible with the positively charged HiPIPs. With the negatively charged HiPIPs, the positively charged and flexible bridging promoter poly(L-lysine) is required. The stability of the response can be improved by morpholin, aspartate, tryptophan, or 4,4'-dipyridyl. These "stabilizers" prevent the blocking of the electrode by denatured protein. The redox potential of 500 mV found for R. salinarum iso-2 is the highest HiPIP potential reported. The presence of histidines in the sequence does not per se predict a pH-dependent redox potential. Only C. vinosum and R. gelatinosus HiPIPs show a weak but significant pH dependence with a difference of 35 mV between the low- and the high-pH form and maximum slopes of -20 mV/unit. The dependence of the midpoint potential on temperature and on ionic strength varies over the different HiPIPs. The dependence of the potentials on square root of I cannot be fully explained by the Debye-Hückel theory because the linearity exceeds the limiting concentration and only small negative slopes are observed (o to -28 mV/square root of M) Combination of the sequences, the optical spectra, the overall charges, and the redox thermodynamics suggests that existence of two groups of HiPIPs. One group consists of Chromatium-like HiPIPs with redox potentials between 300 and 350 mV, modulated only by the solvation of the cluster. The second group is formed by Ectothiorhodospira-like HiPIPS with potentials between 50 and 500 mV, modulated by the overall charge of the peptide (25 mV/unit) and by the solvation of the cluster.

Loss of hypoxic ventilatory response following bilateral neck dissection.

Modified radical neck or combined radical and modified radical neck surgery is performed for treatment of head and neck cancer. Because of the extensive nature of the surgery, including dissection around the carotid vessels, we prospectively evaluated hypoxic ventilatory responses preoperatively and postoperatively in five patients. The change in ventilation to percent desaturation varied between -0.22 and -0.60 L/min per percent desaturation in the five study patients. In the postoperative evaluation, two of five patients showed flattened responses compared with the preoperative measurements due to denervation of their carotid bodies. Two patients showed increased responses due to loss of upper airway resistance from tracheostomy. We conclude that after bilateral neck dissection for cancer surgery some patients may lose their hypoxic ventilatory responses due to carotid body denervation.