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Biomedical subjects

Marco L A Sivilotti

Publications and source records attributed to Marco L A Sivilotti.

12 recordsLinked to original sources
PubMed2006

Should spectrophotometry be used to identify xanthochromia in the cerebrospinal fluid of alert patients suspected of having subarachnoid hemorrhage?

BACKGROUND AND PURPOSE: The absence of xanthochromia in the cerebrospinal fluid (CSF) is often used to exclude subarachnoid hemorrhage (SAH). Authorities advocate spectrophotometry to measure xanthochromia, but most North American hospitals use visual inspection. We studied the diagnostic accuracy of spectrophotometry for SAH, and its potential impact on current practice. METHODS: This was a prospective cohort study comparing the diagnostic accuracy of tests. The study was set in 3 university-affiliated tertiary care emergency departments. We enrolled consecutive neurologically intact adults with nontraumatic headache undergoing lumbar puncture (LP) to rule out SAH. CSF was centrifuged, frozen and analyzed later in batch. SAH was defined by (1) subarachnoid blood on CT, (2) >5x10(6) red blood cells/L in the final CSF tube and positive angiography, or (3) visible xanthochromia in CSF and positive angiography. All subjects lacking a normal CT and LP were telephoned at 30 days. RESULTS: We enrolled 220 patients (mean age 42+/-16 years; CT rate 87.7%; angiography rate 5.9%). Two SAHs were identified: 1 with red blood cells without xanthochromia in the CSF and 1 with visibly xanthochromic CSF. The specificity of xanthochromia was 97% (95% CI: 92% to 99%) for visual inspection, but as low as 29% (95% CI: 23% to 35%) for 2 of the spectrophotometric definitions. Introducing spectrophotometry could lead to angiography in as many as 11% to 71% of patients undergoing LP. CONCLUSIONS: Spectrophotometric definitions of xanthochromia have only moderate to low specificity for SAH. Using spectrophotometry could increase angiography rates, thereby identifying more incidental aneurysms, increasing patient anxiety and exposing patients to unnecessary surgical or investigational complications without benefit.

Adult↗
PubMed2006

Multiple centrally acting antidotes protect against severe organophosphate toxicity.

BACKGROUND: Accumulation of acetylcholine in the central nervous system is believed to account for the rapid lethality of organophosphate pesticides and chemical nerve agents. Diazepam is known to supplement atropine therapy, but its specific mechanism of action is uncertain. OBJECTIVES: To test four centrally acting agents for early antidotal efficacy in severe dichlorvos poisoning in the murine model. METHODS: The up-and-down method was used to dose four candidate antidotes: diazepam, xylazine, morphine, and ketamine. Antidotes were administered subcutaneously to unsedated adult Sprague-Dawley rats who were pretreated with 3 mg/kg intraperitoneal glycopyrrolate. All animals received 20 mg/kg of dichlorvos subcutaneously 5 minutes later. A blinded observer adjudicated the outcomes of 10-minute mortality and survival time. RESULTS: All animals pretreated with either no antidote (8/8 deaths) or glycopyrrolate alone (8/8) died within 10 minutes of dichlorvos injection. Pretreatment with diazepam (3/9 deaths), or xylazine (3/9), decreased lethality substantially (Fisher p = 0.007; median effective doses, 0.12 mg/kg and 3.0 mg/kg, respectively). Intermediate doses of morphine (3.1 to 5.5 mg/kg) resulted in survival, but higher doses did not, presumably because of excessive respiratory depression (7/11 deaths; p = 0.09). Ketamine (7/8 deaths) was ineffective as an antidote. Survival times also were prolonged in the diazepam and xylazine groups (log-rank p < 0.001) and, to a lesser degree, the morphine group (p = 0.07). CONCLUSIONS: Doses of diazepam, xylazine, and morphine below those used for deep sedation protect against severe dichlorvos poisoning, implying that several distinct central mechanisms are each sufficient to avert lethality. These findings suggest new possibilities for prophylaxis or therapy.

Animals↗
PubMed2005

A risk quantification instrument for acute acetaminophen overdose patients treated with N-acetylcysteine.

STUDY OBJECTIVE: The risk of hepatotoxicity after acute acetaminophen overdose varies with timed serum acetaminophen concentration and delay to treatment. The ability to accurately predict hepatotoxicity is needed to reduce confusion about the optimal treatment regimen for individual patients and the effects of risk modifiers such as ethanol. We quantitatively estimate the risk of hepatotoxicity based on the degree and duration of pretreatment exposure to supratherapeutic concentrations of acetaminophen. METHODS: We examined all hospitalizations for acute acetaminophen overdose within a retrospective multicenter Canadian registry. We used a previously developed composite measure incorporating timed serum acetaminophen concentration and time to N-acetylcysteine treatment into a single parameter. We then modeled hepatotoxicity on this parameter, as well as age, sex, and ethanol use. Hepatotoxicity was defined as peak aminotransferase level of 1,000 IU/L or greater at 24 hours or longer. RESULTS: Of 1,270 admitted patients treated mostly with intravenous N-acetylcysteine for less than 24 hours, our model accurately identified the 94 patients who developed hepatotoxicity (discriminatory index 0.93). Hepatotoxicity occurred in none of the 313 patients (95% confidence interval [CI] 0% to 1.0%) above the traditional 150 mug/mL treatment line who were classified as low risk (<1%) using our instrument. After adjustment for severity of exposure, the risk of hepatotoxicity was considerably higher in the absence of coingested ethanol (median hepatotoxic dose 16.5 mmol/L x hour [95% CI 8.74 to 31.0 mmol/L x hour] versus 27.1 mmol/L x hour [95% CI 11.1 to 66.3 mmol/L x hour]), particularly among alcoholics (4.79 mmol/L x hour [95% CI 2.13 to 10.8 mmol/L x hour]). CONCLUSION: Our risk prediction instrument identifies a large group of low-risk patients for whom 20-hour intravenous N-acetylcysteine therapy is sufficient. Our results suggest that acute and chronic ethanol use dramatically influences acetaminophen toxicity. This work may facilitate the evaluation of individualized treatment strategies for higher-risk patients.

Acetaminophen↗
PubMed2005

A new predictor of toxicity following acetaminophen overdose based on pretreatment exposure.

INTRODUCTION: Despite extensive clinical experience, no dose-response curve exists for acetaminophen toxicity in man. The absence of accurate toxicodynamics has hampered efforts to optimize patient therapy and to identify risk modifiers following overdose. We set out to parameterize both the degree and duration of pretreatment exposure into a single, continuous measure of exposure, which will serve as the x-axis of an eventual dose-response curve. METHODS: The model was constructed from pharmacokinetic first principles, using as inputs the vertical distance above the Rumack-Matthew nomogram line (expressed as the equivalent serum acetaminophen concentration 4 h after ingestion) and the delay to antidote therapy (tNAC). A no-effect dose ([APAP]threshold) and lag time (ti) were assumed. RESULTS: The area under the serum acetaminophen concentration vs. time curve bounded by [APAP]threshold, ti and tNAC represents our proposed time-weighted measure of exposure. We demonstrate that this non-negative area estimates the cellular burden of toxic adducts formed following overdose. This measure is also easily calculated at patient presentation using clinical data and allows for both declining serum acetaminophen concentrations and variable delays to antidote therapy. DISCUSSION: We describe a new, pharmacokinetically based measure of exposure following acute acetaminophen overdose treated with N-acetylcysteine. Using this measure should enhance the analysis of nonexperimental clinical data and permit more accurate characterization of acetaminophen toxicodynamics. Ultimately, this approach may facilitate progress on many of the long-standing controversies regarding acetaminophen toxicity in man.

Acetaminophen↗
PubMed2005

Pharmacokinetic effects of diphenhydramine or oxycodone in simulated acetaminophen overdose.

OBJECTIVES: To determine the effects of co-ingested diphenhydramine (DPH) or oxycodone (OXY) on the absorption kinetics of simulated acetaminophen (APAP) overdose. METHODS: This was an institutional review board-approved, prospective crossover study of ten healthy human volunteers ingesting 5 grams of APAP, 5 grams of APAP + 250 mg of DPH (APAP+DPH), or 5 grams of APAP + 0.5 mg/kg of OXY (APAP+OXY). Serum APAP concentrations (APAPs) were measured hourly from zero through eight hours and again at 24 hours, and basic noncompartmental pharmacokinetic parameters were compared. RESULTS: For APAP alone, the mean parameters were: maximum APAP concentration ([APAP](max)) 71.8 microg/mL, time to peak [APAP] (t(max)) 1.71 hours, and area under the receiver operating characteristic curve (AUC(0-8)) 318.3 microg-hr/mL. For APAP+DPH, the mean parameters were: [APAP](max) 67.6 microg/mL, t(max) 1.90 hours, and AUC(0-8) 297.7 microg-hr/mL. For APAP+OXY, the parameters were: [APAP](max) 42.9 microg/mL, t(max) 2.87 hours, and AUC(0-8) 232.1 microg-hr/mL. Compared with APAP alone, APAP+OXY had a 27% lower AUC, a 40% lower [APAP](max), and a 68% longer t(max). Co-ingested DPH had no significant effect on APAP absorption, except a 6% decrease in the AUC. CONCLUSIONS: Co-ingested OXY, but not DPH, delayed absorption of APAP. This suggests a potential role for activated charcoal administration beyond one hour postingestion after mixed ingestions that include OXY.

Absorption↗
PubMed2004

Oxidant stress and haemolysis of the human erythrocyte.

The erythrocyte is a highly specialised cell with a limited metabolic repertoire. As an oxygen shuttle, it must continue to perform this essential task while exposed to a wide range of environments on each vascular circuit, and to a variety of xenobiotics across its lifetime. During this time, it must continuously ward off oxidant stress on the haeme iron, the globin chain and on other essential cellular molecules. Haemolysis, the acceleration of the normal turnover of senescent erythrocytes, follows severe and irreversible oxidant injury. A detailed understanding of the molecular mechanisms underlying oxidant injury and its reversal, and of the clinical and laboratory features of haemolysis is important to the medical toxicologist. This review will also briefly review glucose-6-phosphate deficiency, a common but heterogeneous range of enzyme-deficient states, which impairs the ability of the erythrocyte to respond to oxidant injury.

Erythrocytes↗
PubMed2003

Does the sedative agent facilitate emergency rapid sequence intubation?

OBJECTIVES: To ascertain whether the sedative agent administered during neuromuscular-blocking agent-facilitated intubation (rapid sequence intubation [RSI]) influences the number of attempts and overall success at RSI. METHODS: Records were drawn from an ongoing, prospective multicenter registry of emergency department intubations. Conditional logistic regression stratified by institution was used to identify factors associated with multiple intubation attempts and unsuccessful RSI. RESULTS: Of 3,407 intubations over 33 months in 22 institutions, 2,380 involved RSI. After correcting for the specialty and experience of the intubator and for the presence of airway aberrancy, the sedative agent was significantly associated with the number of attempts at intubation (p = 0.002). Specifically, the use of etomidate (adjusted odds ratio [OR] 0.35 [95% CI = 0.17 to 0.72]), ketamine (OR 0.27 [95% CI = 0.11 to 0.65]), a benzodiazepine (OR 0.47 [95% CI = 0.23 to 0.95]), or no sedative agent (OR 0.51 [95% CI = 0.23 to 1.13]) prior to neuromuscular blockade was associated with a lower likelihood of successful intubation on the first attempt, as compared with thiopental, methohexital, or propofol. The adjusted odds ratios for the likelihood of overall success had similar point estimates, but did not reach statistical significance due to lack of power (p = 0.2, with 36 unsuccessful intubations). Among patients receiving etomidate, intubation was more likely to be successful on the first attempt with increasing doses of either etomidate or succinylcholine. CONCLUSIONS: Thiopental, methohexital, and propofol appear to facilitate RSI in emergency department patients, independent of patient characteristics or intubator training. A deeper plane of anesthesia may improve intubating conditions in emergency patients undergoing RSI by complementing incomplete muscle paralysis.

Adolescent↗