Intrathecal Morphine Plus General Anesthesia in Cardiac Surgery: Effects on Pulmonary Function, Postoperative Analgesia, and Plasma Morphine Concentration

OBJECTIVES: To evaluate the effects of intrathecal morphine on pulmonary function, analgesia, and morphine plasma concentrations after cardiac surgery. INTRODUCTION: Lung dysfunction increases morbidity and mortality after cardiac surgery. Regional analgesia may improve pulmonary outcomes by reducing pain, but the occurrence of this benefit remains controversial. METHODS: Forty-two patients were randomized for general anesthesia (control group n=22) or 400 µg of intrathecal morphine followed by general anesthesia (morphine group n=20). Postoperative analgesia was accomplished with an intravenous, patient-controlled morphine pump. Blood gas measurements, forced vital capacity (FVC), forced expiratory volume (FEV), and FVC/FEV ratio were obtained preoperatively, as well as on the first and second postoperative days. Pain at rest, profound inspiration, amount of coughing, morphine solicitation, consumption, and plasma morphine concentration were evaluated for 36 hours postoperatively. Statistical analyses were performed using the repeated measures ANOVA or Mann-Whiney tests (*p<0.05). RESULTS: Both groups experienced reduced FVC postoperatively (3.24 L to 1.38 L in control group; 2.72 L to 1.18 L in morphine group), with no significant decreases observed between groups. The two groups also exhibited similar results for FEV1 (p=0.085), FEV1/FVC (p=0.68) and PaO2/FiO2 ratio (p=0.08). The morphine group reported less pain intensity (evaluated using a visual numeric scale), especially when coughing (18 hours postoperatively: control group= 4.73 and morphine group= 1.80, p=0.001). Cumulative morphine consumption was reduced after 18 hours in the morphine group (control group= 20.14 and morphine group= 14.20 mg, p=0.037). The plasma morphine concentration was also reduced in the morphine group 24 hours after surgery (control group= 15.87 ng.mL-1 and morphine group= 4.08 ng.mL-1, p=0.029). CONCLUSIONS: Intrathecal morphine administration did not significantly alter pulmonary function; however, it improved patient analgesia and reduced morphine consumption and morphine plasma concentration

Pharmacokinetic-pharmacodynamic correlation of imipenem in pediatric burn patients using a bioanalytical liquid chromatographic method

A bioanalytical method was developed and applied to quantify the free imipenem concentrations for pharmacokinetics and PK/PD correlation studies of the dose adjustments required to maintain antimicrobial effectiveness in pediatric burn patients. A reverse-phase Supelcosil LC18 column (250 x 4.6 mm 5 micra), binary mobile phase consisting of 0.01 M, pH 7.0 phosphate buffer and acetonitrile (99:1, v/v), flow rate of 0.8 mL/min, was applied. The method showed good absolute recovery (above 90%), good linearity (0.25-100.0 µg/mL, r;2;=0.999), good sensitivity (LLOQ: 0.25 µg/mL; LLOD: 0.12 µg/mL) and acceptable stability. Inter/intraday precision values were 7.3/5.9%, and mean accuracy was 92.9%. A bioanalytical method was applied to quantify free drug concentrations in children with burns. Six pediatric burn patients (median 7.0 years old, 27.5 kg), normal renal function, and 33% total burn surface area were prospectively investigated; inhalation injuries were present in 4/6 (67%) of the patients. Plasma monitoring and PK assessments were performed using a serial blood sample collection for each set, totaling 10 sets. The PK/PD target attained (40%T&gt;;MIC) for each minimum inhibitory concentration (MIC: 0.5, 1.0, 2.0, 4.0 mg/L) occurred at a percentage higher than 80% of the sets investigated and 100% after dose adjustment. In conclusion, the purification of plasma samples using an ultrafiltration technique followed by quantification of imipenem plasma measurements using the LC method is quite simple, useful, and requires small volumes for blood sampling. In addition, a small amount of plasma (0.25 mL) is needed to guarantee drug effectiveness in pediatric burn patients. There is also a low risk of neurotoxicity, which is important because pharmacokinetics are unpredictable in these critical patients with severe hospital infection. Finally, the PK/PD target was attained for imipenem in the control of sepsis in pediatric patients with burns.;Desenvolveu-se e aplicou-se método bioanalítico para quantificar concentrações de imipenem livre para estudos de farmacocinética (PK) e de correlação PK/PD dos ajustes de dose requeridos para manter a efetividade antimicrobiana em pacientes pediátricos queimados. Utilizou-se coluna Supelcosil LC18 (250 x 4,6 mm 5 micra), fase móvel binária, consistindo de tampão fosfato 0,01M pH 7,0 e acetonitrila (99:1, v/v) e fluxo de 0,8 mL/min. O método mostrou boa recuperação absoluta (acima de 90%), boa linearidade (0,25-100,0 µg/mL, r;2;=0.999), boa sensibilidade (LLOQ: 0,25 µg/mL; LLOD: 0,12 µg/mL) e estabilidade aceitável. Os valores de precisão inter/intradia foram 7,3/5,9% e a exatidão média foi de 92,9%. O método bioanalítico foi aplicado para quantificar concentrações de fármaco livre em crianças com queimaduras, Seis pacientes pediátricos queimados (idade média de 7,0 anos, 27,5 kg), com função renal normal e 33% da superfície total queimada foram investigados prospectivamente. Lesões por inalação estavam presentes em 4/6 (67%) dos pacientes. O monitoramento plasmático e a as avaliações de PK foram efetuadas utilizando coleção de amostras seriais de sangue para cada série, totalizando 10 conjuntos. O alvo PK/PD alcançado (40%T>;MIC) para cada concentração inibitória mínima (MIC: 0,5, 1,0, 2,0, 4,0 mg/L) ocorreu em porcentagem maior do que 80% dos conjuntos investigados e 100% após o ajuste de dose. Em conclusão, a purificação das amostras do plasma usando técnica de ultrafiltração seguida de quantificação das medidas do imipenem no plasma usando método de cromatografia líquida é bastante simples, útil e necessita de pequenos volumes para as amostras de sangue. Além disso, pequena quantidade de plasma (0,25 mL) é necessário para garantir a efetividade do fármaco nos pacientes pediátricos queimados. Há, ainda, baixo risco de neurotoxicidade, o que é importante, visto que as farmacocinéticas são imprevisíveis nesses pacientes críticos, com grave infecção hospitalar. Finalmente, o alvo PK/PD foi alcançado para o imipenem no controle da sepse em pacientes pediátricos com queimaduras.

Farmacocinética da vancomicina em neonatos pré-termo

OBJETIVE: The objective of the present study was to evaluate the kinetic disposition of vancomycin in preterm infants with emphasis on the apparent volume of distribution, biological half-life, and total body clearance as well as whether their variations cause significant modification of the trough plasma concentration of the drug, depending on the postconceptional age (PCA) and the postnatal age (PNA). MATERIAL AND METHOD: Twenty-five selected patients were distributed into 2 groups which differed significantly in terms of mean PCA (31.2-32.3 weeks in group 1, n = 13; 33.5-34.1 weeks in group 2, n = 12: CI95%, P < .001) and PNA (group 1, 12.0-18.5 days; group 2, 18.0-34.0 days, CI95%, P < .05). The parents were informed and signed a written consent for participation of the infants in the protocol that had been previously approved by the Ethics Committee of the hospital. RESULTS: Apparent volume of distribution was significantly increased in group 1 compared with patients of group 2 (0.85 vs. 0.56 L/kg, respectively; P = .01,). Additionally multiple linear regression revealed a good linear correlation (r = 0.85) of trough plasma concentration of vancomycin with the apparent volume of distribution and also with the biological half-life in patients of group 1, while a good correlation (r = 0.91) was obtained for the trough plasma concentration with total body clearance in infants of group 2. The influence of these kinetic parameters on the trough concentration of vancomycin in preterm infants seems to vary according to PCA and PNA. CONCLUSION: In conclusion, the trough plasma concentration of vancomycin depends on the pharmacokinetics, and multiple linear correlation indicates that it varies according to the postconceptional and postnatal age of preterm infants.OBJETIVO: O objetivo do presente estudo foi investigar a farmacocinética da vancomicina em neonatos pretermo, considerando a idade pós-conceptual e também a idade pós-natal para determinar se as alterações no volume aparente de distribuição, meia-vida biológica e depuração plasmática causam variação significativa no vale plasmático da vancomicina. MATERIAL E MÉTODO: Os vinte e cinco pacientes selecionados foram distribuídos em dois grupos, que diferiram significativamente em termos de idade pós-conceptualgrupo 1, n=13: 31,2-32,3 semanas; grupo 2, n=12: 33,5-34,1 semanas, IC95%,

Influence of cardiopulmonary bypass on cefuroxime plasma concentration and pharmacokinetics in patients undergoing coronary surgery

The aims of this study were to evaluate the influence of cardiopulmonary bypass (CPB) on the plasma concentrations and pharmacokinetics of cefuroxime and to assess whether the cefuroxime dose regimen (a 1.5 g dose, followed by 750 mg every 6 h for 24 h) is adequate for cardiac surgery antibiotic prophylaxis. A prospective, controlled, observational study compared patients undergoing coronary surgery with CPB (CPB group, n = 10) or off-pump surgery (off-pump group, n = 9). After each cefuroxime dose, blood samples were sequentially collected and analysed using high-efficiency chromatography. For demographic data and pharmacokinetic parameters, the authors used Fisher's exact test for nominal variables and Student's t-test and the Mann-Whitney U-test for parametric and non-parametric variables, respectively. Plasma concentrations were compared using ANOVA, and the percentage of patients with a remaining plasma concentration of &gt; 16 mg/l within 6 h after each bolus was quantified in tabular form. After each cefuroxime bolus was administered, both groups presented a significant decrease in plasma concentration over time (P &lt; 0.001), without differences between the groups. The mean CPB time of 59.7 +/- 21.1 min did not change cefuroxime plasma concentrations or pharmacokinetics. The mean clearance +/- SD (ml/kg/min) and median elimination half-life (h) of the CPB group versus the off-pump group were 1.7 +/- 0.7 versus 1.6 +/- 0.6 (P = 0.67), respectively, and 2.2 versus 2.3 (P = 0.49), respectively. Up to 3 h following the first bolus of 1.5 g, but not after 6 h, all patients had plasma concentrations &gt; 16 mg/l (CPB group = 20% and off-pump group = 44%). However, after all 750 mg boluses were administered, concentrations &lt; 16 mg/dl were reached within 3 h. CPB does not influence cefuroxime plasma concentrations. The dosing regimen is adequate for the intraoperative period, but in the immediate postoperative period, it requires further review.Sao Paulo Research Foundation (FAPESP, Brazil)Sao Paulo Research Foundation (FAPESP), Sao Paulo, Brazi

Obesity influences propranolol pharmacokinetics in patients undergoing coronary artery bypass grafting employing cardiopulmonary bypass

As concentrações plasmáticas e a disposição cinética do propranolol podem ser alteradas pela circulação extracorpórea (CEC). Investigou-se a influência da obesidade na farmacocinética do propranolol em pacientes submetidos à revascularização do miocárdio empregando a CEC. Investigaram-se quinze pacientes, recebendo cronicamente propranolol no pré- (10-40 mg, 2 a 3 vezes ao dia PO) e no pós-operatório (10 mg, 1 vez ao dia) sendo os mesmos distribuídos em dois grupos: obesos (n = 9, média 29,4) kg/m²; e não-obesos (n = 6, média 24,8 kg/m²). Colheram-se amostras seriadas de sangue nos períodos pré- e pós-operatório (Ä); determinaram-se as concentrações plasmáticas do propranolol através da cromatografia líquida de alta eficiência. Aplicou-se o software PK Solutions 2.0 para estimativa dos parâmetros cinéticos. Não se registrou alteração na farmacocinética do propranolol avaliada através dos parâmetros meia-vida biológica (t1/2), volume de distribuição aparente (Vd/F) e depuração plasmática (CL T/F) no grupo de pacientes não-obesos, enquanto prolongamento relevante da t1/2 (3,2 para 11,2 h, pPropranolol plasma levels and kinetic disposition may be altered by hypothermic cardiopulmonary bypass (CPB-H). We investigated the potential influence of obesity on propranolol pharmacokinetics in patients undergoing coronary artery bypass grafting employing CPB-H. Fifteen patients, receiving propranolol perorally pre- (10-40 mg, 2-3 times a day) and post-operatively (10 mg, once a day) were distributed in two groups, based on body mass index (BMI), in obese (n = 9, BMI: mean 29.4 kg/m²) and non-obese (n=6, BMI: mean 24.8 kg/m²). A serial of blood samples was collected at the pre- and post-operative periods at time dosing interval (Ä); propranolol plasma levels were measured one day before and after surgery using a high performance liquid chromatographic procedure described previously. PK Solutions software 2.0 was applied to obtain pharmacokinetic parameters. No changes on kinetic parameters as biological half-life (t1/2, p = 0.0625, NS), volume of distribution (Vd/F, p=0.8438, NS) and plasma clearance (CL T/F, p = 0.1563, NS) were obtained for the non-obese patients, while a prolongation of t1/2 (3.2 to 11.2 h, p< 0.0039), an increase on Vd/F (3.0 to 7.7 L/kg,

Micrométodo para quantificação de cefuroxima em plasma através da cromatografia líquida de alta eficiência: aplicação na profilaxia de pacientes submetidos à cirurgia cardíaca

O objetivo desta investigação foi desenvolver metodologia analítica adequada, simples e precisa para quantificação da cefuroxima plasmática para controle de pacientes cirúrgicos em profilaxia com esse antimicrobiano. Realizou-se a quantificação da cefuroxima na matriz biológica através da cromatografia líquida de alta eficiência CLAE-UV. Apenas 200 µL de plasma foram requeridos para a precipitação das proteínas com acetonitrila. Empregou-se coluna de fase reversa (NovaPak C18, 150 x 3,9 mm, 4 µm) e os picos foram eluídos isocraticamente com fase móvel (tampão acetato 0,375 M, pH 5,0 e acetonitrila, 96:4, v/v, 0,8 mL/min) em 12,5 min (cefuroxima) e 4,0 min (vancomicina, padrão interno) sendo os picos monitorados a 280 nm. Os limites de confiança são referidos a seguir: 0,2-100 µg/mL (linearidade, r² 0,9963), 0,1 µg/mL (sensibilidade: LD), 98,2% e 96,9% (exatidão intra- e inter-dias), 3,2% e 4,2% (precisão intra- e inter-dias), e boa estabilidade e recuperação (99,2%). A metodologia analítica foi aplicada para quantificação de cefuroxima no plasma de pacientes em profilaxia no período transoperatório de cirurgia cardíaca. Administraram-se 6 g i.v. bolus de cefuroxima nas 24 horas, divididas em 4 doses de 1,5 g; após a última dose no início do pós-operatório tardio, as concentrações plasmáticas médias foram de 108,0 µg/mL (zero), 32,8 µg/mL (3ª hora), 9,9 µg/mL (6ª hora), 3,4 µg/mL (9ª hora) e 0,8 µg/mL (12ª hora). O método analítico descrito mostrou-se simples, rápido e seguro garantindo sensibilidade e seletividade suficientes para a quantificação da cefuroxima plasmática e monitoramento da antibioticoprofilaxia no paciente cirúrgico.An improved, simple, selective and sensitive micromethod based on HPLC-UV is described to determine cefuroxime plasma levels, a second generation cephalosporin. Once changes on pharmacokinetics of drugs in patients submitted to heart surgery with cardiopulmonary bypass and hypothermia (CPB-H) were reported previously, the objective of the present study was to investigate cefuroxime plasma levels for antimicrobial prophylaxis of infections in those patients after surgery using HPLC-UV. Only 200 µL of plasma were required, and cefuroxime was determined by a chromatographic method using reversed phase system, after a simple clean up of plasma samples. Peaks monitored at 280 nm were eluted isocratically at 12.5 min (cefuroxime) and at 4.0 min (vancomicyn, internal standard,) from a 4 µm, NovaPak column (150 x 3.9 mm) using a binary mobile phase at flow rate 0.8 mL/min, consisting of 0.375 M acetate buffer, pH 5,0 and acetonitrile, 96:4 (v/v). The method validated with basis of parameters evaluated for the confidence limits of cefuroxime measurements in spiked blank plasma, presents 0.1 µg/mL sensitivity, 0.2 - 200 µg/mL linearity, (r² 0.998), systematic error of 98.2% and 96.9% (intra- and interday accuracy), intra- and interday precision (CV %: 3.2 % and 4.2 %). A good stability and high percentage of recovery (99.2%) were obtained. Patients received cefuroxime 6 g i.v. bolus (1,5 g, 4 times in 24 hours), showed in the first postoperative day plasma levels of 108.0 µg/mL (zero), 32.8 µg/mL (3rd h), 9.9 µg/mL (6th h), 3.4 µg/mL (9th h) and 0.8 µg/mL (12th h), after the last dose

Monitoramento do propranolol plasmático em crianças operadas da tetralogia de Fallot através de micrométodo utilizando a cromatografia líquida de alta eficiência

OBJECTIVE: To evaluate the analytical micromethod using liquid chromatography for the quantification of propranolol in children submitted to surgery of tetralogy of Fallot (TLF). Methods: Only 0.2 mL of plasma is required for the assay. Peaks eluted at 8.4 (Propranolol) and 17.5 min (verapamil, internal standard) from a C18 column, with a mobile phase 0.1 M acetate buffer, pH 5.0, and acetonitrile (60:40, v/v) at flow rate 0.7 mL/min, detected at 290 nm (excitation) and 358 nm (emission). Surgery was started 776 min of drug administration (8.7mg, mean); seven blood samples were collected from six patients (4M/2F; 2.1yrs;11.5kg; 0.80m; 18.9kg/m²). RESULTS: Confidence limits of the method showed high selectivity and recovery, sensitivity of 0.02ng/mL, good linearity (0.05-1000ng/mL), precision of 8.6% and accuracy of 3.1%. The mean duration of surgery was 283.2min, with the patients remaining under cardiopulmonary bypass (CPB) for 114min. A declining curve of propranolol plasma concentration was obtained after the last dose in the night that preceded the day of surgery. Plasma concentration also was normalized with hematocrit due to the hemodilution caused by the CPB procedure. On the other hand a decrease on drug plasma concentration was obtained between periods, the beginning of surgery to the postoperative day 2 (7.09 ng/mL and 0.05 ng/mL, pOBJETIVO: Avaliar o micrométodo analítico empregando a cromatografia líquida para quantificação de propranolol em crianças operadas de tetralogia de Fallot (TLF). MÉTODO: Requereu-se apenas volumes de 0,2mL de plasma para a realização do ensaio. Os picos foram eluídos em 8.4 (Propranolol) e 17.5 min (verapamil, padrão interno) de uma coluna C18, com fase móvel (tampão acetato 0,1 M pH 5,0 e acetonitrila, 60:40, v/v) em fluxo de 0,7 mL/min, sendo detectados em 290 nm (excitação) e em 358 nm (emissão). A cirurgia iniciou-se 776 min depois da dose administrada (8,7mg, média) e sete amostras de sangue foram coletadas de seis pacientes (4M/2F; 2,1 anos;11,5kg; 0,80m;18,9kg/m²). RESULTADOS: Os limites de confiança do método analítico evidenciaram alta seletividade e recuperação, sensibilidade (0,02ng/mL), boa linearidade (0,05-1000ng/mL), precisão de 8,6% e exatidão de 3,1%. A duração média da cirurgia foi de 283,2min, com os pacientes em circulação extracorpórea (CEC) durante 114min. Uma curva de declínio do propranolol no plasma foi obtida após a última dose na noite que precedeu o dia da intervenção. A concentração plasmática foi normalizada com o hematócrito devido à hemodiluição causada pela CEC. Por outro lado obteve-se decréscimo nas concentrações plasmáticas entre os períodos início da cirurgia para o 2º dia de pós-operatório (7,09 ng/mL e0,05 ng/mL,

Disposição cinética do atenolol em pacientes coronarianos submetidos a revascularização do miocárdio

Myocardium ischemia is an important factor of risk for mortality and cardiovascular events in the perioperative period of cardiac and non cardiac surgeries. However, the prophylactic administration of beta-blocker agents could reduce these risks. Physiologic changes, occurred during the coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB), could alter plasma concentration and pharmacokinetics of many drugs. This study investigated the pharmacokinetics of atenolol in patients with unstable angina and without renal dysfunction, submitted to CABG surgery and treated chronically with atenolol PO. For pharmacokinetic analysis, 13 blood samples were collected after doses administrated pre- and post-operatively. Compared to the pre-operative period, it was verified a non-significant reduction in the apparent volume of distribution and plasma clearance after the surgery, remaining unchanged the biological half-life, p>;0.05 (NS). A negative linear correlation between plasma clearance and elimination half-life was demonstrated in both periods of the study (r: -0.77 p=0.06, pre-surgery and r: -0.89, p=0.06, post-surgery), while a correlation between volume of distribution and biological half-life was established only before revascularization (r: 0,54 p= 0,03 , pre-surgery and r: 0,09, p=0,03, post-surgery). We suggest that the CABG surgery leads to the normalization of the extension of distribution of atenolol.A isquemia miocárdica é um importante fator de risco para a mortalidade e eventos cardiovasculares no perioperatório de cirurgias cardíacas e não-cardíacas, sendo que a administração profilática de beta-bloqueadores nesse período, reduz estes riscos. Sabe-se que alterações fisiológicas ocorridas durante a cirurgia de revascularização do miocárdio (RM) com circulação extracorpórea (CEC) podem afetar as concentrações plasmáticas e a cinética de muitos fármacos. Neste estudo, investigou-se a farmacocinética do atenolol em pacientes com angina instável e sem prejuízo renal, submetidos à revascularização com CEC e em terapia crônica com atenolol peroral. O estudo farmacocinético exigiu coleta de amostras sangüíneas seriadas após as doses pré- e pós-operatória. Comparado ao pré-operatório, registrou-se redução não significativa no volume de distribuição e na depuração plasmática após a cirurgia, permanecendo inalterada a meia-vida biológica (p>;0,05). Uma correlação linear negativa entre meia-vida e depuração pode ser estabelecida nos dois períodos do estudo (r: -0,77, p= 0,06 no pré-operatório e r: -0,89, p= 0,06 no pós-operatório), enquanto que se estimou correlação linear direta entre volume de distribuição e meia-vida biológica apenas no pré-cirúrgico (r: 0,54, p= 0,03 no pré-operatório e r: 0,09, p= 0,03 no pós-operatório). Conclui-se que a cirurgia de revascularização auxilia no restabelecimento da extensão da distribuição do atenolol