A review of the NG17 recommendations for the use of basal insulin in type 1 diabetes.

AIMS: To revisit the data analysis used to inform National Institute of Health and Care Excellence (NICE) NG17 guidance for initiating basal insulin in adults with type 1 diabetes mellitus (diabetes). METHODS: We replicated the data, methodology and analysis used by NICE diabetes in the NG17 network meta-analysis (NMA). We expanded this data cohort to a more contemporary data set (extended 2017 NMA) and restricted the studies included to improve the robustness of the data set (restricted 2017 NMA) and in a post hoc analysis, changed the index comparator from neutral protamine Hagedorn (NPH) insulin twice daily to insulin detemir twice daily. RESULTS: The absolute changes in HbA1c were similar to those reported in the NG17. However, all 95% credible intervals for change in HbA1c point estimates crossed the line of null effect, except for detemir twice daily (in the NICE and extended 2017 NMAs) and NPH four times daily. In the detemir twice-daily centred post hoc analysis, the 95% credible intervals for change in HbA1c crossed the line of null effect for all basal therapies, except NPH. CONCLUSIONS: In NG17, comparisons of basal insulins were based solely on efficacy of glycaemic control. Many of the trials used in this analysis were treat-to-target, which minimize differences in HbA1c . In the NMAs, statistical significance was severely undermined by the wide credible intervals. Despite these limitations, point estimates of HbA1c were used to rank the insulins and formed the basis of NG17 guidance. This study queries whether such analyses should be used to make specific clinical recommendations.

Local infusion of the nitric oxide donor Sin-1 after angioplasty. Effects on intimal hyperplasia in porcine coronary arteries.

PURPOSE: To investigate the development of intimal hyperplasia in response to percutaneous transluminal coronary angioplasty (PTCA) followed by local delivery of the nitric oxide (NO) donor 3-morpholino-sydnonimine (SIN-1). MATERIAL AND METHODS: Overdilation PTCA was performed in coronary arteries in 20 healthy pigs. One of the dilated segments was additionally treated with local delivery of SIN-1 for 10 min. Segments distal to the treated part of the arteries served as controls. Arteries were radiographically depicted and analyzed after 1 and 8 weeks for actin, myosin and intermediate filaments (IF), nitric oxide synthetase (NOS) and histological evaluation. RESULTS: Segments treated with PTCA+SIN-1 showed a significantly (p=0.03) larger luminal diameter compared with PTCA only treated segments. The luminal loss after SIN-1 was not significant compared with the diameter prior to treatment. Endothelial NOS content was significantly lower in the PTCA+SIN-1 group compared with the PTCA group after 1 (p=0.03) and 8 weeks (p=0.013). IF/actin ratio after 1 week was significantly increased in PTCA-treated segments compared with untreated controls (p=0.004), and compared with PTCA+SIN-1-treated segments (p=0.004). CONCLUSION: PTCA-induced intimal hyperplasia was potently inhibited by local delivery of the NO donor SIN-1. Momentary events at the time of injury play a significant role in the development of intimal hyperplasia and long-lasting down-regulation of the endothelial NOS expression after SIN-1 exposure is suggested. The IF/actin ratio can be useful as an early marker of intimal hyperplasia.

[The pattern of medication errors in connection with intravenous administration at an intensive care unit]. / Fejlmønsteret ved intravenøs medicinadministration på en intensiv afdeling.

In a static study, medication errors in intravenous administration were registered in a multidisciplinary intensive care unit. The most frequent type of errors included administration of incorrect doses, but also administration of diluted drugs over an excessive time period, use of previously opened ampoules, administration of unauthorized drugs, wrong infusion rates, dissolution of drugs in incorrect media, dissolution of drugs in incorrect volumes of dissolution media and wrong dosage form errors were observed.

Uncompensated blood loss is not tolerated during acute normovolemic hemodilution in anesthetized pigs.

UNLABELLED: Clinically, hemodilution to a hematocrit of 9% has been studied, but the effects of hypovolemia during this degree of hemodilution have not been elucidated. We studied the response to blood loss during extreme hemodilution and evaluated indicators of hypovolemia. Systemic and myocardial hemodynamics, oxygen transport, and blood lactate concentrations were measured in 12 anesthetized pigs exposed to a graded blood loss of 10, 20, 30, and 40 mL/kg. Six animals were hemodiluted (hematocrit 10.8% +/- 1.4%, mean +/- SD), and six animals served as controls (hematocrit 34.6% +/- 1.5%). Hemodilution decreased systemic oxygen delivery to 9.5 +/- 0.6 mL x kg(-1) x min(-1) (controls 21.7 +/- 3.9 mL x kg(-1) x min(-1)) (P < 0.01) despite a 31% increase in cardiac output. Systemic oxygen uptake was unchanged. Arterial lactate increased to 3.3 +/- 1.1 mM/L (controls 1.6 +/- 0.6 mM/L) (P < 0.05), and mixed venous oxygen saturation (SvO2) decreased to 38.2% + 4.8% (controls 68.6% +/- 2.9%) (P < 0.01). At a blood loss of 10 mL/kg, cardiac output continued to be greater in the hemodiluted animals (P < 0.01). Arterial blood pressure decreased to 61 +/- 8 mmHg (controls 84 +/- 18 mm Hg) (P < 0.05), whereas heart rate was unchanged. Systemic oxygen delivery decreased to 8.8 +/- 1.2 mL x kg(-1) x min(-1) (controls 14.1 +/- 2.5 mL x kg(-1) x min(-1)) (P < 0.01). Systemic oxygen uptake was maintained by a further increase in oxygen extraction, and SvO2 decreased to 29.7% +/- 7.3%, compared with 55.3% +/- 9.0% in controls (P < 0.01). Arterial lactate increased to 4.9 +/- 1.4 mM/L (controls 1.8 +/- 0.8 mM/L) (P < 0.01). Myocardial oxygen delivery and lactate uptake were unchanged. When the blood loss equaled 30 mL/kg, myocardial lactate production occurred, and two hemodiluted animals died of circulatory failure. Central venous and capillary wedge pressures changed minimally during the blood loss and did not differ between groups. We conclude that a decrease in arterial blood pressure and SvO2 were early signs of hypovolemia during hemodilution, whereas central venous pressure and pulmonary capillary wedge pressure were insensitive indicators. IMPLICATIONS: Anesthetized pigs with extremely low hemoglobin levels (one third of normal) showed poor tolerance to blood loss >10 mL/kg. A decreasing arterial blood pressure, a decreasing oxygen saturation in the venous blood, and an increase in arterial blood lactate concentration were useful indicators of blood loss.

Central and mixed venous blood oxygen correlate well during acute normovolemic hemodilution in anesthetized pigs.

BACKGROUND: Central venous oxygen saturation (ScvO2) and oxygen tension (PcvO2), obtained from the superior vena cava, correlate well with mixed venous (pulmonary arterial) oxygen saturation (SvO2) and tension (pvO2) when the hematocrit is normal. The present study was undertaken to assess whether extreme hemodilution affects this relation. METHODS: We compared mixed and central venous blood during graded arterial desaturation (inspired fraction of oxygen (FIO2) between 1.0 and 0.10) in 10 hemodiluted pigs, and in 10 pigs with normal hematocrit (control), during fentanyl-ketamine-pancuronium anesthesia and mechanical ventilation. RESULTS: Arterial oxygen saturation decreased from 100% at FIO2 = 1.0 to 44 +/- 12% at FIO2 = 0.10 (mean +/- SD). Venous oxygen saturation ranged from 3.5% to 97.3%. The regression coefficient between SvO2 and ScvO2 was 0.97 (R2 = 0.93, bias -2.4 +/- 5.8%) in the hemodiluted and 0.99 (R2 = 0.97, bias -3.0 +/- 5.0%) in the control group. Venous oxygen tension values ranged from 0.5 kPa to 9.5 kPa, and the regression coefficient for oxygen tension was 0.94 (R2 = 0.89, bias -0.20 +/- 0.47 kPa) in the hemodiluted and 0.99 (R2 = 0.97, bias -0.43 +/- 0.48 kPa) in the control group. The regression coefficient for pH was 0.95 in the hemodiluted and 0.98 in the control animals. CONCLUSION: The findings indicate that also during hemodilution monitoring of central venous blood oxygen may be as useful as monitoring of mixed venous blood oxygen.

Nitrous oxide reduces inspired oxygen fraction but does not compromise circulation and oxygenation during hemodilution in pigs.

BACKGROUND: The use of nitrous oxide (N2O) during hemodilution has been questioned. Nitrous oxide reduces the inspired oxygen fraction (F1O2), depresses myocardial function and may reduce cardiac output (CO) and systemic oxygen delivery (DO2SY). The aim of this study was to evaluate the importance of the effects of nitrous oxide on systemic and myocardial circulation and oxygenation during extreme, acute, normovolemic hemodilution. METHODS: Ten midazolam-fentanyl-pancuronium anesthetized pigs were exposed to 65% N2O before and after extreme isovolemic hemodilution (hematocrit 33 +/- 1% and 10 +/- 1%, respectively). Systemic and myocardial hemodynamics, oxygen delivery and consumption and blood lactate were measured before (at F1O2 1.0 and 0.35) and during N2O exposure. RESULTS: Hemodilution caused an increase in CO from 137 +/- 43 to 229 +/- 32 ml.kg-1.min-1 (P < 0.01), a decrease in systemic vascular resistance (from 42 +/- 14 to 20 +/- 4 mmHg.L-1.min-1, P < 0.05), a decrease in mean arterial blood pressure (from 119 +/- 19 to 100 +/- 26 mmHg, P < 0.05) and a decrease in DO2SY from 21.1 +/- 6.9 to 13.7 +/- 2.1 ml.kg-1.min-1 (P < 0.01). Cardiac venous blood flow increased by 135% (P < 0.01) and cardiac venous saturation from 25 +/- 6 to 41 +/- 5% (P < 0.05). After hemodilution, changing F1O2 from 1.0 to 0.35 reduced arterial blood oxygen content from 59.4 +/- 3.7 to 52.3 +/- 5.1 ml.L-1 (P < 0.01), mixed venous saturation (SvO2) from 75 +/- 9 to 47 +/- 7% (P < 0.05) and DO2SY from 13.7 +/- 2.1 to 11.9 +/- 2.3 ml.kg-1.min-1 (P < 0.05). Dissolved oxygen at F1O2 = 1.0 and F1O2 = 0.35 constituted 25.4 +/- 3.1% and 10.1 +/- 1.5%, respectively, of systemic oxygen delivery after hemodilution, compared with 10.7 +/- 1.2% and 3.9 +/- 0.5% before hemodilution (P < 0.01). Left ventricular oxygen delivery and consumption were unchanged. Exposure to N2O did not affect mean arterial blood pressure or systemic vascular resistance before or after hemodilution. After hemodilution during N2O-exposure, CO and DO2SY decreased by 9% (P < 0.01 and P < 0.05, respectively), but no changes in SvO2, systemic oxygen uptake or arterial lactate were observed. The effect of N2O on myocardial oxygenation was similar before and after hemodilution; cardiac venous blood flow, left ventricular oxygen delivery and uptake decreased, but no animals showed left ventricular lactate production. CONCLUSION: Nitrous oxide did not compromise systemic and myocardial circulation and oxygenation during acute normovolemic hemodilution in pigs. Possible adverse effects from the use of nitrous oxide during hemodilution seem to be related to a reduced F1O2, reducing the safety margin for systemic oxygen delivery.

Hemodilution significantly decreases tolerance to isoflurane-induced cardiovascular depression.

BACKGROUND: Hemodilution is used to reduce the need for allogenic blood transfusion. The aim of this study was to evaluate to what extent acute extreme normovolemic hemodilution affects the circulatory response to isoflurane. METHODS: Ten midazolam-fentanyl-pancuronium anesthetized pigs were exposed to isoflurane at end-tidal concentrations of 0, 0.5, 1.0, 1.5 and 2%, before and after extreme normovolemic hemodilution (hematocrit 33 +/- 3% and 11 +/- 1%, respectively). Systemic and myocardial hemodynamics and oxygen delivery and consumption were measured. RESULTS: At zero end-tidal isoflurane concentration, hemodilution caused an increase in cardiac output (from 157 +/- 12 to 227 +/- 39 ml kg min-1, P < 0.01) a decrease in systemic vascular resistance (from 39 +/- 7 to 18 +/- 5 mmHg.L-1.min-1, P < 0.01) a decrease in mean arterial blood pressure (MAP) (from 130 +/- 13 to 91 +/- 13 mmHg, P < 0.01) and a decrease in systemic oxygen delivery (from 23.1 +/- 2.7 to 11.8 +/- 1.7 ml.kg-1.min-1, P < 0.01). When the end-tidal isoflurane concentration was increased from 0 to 2% after hemodilution, cardiac output decreased by 86 +/- 37 ml.kg-1.min-1, as compared with 36 +/- 20 ml.kg-1.min-1 (P < 0.01) before hemodilution. Likewise, systemic vascular resistance decreased with increasing isoflurane concentrations; at 2%, the decrease was 7 +/- 4 mmHg.L-1.min-1 after hemodilution and 18 +/- 5 mmHg.L-1.min-1 before hemodilution (P < 0.01). At an end-tidal isoflurane concentration of 2%, MAP had decreased to 43 +/- 6 mmHg after hemodilution, and to 61 +/- 15 mmHg before hemodilution (P < 0.01). After hemodilution, isoflurane concentrations above 1% decreased systemic oxygen delivery enough to cause delivery-dependent oxygen consumption and hyperlactemia; and at 2% isoflurane, myocardial blood flow became insufficient, as indicated by myocardial lactate production. CONCLUSIONS: isoflurane-induced cardiovascular depression had adverse effects on cardiac output and oxygen delivery during extreme hemodilution because: 1) The vasodilatory effect of isoflurane was insufficient to compensate for the myocardial depression, and also contributed to a critically low arterial blood pressure; 2) A decrease in cardiac output produced delivery-dependent oxygen consumption and hyperlactemia; and 3) A decrease in myocardial blood flow caused myocardial ischemia which may have exacerbated the myocardial depression.

Circulatory effects of hypoxia, acute normovolemic hemodilution, and their combination in anesthetized pigs.

BACKGROUND: Because hemodilution decreases the oxygen-carrying capacity of blood, it was hypothesized that severe hemodilution would decrease the tolerance to alveolar hypoxia. METHODS: Hemodynamics, oxygen transport, and blood lactate concentrations were compared in ten pigs with normal hematocrit (33 +/- 4%), and ten hemodiluted pigs (hematocrit 11 +/- 1%; mean +/- SD) anesthetized with ketamine-fentanyl-pancuronium during stepwise decreases in inspired oxygen fraction (FIO2; 1.0, 0.35, 0.21, 0.15, 0.10, 0.05). RESULTS: Median systemic oxygen delivery (DO2SY) became critical (the DO2SY value when arterial lactate exceeded 2.0 mmol.l-1) at 10.4 ml.kg-1.min-1 (range 6.9-16.1) in hemodiluted animals and at 11.8 ml.kg-1.min-1 (5.9-32.2) in animals with normal hematocrits (NS). The relationship between mixed venous oxygen saturation and arterial lactate values was less consistent and median critical mixed venous oxygen saturation was higher (P < 0.05) in the hemodiluted group (35%, range 21-64), than in animals with normal hematocrits (21%, 7-68%). In animals with normal hematocrit, decreasing FIO2 from 1.0 to 0.10 resulted in a decrease in DO2SY from 26.3 +/- 9.1 to 9.3 +/- 3.9 ml.kg-1.min-1 (P < 0.01). Cardiac output did not change, systemic oxygen extraction ratio increased from 0.23 +/- 0.08 to 0.68 +/- 0.13 (P < 0.01), and arterial lactate from 0.9 +/- 0.2 to 3.4 +/- 3.0 mmol.l-1 (P < 0.05). Cardiac venous blood flow, as measured by retrograde thermodilution, increased from 5.7 +/- 2.9 to 12.6 +/- 5.7 ml.kg-1.min-1 (P < 0.01). When FIO2 was reduced to 0.05, three animals became hypotensive and died. In the second group, hemodilution increased cardiac output and systemic oxygen extraction ratio (P < 0.01). Cardiac venous blood flow increased from 4.1 +/- 1.7 to 9.8 +/- 5.1 ml.kg-1.min-1 (P < 0.01), and cardiac venous oxygen saturation from 22 +/- 5 to 41 +/- 10% (P < 0.01). During the subsequent hypoxia, cardiac output and DO2SY were maintained until FIO2 = 0.15 (DO2SY = 10.1 +/- 3.3 ml.kg-1.min-1). Cardiac venous blood flow was then 18.5 +/- 10.7 ml.kg-1.min-1 (P < 0.01), but in spite of this, myocardial lactate production occurred. At FIO2 = 0.10 (DO2SY = 7.7 +/- 3.0 ml.kg-1.min-1), arterial lactate concentration increased to 8.5 +/- 2.3 mmol.l-1 (P < 0.01), and most animals became hypotensive. All hemodiluted animals died when FIO2 was decreased to 0.05 (P < 0.01 when compared to animals with normal hematocrit). CONCLUSIONS: Systemic and myocardial lactate production occurred at similar systemic oxygen delivery rates in hemodiluted and nonhemodiluted animals. Mixed venous oxygen saturation may be a less reliable indicator of inadequate oxygen delivery during hemodilution.

[Parallel import of drug preparations. A study of price development of parallel import preparations versus original preparations]. / Parallelimporterede praeparater. En undersøgelse af prisudviklingen for parallelimporterede proeparater versus originalproeparaterne.

Price developments for the first parallel imported preparations and the corresponding original preparations have been followed over the period 1st January 1992 to 1st June 1992 with the aim of registering any possible effects of the parallel import on price levels. Altogether 174 parallel imported preparations--including different strengths and administration forms--received marketing permission in the period, and by 1st June 1992 74 parallel imported preparations had come on the market. The main part of the parallel imported preparations are marketed at a lower price than the original preparations. At the end of the investigation period, 56% of the marketed parallel imported preparations were being sold at a price that was on average 5-10% below that of the corresponding original preparation; 24% were being sold at a price 0-4% below the original and 20% were being sold at more than 10% below the original preparations. The effect on the prices of the original preparations has been variable. In the beginning of the study period we saw four examples of large reductions in the price of original preparations (up to 45%) after the parallel imports began to be marketed, but at the end of the study period the marketing of the cheaper preparations seemed to have no effect on the prices of the original preparations, which remained unchanged.

Hemodilution during bone marrow harvesting in children.

Eight children (1-17 yr) underwent bone marrow harvesting while in cytostatic-induced remission of their disease (leukemia [n = 6], Ewing sarcoma, and non-Hodgkin lymphoma). After the induction of general anesthesia, all patients were loaded with 10 mL/kg of a 6% high-molecular dextran solution (Macrodex--Pharmacia), which resulted in a significant preoperative decrease in hematocrit (Hct) from 32% +/- 6% to 28% +/- 5% (hypervolemic hemodilution) and also allowed the procedure to be performed without systemic heparinization. The blood aspirated during the harvest (24 +/- 6 mL/kg; mean +/- SD) was replaced with a solution of 6% dextran and Ringer's acetate solution, and the Hct decreased from 28% +/- 5% to a minimum of 18% +/- 3%. Immediately after the harvest, 10 mL/kg of homologous packed red blood cells was transfused, increasing Hct to 25% +/- 3%. Oxygen saturation in the superior caval vein (ScvO2) decreased from 79% +/- 4% before the harvest to 70% +/- 3% (P less than 0.01) at the end of it, and then increased to 74% +/- 3% after the transfusion of homologous packed red blood cells. There was a strong linear correlation between mean values for Hct and ScvO2 during the various stages (r = 0.99). Mean heart rate decreased gradually during the procedure, from 106 +/- 10 to 86 +/- 7 beats/min. There was no significant change in arterial pressure, but cardiac output measured by impedance cardiography was about 30% greater during harvesting than during undisturbed anesthesia. Pulse oximetric saturation was 99% or 100% throughout. Caval venous blood lactate and pyruvate concentrations remained within normal limits in all children.(ABSTRACT TRUNCATED AT 250 WORDS)

The isolated mouse atria as a new model for testing cardioactive drugs with special reference to doxorubicin (Adriamycin).

Spontaneously beating isolated atria from mice were used as a new in vitro model to characterize the mechanism of the cardiotoxic action of the anthracycline cytostatic doxorubicin (Adriamycin). After stabilization at 28 degrees the atria showed a contractile rate and--force of 284 +/- 31 (S.D.) beats/min. and 49 +/- 6.5 mg. Doxorubicin (Dox) (10(-6)-10(-5) M) had a positive chronotropic action per se and decreased the pD2 for the chronotropic action of isoprenaline in a dose-dependent way. However only the effect of the higher concentration proved statistically significant, a concentration which also caused a marked decrease (63%) of the Emax. Pretreatment with Dox 15 mg/kg intraperitoneally 72 hr previously did not influence the pD2 but caused a significant increase in the Emax of the isoprenaline concentration response curve. The results indicate that Dox in vitro interferes with the beta-adrenoceptor function of isolated mouse atria in an unspecific way and that the subacute cardiotoxicity of Dox in mice is probably not due to interference with the beta-adrenoceptor system. Further it is concluded that isolated atria from mice may be a useful model for testing cardioactive drugs.

Cardiotoxic effects and the influence on the beta-adrenoceptor function of doxorubicin (Adriamycin) in the rat.

The possible relationship between the effect of the anthracycline-cytostatic doxorubicin (Dox) on the cardiac beta-adrenoceptor function in vitro and the development of delayed cardiotoxicity in vivo has been investigated in the rat. Dox (10(-5)-10(-4) M) blocked the chronotropic effect of isoprenaline on isolated atria in a competitive manner. Treatment with a single dose of Dox 5 mg/kg intravenously caused marked ECG changes manifested by progressive prologations of the Q alpha T and S alpha T-intervals, which amounted to 37% and 58% respectivity 5 weeks after the medication. At this time no beta-blocking action was detectable when tested on the isolated atria in the same rats. The results indicate that the delayed cardiotoxicity induced by Dox is not mediated by an interference with the cardiac beta-adrenoceptor function.

[Total intravenous anesthesia in direct laryngoscopy. A comparison of methohexital (Brietal) and thiopental]. / Total intravenøs anaestesi til direkte laryngoskopi. En sammenligning mellem metohexital (Brietal) og tiopental.

A material of 36 patients to be submitted to direct laryngoscopy was subdivided at random in a double blind investigation to total intravenous anaesthesia with metohexitone or thiopentone. Alfentanil was employed as an analgesic and relaxation was obtained with vecuronium. The anaesthesia was maintained with continuous barbiturate infusion and supplementary alfentanil and vecuronium. The patients in the metohexitone group showed significantly faster recovery with an average of seven minutes as compared with 20 minutes in the thiopentone group and significantly more had Glasgow coma scores of over 12 after 30 minutes. After 60 and 90 minutes, no significant differences could be demonstrated between the groups. It is concluded that thiopentone is unsuitable for total intravenous anaesthesia for direct laryngoscopy whereas metohexitone was particularly suitable. Metohexitone is proposed as an alternative to the more recent and more expensive propofol. The frequency of pain on injection of metohexitone does not differ from that with propofol and this may be reduced by employing a vein in the cubital fossa instead of a vein on the dorsum of the hand.

The anaesthetic management of an infant with frontometaphyseal dysplasia (Gorlin-Cohen syndrome).

We describe an infant with frontometaphyseal dysplasia, who presented to us twice for anaesthesia for orthopaedic surgery. These patients have facial asymmetry, mandibular hypoplasia, bradycardia, restrictive lung disease, primary pulmonary hypertension, skeletal abnormalities and difficult endotracheal intubation. The patient also showed laryngeal stridor because of laryngomalacia, vocal cord paralysis and subglottic stenosis. Light premedication along with atropine, ECG and blood pressure monitoring, gradual inhalational induction and intubation of the spontaneously breathing patient, careful positioning and postoperative CPAP are recommended.

The double J-spring guide wire and its hazards. Partially retained double J-wire: a complication during central venous catheterization. Case report.

A case is presented in which the outer part of a double J-spring guide wire was retained in the patient because of separation of the two parts. Warning against the use of this kind of wire is given.