Local Anesthetic Plasma Concentrations as a Valuable Tool to Confirm the Diagnosis of Local Anesthetic Systemic Toxicity? A Report of 10 Years of Experience.

BACKGROUND: Local anesthetic systemic toxicity (LAST) has been reported as a serious complication of local anesthetic (LA) peripheral injection. The signs and symptoms of LAST are highly variable, and the challenge remains to confirm its diagnosis. In this context, the determination of LA plasma concentration appears as a valuable tool to confirm LAST diagnosis. The aims of this study were to describe observed LA concentrations in patients suspected with LAST and their contribution to diagnostic confirmation. METHODS: We retrospectively reported suspected LAST in patients for which at least one plasma LA concentration was determined to confirm diagnosis of LAST. Data collection came from our pharmacological laboratory's database. Clinical signs and symptoms of toxicity, their onset time and observed LA concentrations were used to confirm LAST diagnosis. RESULTS: 33 patients who presented with suspected LAST after ropivacaine and/or lidocaine administration were included. Prodromal symptoms were observed in 13 patients. Isolated central nervous system (CNS) toxicity occurred in 11 patients, and combined CNS and cardiovascular toxicity occurred in 12. One, two or three venous plasma samples were performed in 11, 3 and 19 patients, respectively. Toxic plasma LA concentrations were observed in three patients, receiving peripheral LA injection using lidocaine (16.1 µg/mL) and ropivacaine (4.2 and 4.8 µg/mL). CONCLUSION: This study presents an important biological and clinical dataset of patients who presented with suspected LAST. Plasma LA concentrations could bring valuable information in the diagnosis of LAST but requires rigorous sample protocols.

Population pharmacokinetic model for tumescent lidocaine in women undergoing breast cancer surgery.

PURPOSE: Tumescent lidocaine anesthesia (TLA) is an opportunity to perform mastectomy for breast cancer without general anesthesia in elderly women. Few reports are available on the pharmacokinetics of lidocaine in a context of TLA during a unilateral mastectomy. The aim of this study was to describe lidocaine pharmacokinetics in elderly women undergoing breast cancer surgery after TLA and to explore the risk of the toxicity of this technique. METHODS: A prospective study was conducted to examine the pharmacokinetics of lidocaine in women undergoing TLA. TLA consists of an intradermal lidocaine instillation (20 mL, 1% [200 mg]) followed by a tumescent lidocaine infiltration (100 mL of 1% lidocaine [1000 mg] and 0.5 mg epinephrine to 1 L Ringer's lactate) via an infusion pump. A population pharmacokinetic (popPK) analysis was performed using the nonlinear mixed effects model (NONMEM). RESULTS: The analysis included 116 observations from 17 women with a median (range) age of 83.4 (60.5-90.0). The median tumescent lidocaine dose was 800 mg (range 375-1000 mg) infused over 48.0 ± 11.0 min. A one-compartment disposition model with first order absorption, two input compartments, and a central elimination best described the pharmacokinetics of lidocaine. The estimates (between subject variability; relative standard error, %) of apparent volume, apparent clearance, tumescent absorption rate, and instillation absorption rate were 195.0 (46.3; 14.5%) L, 24.7 (48.9; 13.3%) L h-1, 0.28 (39.6; 13.8%) h-1, and 2.56 (135.3; 44.9%) h-1, respectively. CONCLUSIONS: This is the first popPK model developed to describe kinetic profiles of TLA. These findings confirm the slow diffusion of lidocaine from the tumescent deposit.

Intensive care and pregnancy: Epidemiology and general principles of management of obstetrics ICU patients during pregnancy.

In developed countries, the rate of obstetric ICU admissions (admission during pregnancy or the postpartum period) is between 0.5 and 4 per 1000 deliveries and the overall case-fatality rate is about 2%. The most two common causes of obstetric ICU admissions concerned direct obstetric pathologies: obstetric hemorrhage and hypertensive disorders of pregnancy. This review summarized the principles of management of critically ill pregnant patient. Its imply taking care of two patients in the same time. A coordinated multidisciplinary team including intensivists, anesthesiologists, obstetricians, pediatricians and pharmacists is therefore necessary. This team must work effectively together with regular staff aiming to evaluate daily the need to maintain the patient in intensive care unit or to prompt delivery. Keeping mother and baby together and fetal well-being must be balanced with the need of specialized advanced life support for the mother. The maternal physiological changes imply various consequences on management. The uterus aorto-caval compression implies tilting left the parturient. In case of cardiac arrest, uterus displacement and urgent cesarean delivery are needed. The high risk of aspiration and difficult tracheal intubation must be anticipated. Even during acute respiratory distress syndrome, hypoxemia and permissive hypercapnia must be avoided due to their negative impact on the fetus. Careful analysis of the benefit-risk ratio is needed before all drug administration. Streptococcal toxic shock syndrome and perineal fasciitis must be feared and a high level of suspicion of sepsis must be maintained. Finally the potential benefits of an ultrasound-based management are detailed.

Postoperative analgesia after caesarean section with transversus abdominis plane block or continuous infiltration wound catheter: A randomized clinical trial. TAP vs. infiltration after caesarean section.

OBJECTIVE: Single shot transversus abdominis plane (TAP) block and continuous local anesthetic infiltration wound catheter (CLAIWC) decreased the morphine consumption after caesarean section. The aim of this study was to compare the analgesic efficacy of CLAIWC and ultrasound-guided TAP block. METHOD: Sixty patients undergoing caesarean section were prospectively randomized. After the caesarean section, the postoperative analgesia was randomized to either a CLAIWC localized below the fascia with an elastomeric pump for 48hours or a bilateral ultrasound-guided TAP block with injection of ropivacaine. Every patient had a morphine pump patient-controlled analgesia. The primary outcome was the morphine consumption during the first 48hours. Secondary outcomes were pain score levels, adverse effects of opioids, and patient satisfaction. Variables were collected during 48hours after the caesarean section. RESULTS: Median cumulative 48-hour morphine consumption was 17 [8-51] mg in the TAP group versus 21 [7-34] mg in the CLAIWC group (P=0.3). We did not find a difference between the groups regarding pain, side effects and satisfaction scores. CONCLUSION: As part of a multimodal analgesic regimen, there is no significant difference between the TAP block and CLAIWC for postoperative analgesia after a caesarean section.

Effects of sufentanil or ketamine administered in target-controlled infusion on the cerebral hemodynamics of severely brain-injured patients.

OBJECTIVE: The manual injection of a bolus of opioid in patients with brain injury induces an increase in intracranial pressure related to a decrease in mean arterial pressure. Such an effect has not been observed with the use of ketamine. The use of target-controlled infusion would minimize or suppress this adverse effect of opioid. This study evaluated the effects of an increase in plasma concentrations of sufentanil or ketamine administered by target-controlled infusion on cerebral hemodynamics. DESIGN: Prospective, randomized study. SETTING: Intensive care unit in a trauma center. PATIENTS: Thirty patients with severe traumatic brain injury. INTERVENTIONS: Patients were assigned to receive sedation consisting of sufentanil-midazolam or ketamine-midazolam using target-controlled infusion. Twenty-four hours after the onset of sedation, the target concentrations of sufentanil or ketamine were doubled for 15 mins. Blood samples were collected to determine the actual plasma concentration of sufentanil and ketamine, before and 15 mins after concentration change. MEASUREMENTS AND MAIN RESULTS: The baseline values of intracranial pressure and cerebral perfusion pressure were similar in both groups. The two-fold increase in drug concentrations did not involve a significant change for intracranial pressure, cerebral perfusion pressure, and mean velocity of middle cerebral artery in both the ketamine and the sufentanil groups. The measured plasma concentrations of sufentanil and ketamine were 0.4 +/- 0.2 ng/mL and 2.6 +/- 2.2 mug/mL, respectively, before the increase in concentrations and 0.7 +/- 0.4 ng/mL and 5.5 +/- 3.8 mug/mL after. CONCLUSIONS: The present study shows that the increase in sufentanil or ketamine plasma concentrations using a target-controlled infusion is not associated with adverse effects on cerebral hemodynamics in patients with severe brain injury. The use of target-controlled infusion could be of interest in the management of severely brain-injured patients. However, there is a need for specific pharmacokinetic models designed for intensive care unit patients.

Increasing mean arterial pressure in patients with septic shock: effects on oxygen variables and renal function.

OBJECTIVE: To measure the effects of increasing mean arterial pressure on oxygen variables and renal function in septic shock. DESIGN: Prospective, open-label, randomized, controlled study. SETTING: Medical-surgical intensive care unit of a tertiary care teaching hospital. PATIENTS: Twenty-eight patients with a diagnosis of septic shock who required fluid resuscitation and pressor agents to increase and maintain mean arterial pressure > or =60 mm Hg. INTERVENTIONS: Patients were treated with fluid and norepinephrine to achieve and maintain a mean arterial pressure of 65 mm Hg. Then they were randomized in two groups: In the first group (control group, n = 14), mean arterial pressure was maintained at 65 mm Hg, and in the second group (n = 14), mean arterial pressure was increased to 85 mm Hg by increasing the dose of norepinephrine. MEASUREMENTS AND MAIN RESULTS: Hemodynamic variables (mean arterial pressure, heart rate, mean pulmonary artery pressure, pulmonary artery occlusion pressure, cardiac index, systemic vascular resistance index, pulmonary vascular resistance index, left and right ventricular stroke indexes), metabolic variables (oxygen delivery, oxygen consumption-calorimetric method, arterial lactate), and renal function variables (urine flow, serum creatinine, creatinine clearance) were measured. After introduction of norepinephrine, similar values of hemodynamic, metabolic, and renal function variables were obtained in both groups. No changes were observed in group 1 during the study period. Increasing mean arterial pressure from 65 to 85 mm Hg with norepinephrine in group 2 resulted in a significant increase in cardiac index from 4.8 (3.8-6.0) to 5.8 (4.3-6.9) L.min.m. Arterial lactate and oxygen consumption did not change. No changes were observed in renal function variables: urine flow, 63 (14-127) and 70 (15-121) mL; serum creatinine, 170 (117-333) and 153 (112-310) mumol.L; and creatinine clearance, 50 (12-77) and 67 (13-89) mL.min.1.73 m. CONCLUSIONS: Increasing mean arterial pressure from 65 to 85 mm Hg with norepinephrine neither affects metabolic variables nor improves renal function.

Risk factors for late-onset ventilator-associated pneumonia in trauma patients receiving selective digestive decontamination.

OBJECTIVE: To determine the independent risk factors for late-onset ventilator-associated pneumonia (VAP) in trauma patients receiving selective digestive decontamination (SDD). DESIGN: A 4-year, prospective cohort study of trauma patients meeting the following criteria: injury severity score >15, and duration of mechanical ventilation >5 days. Predictors of late-onset VAP occurrence were assessed by logistic regression analysis. POPULATION: All patients received SDD consisting of polymixin E, gentamicin, and amphotericin B applied in nostrils, mouth, and gut with a 3-day course of parenteral cefazolin. VAP was suspected on clinical and radiological signs, and confirmed by the presence of at least one microorganism at a concentration of at least 10(4) CFU/ml on the broncho-alveolar lavage. MEASUREMENT: Independent risk factors for late-onset VAP. RESULTS: A late-onset VAP was diagnosed in 90 (56%) out of 159 patients. Predicting factors for late-onset VAP were: use of non-depolarizing muscle relaxant agents for intubation [3.4 (CI 1.08-10.73)], duration of intubation [1.06 (CI 1.01-1.17)], length of intensive care unit (ICU) stay [1.05 (CI 1.02-1.09)], and prior tracheal colonization [1.03 (CI 1.02-1.21)]. Exposure to prior antimicrobial treatment, except SDD, conferred protection [0.3 (0.12-0.74)]. CONCLUSION: This study confirms the role of duration of intubation, length of ICU stay, and prior tracheal colonization in the development of late-onset VAP. The results also highlight the importance of the initial management on the development of late-onset VAP. The type of neuromuscular blocking agents to intubate trauma patients should be evaluated in future studies.

The effects of remifentanil on endotracheal suctioning-induced increases in intracranial pressure in head-injured patients.

In patients with severe traumatic brain injury, bronchotracheal toilet may be accompanied by deleterious variations in intracranial pressure (ICP). To avoid these effects, IV opioids have been proposed. Twenty mechanically-ventilated patients received 3 ascending IV doses of remifentanil: dose 1 (1 microg/kg bolus, 0.25 microg/kg/min infusion); dose 2 (2 microg/kg bolus, 0.5 microg/kg/min infusion); and dose 3: (4 microg/kg bolus, 1 microg/kg/min infusion). Endotracheal suction was performed 20 min after the beginning of infusion to assess coughing. Heart rate, ICP, mean arterial blood pressure (MAP), cerebral perfusion pressure (CPP), middle cerebral artery mean flow velocity (V(MCA)), and bispectral index were monitored throughout the 30-min study period. Twelve, 15, and 19 patients receiving dose 1, 2, and 3, respectively, required vasopressors to maintain CPP >60 mm Hg. Suctioning resulted in coughing in 16, 15, and 5 patients receiving dose 1, 2, and 3, respectively. An increase in ICP, without change in V(MCA), corresponded to the reduction in MAP consistent with the preservation of autoregulation. Remifentanil used as a continuous infusion in head-injured patients is not an effective drug to block responses to suctioning.

Renal effects of norepinephrine in septic and nonseptic patients.

OBJECTIVE: To assess the effects of a norepinephrine-induced vasoconstriction on renal function in septic and nonseptic patients. DESIGN: Open-label prospective study. SETTING: Medical-surgical ICU in an urban teaching hospital. PATIENTS: Fourteen patients with septic shock and 12 uninfected patients with head trauma (Glasgow coma score, < 8). INTERVENTIONS: Patients received norepinephrine infusion to increase systemic vascular resistance index (SVRI), and to raise mean arterial BP (MAP) to > 70 mm Hg in the septic group and cerebral perfusion pressure (CPP) to > 70 mm Hg in the head trauma group. MEASUREMENTS AND MAIN RESULTS: MAP and SVRI increased in both groups (p < 0.001), and CPP significantly increased in the head trauma group (p < 0.001). The cardiac index was not modified in either group. Norepinephrine infusion reestablished urine flow in 12 of the 14 septic patients (p < 0.001), with a decrease in serum creatinine levels (p < 0.001) and an increase in creatinine clearance rate (p < 0.001) after 24 h. Urine parameters were not affected in the head trauma group. CONCLUSION: Within the limitation of the present study, norepinephrine administration induces a marked vasoconstriction in septic and nonseptic patients. Norepinephrine has positive effects on renal function in septic patients but has no significant effect on the same urinary parameters when administered to uninfected patients with normal renal function.

Safety of sedation with ketamine in severe head injury patients: comparison with sufentanil.

OBJECTIVE: The aim of the study was to compare the safety concerning cerebral hemodynamics of ketamine and sufentanil used for sedation of severe head injury patients, both drugs being used in combination with midazolam. DESIGN: Prospective, randomized, double-blind study. SETTING: Intensive care unit in a trauma center. PATIENTS: Twenty-five patients with severe head injury. INTERVENTIONS: Twelve patients received sedation with a continuous infusion of ketamine-midazolam and 13 with a continuous infusion of sufentanil-midazolam. All patients were mechanically ventilated with moderate hyperventilation. MEASUREMENTS AND MAIN RESULTS: Prognostic indicators (age, Glasgow Coma Scale scores, computed tomography diagnosis, and Injury Severity Scale score) were similar in the two groups at study entry. Measurements were carried out during the first 4 days of sedation. The average infusion rates during this time were 82 +/- 25 micro x kg x min ketamine and 1.64 +/- 0.5 microg x kg x min midazolam in the ketamine group and 0.008 +/- 0.002 microg x kg x min sufentanil and 1.63 +/- 0.37 microg x kg x min midazolam in the sufentanil group. No significant differences were observed between the two groups in the mean daily values of intracranial pressure and cerebral perfusion pressure. The numbers of intracranial pressure elevations were similar in both groups. The requirements of neuromuscular blocking agents, propofol, and thiopental were similar. Heart rate values were significantly higher in the ketamine group on therapy days 3 and 4 ( <.05). With regard to arterial pressure control, more fluids were given on the first therapy day and there was a trend toward greater use of vasopressors in the sufentanil group. Sedative costs were similar in the two groups. CONCLUSION: The results of this study suggest that ketamine in combination with midazolam is comparable with a combination of midazolam-sufentanil in maintaining intracranial pressure and cerebral perfusion pressure of severe head injury patients placed under controlled mechanical ventilation.

Empirical antimicrobial therapy of septic shock patients: adequacy and impact on the outcome.

OBJECTIVE: To assess the adequacy of empirical antimicrobial therapy prescribed in septic shock patients and to evaluate the relationship between inadequate antimicrobial therapy and 30-day mortality. DESIGN: Prospective observational study. SETTING: Medical-surgical (16-bed) intensive care unit in an urban teaching hospital. PATIENTS: A total of 107 patients requiring intensive care admission were prospectively evaluated during the 3-yr period of the study. INTERVENTIONS: Prospective patient surveillance and data collection and assessment of antimicrobial therapy according to microbiological documentation. MEASUREMENTS AND MAIN RESULTS: A source of infection associated with a microbiological documentation was identified in 78 of the 107 patients (72%). Empirical antimicrobial therapy consisted of a pivotal antibiotic (beta-lactam) associated with an aminoglycoside (59 patients) or a fluoroquinolone (21 patients). Vancomycin was added in 14 patients. Sixty-nine of the 78 patients (89%) received an adequate antimicrobial therapy. The mortality rate of patients receiving an adequate antimicrobial therapy was 56%, and seven of the nine patients (78%) receiving an inadequate antimicrobial therapy died (p =.2). Among the 81 patients who were alive on day 3, antimicrobial therapy was modified in agreement to clinical status and microbiological documentation in 80% of cases, with de-escalation in 64% of cases. De-escalation consisted of withdrawing the nonpivotal antibiotic in 42% of patients or switching to a narrow-spectrum beta-lactam antibiotic (22% of cases). CONCLUSION: The prescription of empirical antimicrobial therapy by a senior physician in agreement with practice guidelines made it possible to achieve a crude rate of 89% of adequate antimicrobial therapy in study patients. Inadequate antimicrobial therapy was associated with a 39% excess of mortality. A de-escalation of the empirical therapy was possible in 64% of patients.

Influence on outcome of ventilator-associated pneumonia in multiple trauma patients with head trauma treated with selected digestive decontamination.

OBJECTIVE: Ventilator-associated pneumonia is said to be associated with an increased mortality or a prolonged intensive care unit stay. In multiple trauma, the use of selective digestive decontamination has been reported to decrease morbidity and mortality associated with pneumonia. We performed a study to evaluate the attributable morbidity and mortality of ventilator-associated pneumonia in multiple trauma patients with head trauma treated with selective digestive decontamination. DESIGN: Prospective, matched-paired, case-control study. SETTING: Intensive care unit at a tertiary university hospital. PATIENTS: During a 6-yr period, 324 consecutive multiple trauma patients with head trauma requiring mechanical ventilation for >48 hrs were prospectively followed for the development of VAP. Case-control matching criteria were as follows: 1) age difference within 5 yrs, 2) Glasgow coma scale within five categories, 3) injury severity score within 5 points, 4) APACHE II score within 5 points, 5) ventilation of control patients for at least as long as the cases. The selective digestive decontamination regimen was used in all patients (cases and controls): polymixin E, gentamicin, and amphotericin B. Systemic cefazolin (1 g three times a day) was given for the first 3 days of intensive care unit stay. MEASUREMENTS AND MAIN RESULTS: Analysis was performed on 58 pairs that were matched with 100% of success The most common isolates recovered were Staphylococcus aureus (39%) and Haemophilus influenzae (22%). High-risk pathogens were rarely isolated: Pseudomonas aeruginosa (5.1%), Acinetobacter species (8.6%), and methicillin-resistant S. aureus (6.7%). The duration of mechanical ventilation and intensive care unit stay were increased in case patients (11.6 +/- 1.7 and 22.7 +/- 2.9 days, respectively) compared with control patients (9.4 +/- 1.3 and 16.8 +/- 2.9 days, respectively; p <.0006). Mortality was similar in both case (17%) and control (24%) patients. CONCLUSION: Ventilator-associated pneumonia did not seem to increase mortality of multiple trauma patients with head trauma who received selective digestive decontamination. Whether or not this conclusion applied to trauma patients not receiving selective digestive decontamination should be evaluated in further studies.