Relationship between infusion rates, plasma concentrations, and cardiovascular and metabolic effects during the infusion of norepinephrine in healthy volunteers.

OBJECTIVE: To determine the relationship between iv infusion rate, plasma concentrations, and hemodynamic and metabolic actions of norepinephrine. DESIGN: Norepinephrine was administered by using five iv infusion rates (0.01 to 0.2 micrograms/kg/min) for 30 mins each to eight volunteers, for the purpose of constructing cumulative plasma concentration-response curves. SETTING: Laboratory of the Department of Anesthesiology at a university hospital. MEASUREMENTS AND MAIN RESULTS: Systolic and diastolic BP, heart rate, and the plasma concentrations of norepinephrine, glucose, nonesterified fatty acids, and insulin were measured at the end of each infusion rate. During the highest infusion rate, plasma norepinephrine concentrations increased from 199 +/- 75 to 7475 +/- 1071 pg/mL (1.18 +/- 0.44 to 44.18 +/- 6.33 nmol/L). Typical hemodynamic responses, such as increases in BP and decreases in heart rate, were seen, while the plasma concentrations of glucose and nonesterified fatty acids increased from 92 +/- 10 to 132 +/- 17 mg/dL (5.1 +/- 0.6 to 7.3 +/- 0.9 mmol/L) and 11 +/- 4 to 34 +/- 6 mg/dL (0.11 +/- 0.04 to 0.34 +/- 0.06 g/L), respectively, during the 0.2 micrograms/kg/min infusion rate (p less than .05). Despite the increase in glucose concentration, insulin remained at baseline values. Metabolic and hemodynamic effects occurred at similar plasma concentrations throughout the study. CONCLUSIONS: Administration of norepinephrine showed no selective hemodynamic actions. The metabolic responses observed in this investigation were similar to those responses seen during increased endogenous sympathetic nervous system activity, such as stress, exercise, or trauma.     

Hemodynamic and metabolic effects of epinephrine during cardiopulmonary resuscitation in a pig model.

BACKGROUND AND METHODS: This study was designed to assess the effect of epinephrine during cardiopulmonary resuscitation (CPR) on left ventricular myocardial blood flow, systemic oxygen delivery and consumption, and on plasma glucose and lactate concentrations. Fourteen pigs were allocated to receive either 0.9% saline (n = 7), or 45 micrograms/kg epinephrine (n = 7) after 5 mins of ventricular fibrillation, and 3 mins of open-chest CPR. Left ventricular myocardial blood flow was measured with radiolabeled microspheres. Plasma catecholamine concentrations were measured by high-pressure liquid chromatography. RESULTS: During open-chest CPR, mean (+/- SD) values of left ventricular myocardial blood flow before, 90 secs, and 5 mins following drug administration were 49 +/- 10, 46 +/- 12, 43 +/- 15 mL/min/100 g, respectively, in the control group, and 52 +/- 12, 118 +/- 21, 84 +/- 28 mL/min/100 g, respectively, in the epinephrine group (p less than .05 at 90 secs and 5 mins). At the same time points, mean (+/- SD) oxygen delivery indices were 7.7 +/- 3.0, 6.0 +/- 2.1, 6.5 +/- 2.7 mL/min/kg in the control group and 7.6 +/- 2.5, 5.3 +/- 2.1, 5.5 +/- 1.9 mL/min/kg in the epinephrine group (nonsignificant). Mean oxygen consumption indices were 5.8 +/- 2.4, 4.6 +/- 1.6, 5.2 +/- 2.6 mL/min/kg in the control group and 5.4 +/- 1.6, 4.2 +/- 1.6, 4.4 +/- 1.4 mL/min/kg in the epinephrine group (nonsignificant). During CPR and before epinephrine administration, arterial plasma epinephrine concentrations increased from prearrest values of 0.77 +/- 0.70 to 62.1 +/- 48.7 micrograms/L, and plasma norepinephrine concentrations increased from 0.28 +/- 0.32 to 104.3 +/- 57.1 micrograms/L. After administered epinephrine, there was an additional increase to 271 +/- 83 micrograms/L at 90 secs in arterial plasma epinephrine, but no important alteration in the plasma norepinephrine concentration. At no time point could we find a clinically important difference in plasma glucose or lactate concentrations between the two groups. CONCLUSIONS: At a dose of 45 micrograms/kg, epinephrine caused an increase in left ventricular myocardial blood flow after a total of 8 mins of cardiac arrest, including 3 mins of CPR, while not altering systemic oxygen delivery and consumption, plasma glucose, or lactate concentrations.     

Vasopressin decreases endogenous catecholamine plasma concentrations during cardiopulmonary resuscitation in pigs

OBJECTIVE: The purpose of this study was to evaluate the effect of vasopressin vs. saline placebo on catecholamine plasma concentrations during cardiopulmonary resuscitation (CPR). DESIGN: Prospective, randomized laboratory investigation by using an established porcine CPR model with instrumentation for measurement of hemodynamic variables, vital organ blood flow, and return of spontaneous circulation. SETTING: University hospital laboratory. SUBJECTS: Sixteen domestic pigs. INTERVENTIONS: After 15 mins of untreated cardiac arrest and 3 mins of CPR, 16 pigs were randomized to be treated with either 0.8 U/kg vasopressin (n = 8) or placebo (normal saline; n = 8). Arterial epinephrine and norepinephrine plasma concentrations were sampled at prearrest, after 1.5 mins of chest compressions, and at 1.5 mins and 5 mins after drug administration during CPR. MEASUREMENTS AND MAIN RESULTS: In comparison with placebo pigs at 1.5 and 5 mins after drug administration, animals resuscitated with vasopressin had significantly (p < .01) higher mean +/- SEM left ventricular myocardial (131+/-27 vs. 10+/-1 mL x mins(-1) x 100 g(-1) and 62+/-13 vs. 9+/-2 mL x mins(-1) x 100 g(-1)); total cerebral (90+/-8 vs. 14+/-3 mL x mins(-1) x 100 g(-1) and 51+/-4 vs. 12+/-2 mL x mins(-1) x 100 g(-1)); and adrenal gland perfusion (299+/-36 vs. 38+/-7 mL x mins(-1) x 100 g(-1) and 194+/-23 vs. 29+/-5 mL x mins(-1) x 100 g(-1)). Significantly lower mean +/- SEM epinephrine concentrations in the vasopressin pigs compared with the placebo group were measured 1.5 mins and 5 mins after drug administration, (24167+/-7919 vs. 80223+/-19391 pg/mL [p < .01] and 8346+/-1454 vs. 71345+/-10758 pg/mL [p < .01]). Mean +/- SEM norepinephrine plasma concentrations in the vasopressin animals in comparison with placebo were at 1.5 and 5 mins after drug administration significantly lower (41729+/-13918 vs. 82756+/-9904 pg/mL [p = .01] and 10642+/-3193 vs. 62170+/-8797 pg/mL [p < .01]). CONCLUSIONS: Administration of vasopressin during CPR resulted in significantly superior vital organ blood flow, but significantly decreased endogenous catecholamine plasma concentrations when compared with placebo.     

Acute continuous hemofiltration with dialysis: effect on insulin concentrations and glycemic control in critically ill patients.

OBJECTIVES: To quantitate insulin losses and glucose absorption during acute continuous hemofiltration with dialysis and to assess the clinical importance of these changes. DESIGN: Prospective collection of serum and ultradiafiltrate fluid in patients receiving acute continuous hemofiltration with dialysis. Measurements of serum and ultradiafiltrate insulin and glucose concentrations. Calculations of insulin excretion and glucose absorption. Correlation of findings with patient outcome. SETTING: University medical center. PATIENTS: Sixteen ICU patients with acute renal failure. MEASUREMENTS AND MAIN RESULTS: The mean serum glucose concentration before acute continuous hemofiltration with dialysis was 178 mg/dL (9.9 mmol/L) (95% confidence interval 112 to 244 mg/dL [6.2 to 13.6 mmol/L]), increasing to 257 mg/dL (14.3 mmol/L) (95% confidence interval 167 to 347 mg/dL [9.3 to 19.3 mmol/L]) after 4 hrs of acute continuous hemofiltration with dialysis, and stabilizing at 207 mg/dL (11.5 mmol/L) (95% confidence interval 160 to 254 mg/dL [8.9 to 14.1 mmol/L]) at 24 hrs. Mean plasma insulin concentration before acute continuous hemofiltration with dialysis was 34.4 mU/L (95% confidence interval 8.6 to 60.2 mU/L), increasing to 54.4 mU/L at 4 hrs (95% confidence interval 25 to 83.8 mU/L; NS). There was no significant decrease in mean insulin concentration across the filter (51.8 mU/L before filtration vs. 51.9 mU/L after filtration). Insulin was detected in the ultradiafiltrate but its overall mean clearance rate was only 6.2 mL/min, with mean daily losses of 689 mU/day (95% confidence interval 325 to 1053 mU/day). During acute continuous hemofiltration with dialysis, glucose absorption through the filter averaged 134 g/day (95% confidence interval 96.2 to 171.8 g/day). Plasma insulin concentrations were significantly (p < .05) lower in survivors than nonsurvivors (51.7 vs. 123.6 mU/L). CONCLUSIONS: Significant glucose absorption occurs during acute continuous hemofiltration with dialysis and is coupled with minor insulin losses (< 1 U/day) through the filter. These events do not appear to have major clinical impact. A low plasma insulin concentration is associated with diminished mortality rates in this group of patients.     

Lopinavir/ritonavir combined with twice-daily 400 mg indinavir: pharmacokinetics and pharmacodynamics in blood, CSF and semen

OBJECTIVES: To evaluate the steady-state blood plasma (BP), CSF and seminal plasma (SP) pharmacokinetics (PK) of twice-daily indinavir 400 mg and lopinavir/ritonavir. METHODS: Ten HIV-1-positive men on lopinavir/ritonavir participated in a PK study. PK sampling was performed before and 2 weeks after adding indinavir to lopinavir/ritonavir-containing regimens. BP, CSF and SP RNA levels, CD4 counts and blood chemistry were checked at baseline and 2 weeks after indinavir. RESULTS: At baseline: lopinavir parameters (n=10) in BP were within expected levels. Median lopinavir trough concentrations (n=5) in CSF and SP were below the limit of detection (BLD) (i.e. <10 ng/mL) and 248 ng/mL (range 96-2777), respectively. After indinavir: lopinavir C(max), C(min) and AUC(0-12) increased by 9%, 46% and 20%, respectively (P<0.32, P<0.32 and P<0.20). In two of four men lopinavir concentrations in CSF were detectable at 27 and 29 ng/mL. Median SP lopinavir concentration was 655 ng/mL (20-2734). Median indinavir PK parameters were C(max) 3365 ng/mL (range 2130-5194), C(min) 293 ng/mL (14-766), T(max) 2.25 h (1-3), AUC(0-12) 22452 ng/mL.h (11243-33661), and t(1/2) 2.8 h (1.4-3.7). Median indinavir concentrations in CSF and SP were 39 ng/mL (21-86) and 592 ng/mL (96-983). Two of eight men who initially had detectable BP viral load (VL) became BLD (<50 copies/mL) after the addition of indinavir, and in 2/4 men with low-level viraemia in SP (BPVL BLD) their SPVL became BLD after addition of indinavir. CONCLUSIONS: Adding indinavir 400 mg twice daily to lopinavir/ritonavir-containing regimens did not significantly alter the median lopinavir PK parameters. However, wide interpatient variability in lopinavir concentrations was seen. In contrast plasma indinavir levels were >80 ng/mL in seven of eight plasma samples, and all CSF and semen samples collected.     

Glucocorticoid insufficiency in patients who present to the hospital with severe sepsis: a prospective clinical trial

OBJECTIVE: To identify the incidence of secondary adrenal insufficiency in severe sepsis. DESIGN: Prospective clinical trial testing 100 patients with a 250-microg adrenocorticotropic hormone (ACTH) stimulation test. SETTING: County-university teaching hospital. PATIENTS: One hundred patients with sepsis and septic shock. Forty patients had bacteremia and 17% shock. INTERVENTIONS: ACTH, cortisol, aldosterone, and electrolyte concentrations were measured at baseline. Cortisol and aldosterone were measured 30 and 60 mins after ACTH (250 microg). MEASUREMENTS AND MAIN RESULTS: Nine of the 100 patients (9%) failed the ACTH stimulation test (all serum cortisol <20 microg/dL). The 91 patients with sepsis began with a serum cortisol at 29.3 +/- 2.5, and it increased to 40.1 +/- 2.6 and 46.9 +/- 2.7 microg/dL at times 30 and 60 mins, respectively. Serum cortisol in nine septic patients who failed the ACTH stimulation test had an initial concentration of 11.3 +/- 1.8 microg/dL, and it increased at time 30 mins to 14.0 +/- 1.9 microg/dL and at 60 mins to 15.7 +/- 1.8 microg/dL. Four of the nine patients had secondary adrenal insufficiency as determined by a normal aldosterone response to ACTH. The remaining five patients had an absent aldosterone response to ACTH and baseline ACTH concentrations that were not elevated, suggesting adrenal dysfunction. Serum sodium (128 +/- 4 vs. 138 +/- 1 mmol/L, p <.05) and glucose concentrations (121 +/- 20 vs. 163 +/- 11 mg/dL, p <.05) were reduced in the nine patients. Of the four patients with secondary adrenal insufficiency, two had a history of amenorrhea after birth of their children many years earlier. CONCLUSIONS: These data demonstrate that 9% of adults with sepsis fail the ACTH stimulation test due to a mixture of etiologies. A reduced sodium or glucose concentration may be helpful in identifying glucocorticoid (adrenal) insufficiency in patients with sepsis.     

Cardiac Arrhythmias and ECG Abnormalities in Tricyclic Antidepressant Overdose

Background. Ethanol used as an antidote is said to have various adverse effects, particularly in children. The rate of these adverse effects is not known.

Methods. Twenty-one-year retrospective chart review (1980–2000) from suspected methanol poisoning patients treated with ethanol in two large pediatric tertiary care centers.

Results. A total of 60 children (median age of 24 months) received ethanol for suspected methanol poisoning: 39 orally and 21 intravenously. Median initial methanol level was 4.16 mmol/L (13.3 mg/dL) (range 0 to 87.5 mmol/L or 0 to 280 mg/dL). Median duration of ethanol treatment was 16 hours (range 1.5 to 72 hours). None [0% (95% CI 0–5%)] of the 60 patients developed symptomatic hypoglycemia. Of the 50 patients that had a glucose level measured, none [(0% [95% CI 0–6%)] had a serum glucose concentration <2.78 mmol/L (<50 mg/dL). Eight patients [16% (95% CI 8–30%)] had at least one serum glucose concentration between 2.78–3.61 mmol/L (50–65 mg/dL), but none of those had symptoms compatible with hypoglycemia. A total of 42 patients [84% (95% CI 70–92%)] had all their serum glucose concentrations >3.61 mmol/L (>65 mg/dL). There was no identifiable difference in the glucose intake between the serum glucose concentration groups. Six out of the 60 patients [10% (95% CI 4–21%)] were described as more drowsy after ethanol but none was comatose or needed intubation. No child showed signs of hypothermia [0/40 (95% CI 0–8%)] (rectal temperature <35°C), hepatotoxicity (0/12) (AST or ALT>100 U/L) or even thrombophlebitis (0/21). None of the 22 patients with toxic levels of methanol (≥6.2 mmol/L–≥20 mg/dL) died or had ethanol-induced morbidity despite wide variation in ethanol levels.

Conclusion. The rate of clinically important adverse effects related to ethanol used as an antidote to treat methanol poisoning in children was either absent or low in a tertiary care pediatric hospital setting. There was no morbidity or mortality associated with ethanol when it was used despite wide variation in ethanol levels. These results suggest that with appropriate monitoring and intravenous glucose intake in a controlled environment such as a pediatric intensive care unit, ethanol therapy does not carry as many risks as currently believed.     

Ethanol-associated Hypoglycemia Is Uncommon

Objective: To determine the association of ethanol intoxication with hypoglycemia in ED patients. Methods: Retrospective, laboratory log review of 953 consecutive patients who were evaluated for ethanol intoxication in an urban university hospital ED over a three-month period. Simultaneous serum glucose determination was carried out for each patient and associations between ethanol level and glucose were sought. Results: Glucose concentrations were unavailable for 16 patients (1.7%). Of the remaining patients, 584 patients had detectable ethanol concentrations (ethanol-positive), and 353 had no detectable ethanol (ethanol-negative). Ethanol concentrations (mean ± SD) in the ethanol-positive group were 50.11 ± 24.08 mmol/L (231 ± 111 mg/dL), and glucose concentrations were 5.83 ± 1.94 mmol/L (105 ± 35 mg/dL). Hypoglycemia [glucose <3.72 mmol/L (67 mg/dL)] was observed for five (0.9%) ethanol-positive patients. It was classified as mild-moderate [2.78–3.66 mmol/L (50–66 mg/dL)] for four patients (0.7%) and severe [<2.78 mmol/L (50 mg/dL)] for one (0.2%). Ethanol concentrations ranged from 25.60 to 68.33 mmol/L (118 to 315 mg/ dL). There was no correlation between ethanol and glucose concentrations in any subset of the ethanol-positive patient population. In the ethanol-positive group, patients who had several ethanol-positive visits (56 patients, mean 3.6 visits/patient) accounted for four of the five episodes of hypoglycemia, including the one episode of severe hypoglycemia. The frequency of hypoglycemia in repeat visitors (2.0%) was higher than that in the group of patients without repeat visits (0.2%). In the ethanol-negative group, there were four (1.1%) episodes of mild-moderate hypoglycemia and no severely hypoglycemic patient. Hypoglycemia was not more likely to occur among ethanol-positive patients than it was among ethanol-negative patients. Conclusion: Hypoglycemia was uncommonly associated with ethanol intoxication, and was found almost exclusively among patients with several ethanol-positive visits. Glucose and ethanol concentrations do not show any linear correlation; patients with higher ethanol concentrations are not at higher risk of hypoglycemia. Hypoglycemia is not more likely to occur in ethanol-positive than in ethanol-negative patients. Initial glucose screening does not appear to be necessary for all patients suspected of intoxication; selective screening may be more appropriate.     

Two Cases of Thyrotoxicosis due to Redotex Ingestion,a Mexican Weight Loss Drug

BackgroundRedotex? is a Mexican weight-loss supplement that is not U.S. Food and Drug Administration–approved. It consists of the following five ingredients: tri-iodothyronine 75 μg, atropine 0.36 mg, diazepam 8 mg, aloin 16 mg, and d-norpseudoephedrine 50 mg per tablet. There are few case reports with clinically severe ingestions. We report two cases of clinical thyrotoxicosis due to use of Redotex.Case ReportsA 29-year-old woman presented to the emergency department (ED) with anxiety and palpitations. She reported taking Redotex daily for 1 week. Her temperature was 37.1°C, blood pressure (BP) was 166/104 mm Hg, and heart rate (HR) was 140 beats/min. Laboratory analysis was significant for a bicarbonate level of 20 mmol/L (reference 22–29 mmol/L), free T4 0.75 ng/dL (reference 0.93–1.70 ng/dL), and thyroid-stimulating hormone (TSH) 0.05 uIU/mL (reference 0.27–4.20 uIU/mL). She was treated with 2 mg i.v. lorazepam and 20 mg oral propranolol. A 37-year-old woman presented with chest pain, palpitations, and nausea after taking Redotex 1 to 2 tablets daily for 6 weeks. Her HR was 134 beats/min and BP was 130/66 mm Hg. Thyroid function tests on initial presentation showed a TSH of 0.013 uU/mL, free T4 of 0.24 ng/dL, and free T3 of >30 pg/mL. She was treated with propranolol 1 mg i.v. twice per day and 2 doses of lorazepam 1 mg. Both patients had resolution of their symptoms.Why Should an Emergency Physician Be Aware of This?When taken chronically and at recommended doses, Redotex can present with clinically significant T3 thyrotoxicosis. This has not been seen in prior reports.     

Admission Blood Glucose Level and Its Association With Cardiovascular and Renal Complications in Patients Hospitalized With COVID-19

OBJECTIVETo investigate the association between admission blood glucose levels and risk of in-hospital cardiovascular and renal complications.RESEARCH DESIGN AND METHODSIn this multicenter prospective study of 36,269 adults hospitalized with COVID-19 between 6 February 2020 and 16 March 2021 (N = 143,266), logistic regression models were used to explore associations between admission glucose level (mmol/L and mg/dL) and odds of in-hospital complications, including heart failure, arrhythmia, cardiac ischemia, cardiac arrest, coagulation complications, stroke, and renal injury. Nonlinearity was investigated using restricted cubic splines. Interaction models explored whether associations between glucose levels and complications were modified by clinically relevant factors.RESULTSCardiovascular and renal complications occurred in 10,421 (28.7%) patients; median admission glucose level was 6.7 mmol/L (interquartile range 5.8–8.7) (120.6 mg/dL [104.4–156.6]). While accounting for confounders, for all complications except cardiac ischemia and stroke, there was a nonlinear association between glucose and cardiovascular and renal complications. For example, odds of heart failure, arrhythmia, coagulation complications, and renal injury decreased to a nadir at 6.4 mmol/L (115 mg/dL), 4.9 mmol/L (88.2 mg/dL), 4.7 mmol/L (84.6 mg/dL), and 5.8 mmol/L (104.4 mg/dL), respectively, and increased thereafter until 26.0 mmol/L (468 mg/dL), 50.0 mmol/L (900 mg/dL), 8.5 mmol/L (153 mg/dL), and 32.4 mmol/L (583.2 mg/dL). Compared with 5 mmol/L (90 mg/dL), odds ratios at these glucose levels were 1.28 (95% CI 0.96, 1.69) for heart failure, 2.23 (1.03, 4.81) for arrhythmia, 1.59 (1.36, 1.86) for coagulation complications, and 2.42 (2.01, 2.92) for renal injury. For most complications, a modifying effect of age was observed, with higher odds of complications at higher glucose levels for patients age <69 years. Preexisting diabetes status had a similar modifying effect on odds of complications, but evidence was strongest for renal injury, cardiac ischemia, and any cardiovascular/renal complication.CONCLUSIONSIncreased odds of cardiovascular or renal complications were observed for admission glucose levels indicative of both hypo- and hyperglycemia. Admission glucose could be used as a marker for risk stratification of high-risk patients. Further research should evaluate interventions to optimize admission glucose on improving COVID-19 outcomes.     

Patient-derived quality specifications for instruments used in self-monitoring of blood glucose

BACKGROUND: Instruments for self-monitoring of glucose (SMBG) are increasingly used by diabetic patients. Information is limited on how patients use and interpret SMBG results, and no quality specifications for such instruments are based on the opinions of patients. METHODS: Type 1 diabetic patients (n = 201) filled in a questionnaire eliciting daily limits for blood glucose (BG) and changes of BG considered significant at different glucose concentrations. From these responses, patient-derived quality specifications were calculated in different clinical situations with low, intermediate, and high BG concentrations. RESULTS: Mean age of the patients was 31.8 years, mean diabetes duration was 14.7 years, and mean SMBG duration was 10.0 years with a mean frequency of 11.2 measurements/week. The threshold for hypoglycemic symptoms was 3.0 mmol/L (54 mg/dL), and the mean daily BG target window was 4.3-10.4 mmol/L (77-187 mg/dL). The mean absolute BG changes producing actions from the patients ranged from 1.1 mmol/L (20 mg/dL) to 3.6 mmol/L (65 mg/dL). The analytical quality specifications for imprecision depended on the clinical situation. Excluding the hypoglycemic situation, the analytical CV needed to fulfill the expectations of 75% of the patients was 6.4-9.7%. The analytical quality specification for CV at hypoglycemic concentrations was 3.1%. CONCLUSIONS: Instruments for self-measurements of glucose with an imprecision (CV) of < or = 5% and bias < or = 5% meet the expectations of >75% of patients in clinical situations other than hypoglycemia.     

Gut gavage with antiendotoxin antibodies reduces the liberation of tumor necrosis factor-alpha after hemorrhage/resuscitation

OBJECTIVE: To evaluate the effect of gut gavage both alone and with enteral administration of monoclonal antibodies to endotoxin on the liberation of tumor necrosis factor (TNF)-alpha and subsequent hemodynamics after hemorrhage/resuscitation. DESIGN: Dose response intervention, sham-controlled animal study. SETTING: Research laboratory at a university medical center. ANIMALS: Instrumented rats (250-325 g body weight) underwent standardized hemorrhage/resuscitation. INTERVENTIONS: Animal groups received 4 hrs before hemorrhage/resuscitation: gastric gavage with Colyte alone (group 1), combined with E5 antiendotoxin at either 0.2 mg/100 g (group 2) or 2 mg/100 g body weight (group 3), or sham controls (group 4). There were six animals studied in each of the four groups. MEASUREMENTS AND MAIN RESULTS: For animals receiving gut gavage and high-dose E5 antiendotoxin, plasma concentrations of TNF-alpha (pg/mL) at 120 mins after hemorrhage/resuscitation were significantly lower compared with sham controls (16+/-4 group 3; 65+/-36 group 4; mean +/- SD, p < .05). At 300 mins, this same treatment group had a significantly higher mean blood pressure (mm Hg) (110+/-6 group 3; 86+/-7 group 4: p < .05). Also at 300 mins after hemorrhage/resuscitation, plasma lactate concentrations (mmol/L) were significantly lower for all gut gavage treatment groups compared with sham control animals (1.9+/-0.2 group 1; 2.0+/-0.2 group 2; 1.8+/-0.2 group 3; 4.8+/-2.8 group 4, p < .05). CONCLUSIONS: Prior treatment with gut gavage and enterally administered antiendotoxin antibodies reduces TNF-alpha liberation after hemorrhage/resuscitation and confers a subsequent improvement in hemodynamics and decreased plasma lactate concentrations. Such therapy may be efficacious in patients undergoing elective procedures where major hemorrhage is likely or in severely injured patients with continued or recurrent hemorrhage.     

Hyperglycemia exacerbates muscle protein catabolism in burn-injured patients

OBJECTIVE: The purpose of this study was to assess if hyperglycemia influences energy expenditure or the extent of muscle protein catabolism in severely burned adults. DESIGN: Retrospective study. SETTING: Burn intensive care unit at a university hospital. PATIENTS: Adults with burns on >/=40% of their body surface area. INTERVENTIONS: Simultaneous measurement of indirect calorimetry and leg net balance of phenylalanine (as an index of muscle protein catabolism). Patients were stratified by plasma glucose values at the time of metabolic measurements (i.e., normal, glucose at 200 mg/dL). MEASUREMENTS AND MAIN RESULTS: Normal (n = 9; plasma glucose, 109 +/- 13 mg/dL [mean +/- sd]), mildly hyperglycemic (n = 13l plasma glucose, 156 +/- 17 mg/dL), and severely hyperglycemic subjects (n = 7, glucose 231 +/- 32 mg/dL) were similar in age, body weight, extent of burn area, and daily caloric intake. Severe hyperglycemia was associated with significantly higher arterial concentrations of phenylalanine (normal, 0.079 +/- 0.027 micromol/L; severe hyperglycemia, 0.116 +/- 0.028; p <.05) and a significantly greater net efflux of phenylalanine from the leg (normal, -0.067 +/- 0.072 micromol.min(-1).100 mL(-1) leg volume; severe hyperglycemia, -0.151 +/- 0.080 micromol.min(-1).100 mL(-1) leg volume; p <.05). Resting energy expenditure and respiratory quotient were similar between patient groups. CONCLUSIONS: These findings demonstrate an association between hyperglycemia and an increased rate of muscle protein catabolism in severely burned patients. This suggests a possible link between resistance of muscle to the action of insulin for both glucose clearance and muscle protein catabolism.     

Pheochromocytoma in a patient with end-stage renal disease

Pheochromocytoma is a rare tumor. To our knowledge only 15 cases have been reported in patients with end-stage renal disease (ESRD). We describe a 46-year-old woman with ESRD and a history of paroxysmal and difficult-to-control hypertension. During anesthesia for a surgical procedure, the patient experienced blood pressure lability with systolic blood pressures ranging from 76 to 360 mm Hg. Serum catecholamine concentrations were 2,698 pg/ mL (reference value, <750 pg/mL) for norepinephrine, 33 pg/mL (<110 pg/mL) for epinephrine, and 55 pg/mL (<30 pg/mL) for dopamine. The concentrations of plasma metanephrines were 6.84 nmol/L (<0.50 nmol/L) for metanephrine and 14.64 nmol/L (<0.90 nmol/L) for normetanephrine. Abdominal computed tomography showed a right-sided, 4-cm mass posterior to the infrahepatic inferior vena cava. Following blood pressure control with alpha- and beta-adrenergic blockade, the mass was removed. Pathologic examination demonstrated the mass was a pheochromocytoma. The maximum postoperative systolic blood pressure was 160 mm Hg. Postoperative plasma normetanephrine concentration was 2.80 nmol/L, and metanephrine was obscured by interfering substances. This case report and literature review emphasizes the difficulty in diagnosing pheochromocytomas in patients with ESRD despite the myriad of available diagnostic tests.     

Lactic acid kinetics in respiratory alkalosis

OBJECTIVE: To evaluate the impact of respiratory alkalosis on the elimination of intravenously infused lactate. DESIGN: Prospective, randomized, crossover study. SETTING: Medical ICU of a university hospital. PATIENTS: Eight patients treated by ventilatory support for neurologic or neuromuscular diseases. INTERVENTIONS: Patients were investigated on two occasions: during normoventilation (pH 7.42 +/- 0.1, PCO2 41 +/- 2 torr [5.5 +/- 0.2 kPa]) and during respiratory alkalosis (pH 7.59 +/- 0.1, PCO2 27 +/- 2 torr [3.6 +/- 0.2 kPa]) induced by controlled hyperventilation. To evaluate lactate elimination kinetics, 1 mmol/kg body weight of L-lactic acid was infused over 5 mins. MEASUREMENTS AND MAIN RESULTS: Arterial lactate concentrations and blood gas values were determined before and repeatedly after the infusion. Lactate elimination variables were calculated from the plasma curve by using a two-compartment model. Respiratory alkalosis increased plasma lactate from 1.56 +/- 0.1 to 2.49 +/- 0.2 mmol/L (p less than .001). The lactate elimination half-life increased from 4.57 +/- 0.2 mins at pH 7.42, to 9.96 +/- 1.1 mins during pH 7.59 (p less than .01), and beta half-life increased from 12.2 +/- 1.9 to 44.1 +/- 1 mins (p less than .01). Whole-body clearance decreased 40% from 24.2 +/- 2.9 to 14.3 +/- 2.0 mL/kg body weight-min (p less than .01). CONCLUSIONS: Respiratory alkalosis increases the basal concentration of plasma lactate and decreases clearance of infused lactic acid. These findings provide further evidence of the adverse effects of alkalosis.     

Cardiovascular response and stress reaction to flumazenil injection in patients under infusion with midazolam

OBJECTIVES: To evaluate the cardiovascular response and acute stress reaction after arousal induced by a benzodiazepine antagonist, flumazenil, in patients sedated with midazolam. DESIGN: Prospective study. SETTING: Emergency center in a university hospital. PATIENTS: A total of 12 patients were ventilated mechanically under sedation with midazolam. INTERVENTIONS: We monitored the consciousness level, heart rate, systemic blood pressure, pulmonary artery pressure, and pulmonary artery occlusion pressure before and after a bolus injection of 0.5 mg of flumazenil. The score for the consciousness level represents the sum of the scores for eye opening and best motor response, as determined by the Glasgow Coma Scale. We measured the cardiac output, concentrations of norepinephrine, epinephrine, and 3-methoxy-4-hydroxyphenylethyleneglycol in plasma, and concentration of cortisol in serum. We calculated the left ventricular ejection fraction, cardiac index, systemic vascular resistance index, pressure-rate product, systemic oxygen delivery, and systemic oxygen consumption at 0, 10, 30, and 60 mins after injection of flumazenil. MEASUREMENTS AND MAIN RESULTS: The serum benzodiazepine's receptor binding activity in serum was in the range from 50 to 1000 ng/mL before injection of flumazenil. Flumazenil improved the consciousness level from 6.7+/-2.0 to 8.9+/-1.6 and induced transient elevations in heart rate, blood pressure, systolic pulmonary artery pressure, and pulmonary artery occlusion pressure. Left ventricular ejection fraction, oxygen delivery index, and pressure-rate product increased significantly, from 61%+/-8%, 640+/-170 mL/min/m2, and 13,300+/-2600 mm Hg/min at 0 mins to 67% +/-5%, 710+/-220 mL/min/m2, and 16,500+/-4400 mm Hg/min at 10 mins, respectively. Concentrations of norepinephrine and epinephrine in plasma increased significantly, from 890+/-840 pg/mL and 220+/-360 pg/mL, respectively, at 0 mins to 990+/-850 pg/mL and 270+/-300 pg/mL, respectively, at 10 mins. There were no significant changes in the plasma concentration of 3-methoxy-4-hydroxyphenylethyleneglycol, the serum concentration of cortisol after the administration of flumazenil. CONCLUSIONS: Flumazenil did not result in a significant acute stress reaction in midazolam-sedated patients, but it increased myocardial oxygen consumption by enhancing sympathetic nervous activity or antagonizing cardiovascular depression induced by midazolam.     

Longitudinal thrombopoietin plasma concentrations in fetuses with alloimmune thrombocytopenia treated with intrauterine PLT transfusions

BACKGROUND: The purpose of this study was to describe longitudinal thrombopoietin (TPO) plasma concentrations in fetuses with fetomaternal alloimmune thrombocytopenia (FMAIT). STUDY DESIGN AND METHODS: Group 1 was the control group, 8 fetuses with normal hematopoiesis. Group 2 consisted of 4 nonthrombocytopenic fetuses with fetomaternal human PLT antigen incompatibility. Group 3 consisted of 14 fetuses with prenatal-diagnosed severe FMAIT owing to human PLT antigen-1a incompatibility. Fetal PLT counts, MoAb-specific immobilization of PLT antigen score, and TPO plasma concentrations were measured in a total number of 94 serial samples taken by cordocentesis before intrauterine PLT transfusion. RESULTS: Normal fetal TPO plasma concentrations ranged between 15 and 119 pg per mL (Group 1 median, 67 pg/mL). In fetuses with risk of FMAIT but normal PLT counts, TPO concentrations were normal (Group 2 median, 72 pg/mL; range, <15-158 pg/mL). In FMAIT with thrombocytopenia, the median TPO concentration was significantly higher than in Groups 1 and 2 (Group 3 median, 172 pg/mL; range, 15-623 pg/mL; p < 0.001). In the longitudinal analysis, TPO concentrations remained constant (n = 8), peaked only transiently (n = 3), or increased at the end of gestation (n = 3). Elevated TPO concentrations (592 and 623 pg/mL) were detected in one patient, who already had intracranial hemorrhage in utero. CONCLUSION: TPO concentrations are normal or slightly elevated in FMAIT. Further clinical information can be provided by the longitudinal analysis of TPO concentrations in severe FMAIT.     

Pharmacology and tolerability of a single dose of exenatide in adolescent patients with type 2 diabetes mellitus being treated with metformin: A randomized,placebo-controlled,single-blind,dose-escalation,crossover study

Objective: This study assessed the pharmacokinetics, pharmacodynamics, and tolerability of single doses of exenatide in adolescent patients with type 2 diabetes mellitus (T2DM).Methods: This was a randomized, single-blind, dose-escalation, crossover study in adolescent (age 10–16 years) patients with T2DM who were being treated with diet and exercise or a stable dose of metformin, a sulfonylurea, or a combination of metformin and a sulfonylurea for at least 3 months before screening. Eligible patients were allocated to receive single subcutaneous doses of exenatide 2.5 μg, exenatide 5 μg, and placebo, each followed by a standardized meal, on 3 separate days (maximum interval between first and third doses, 5 weeks). Exenatide 2.5 μg always preceded exenatide 5 μg in each treatment sequence. The primary end points were the pharmacokinetics and safety profile of exenatide; secondary end points included postprandial plasma glucose, serum insulin, and plasma glucagon concentrations.Results: The study enrolled 13 adolescent patients with T2DM (7 females, 6 males; mean [SD] age, 15 [1] years; body mass index, 32.5 [5.0] kg/m²; glycosylated hemoglobin, 8.2% [1.5%]). After administration of exenatide 5 μg, the geometric mean (SE) exenatide AUC_0?∞ and C_max were 339.5 (39.6) pg · h/mL and 85.1 (11.5) pg/mL, respectively (n = 12). The exenatide AUC appeared to be dose dependent, although exenatide was not quantifiable in all patients at the 2.5-μg dose; after administration of exenatide 2.5-μg, the geometric mean AUC_0?∞) was 159.2 (23.1) pg · h/mL (n = 6) and the geometric mean C_max was 56.3 (10.1) pg/mL (n = 9). Both exenatide doses were associated with significant reductions in postprandialplasma glucose excursions compared with placebo (P < 0.01); the incremental mean (SE) AUC_15–360min was ?3465.6 (1587.3) mg · min/dL for exenatide 2.5 pg, ?4422.2 (2434.4) mg · min/dL for exenatide 5 μg, and 3457.4 (1615.5) mg · min/dL for placebo. The 2 exenatide doses were also associated with significant reductions in postprandial plasma glucagon concentrations compared with placebo (P < 0.01); the respective incremental mean values for AUC_15–180min were 125.5 (658.4), ?1403.8 (632.1), and 1843.1 (540.6) pg · min/mL. There were no significant differences in serum insulin concentrations between exenatide and placebo. Exenatide was generally well tolerated, with no hypoglycemic events recorded during the study.Conclusions: In these adolescent patients with T2DM, administration of single 2.5- and 5-μg doses of exenatide were associated with dose-dependent increases in plasma exenatide concentrations and improved postprandial glucose concentrations compared with placebo. Both doses appeared to be well tolerated. ClinicalTrials.gov Identifier: NCT00254254.     

Efficacy and effectiveness of anti-digoxin antibodies in chronic digoxin poisonings from the DORA study (ATOM-1)

Context: We hypothesized that in chronic digoxin toxicity, anti-digoxin antibodies (Fab) would be efficacious in binding digoxin, but this may not translate into improved clinical outcomes. Objective: This study aims to investigate changes in free digoxin concentrations and clinical effects on heart rate and potassium concentrations in chronic digoxin poisoning when anti-digoxin Fab are given. Materials and methods: This is a prospective observational study. Patients were recruited if they have been treated with anti-digoxin Fab for chronic digoxin poisoning. Data was entered into a standardised prospective form, supplemented with medical records. Their serum or plasma was collected, analysed for free and bound digoxin and free anti-digoxin Fab concentrations. Results: From September 2013 to February 2015, 36 patients (median age, 78 years; 22 females) were recruited from 18 hospitals. Median heart rate (HR) was 49 beats/min. Initial median digoxin and potassium concentrations were 4.7 nmol/L (3.6?μg/L) (range: 2.3–11.2 nmol/L) and 5.3 mmol/L (range: 2.9–9.2 mmol/L) respectively. Beta-blockers (n?=?18), calcium antagonists (n?=?6), spironolactone and/or angiotensin blocking agents (n?=?24) were also used concomitantly. Renal impairment and gastrointestinal symptoms were present in 31 (86%) and 22 (63%) patients respectively. Five patients died from conditions unrelated to digoxin toxicity. Median change in HR was 8 beats/min post-Fab with no effect on blood pressure; they were 4, 10 and 17 beats/min for the 1, 2 and ≥3 vials of anti-digoxin Fab groups respectively. Concomitant treatments with potassium lowering agents (12/36) and inotropic drugs (7/36) were used. Gastrointestinal effects resolved in all 22 patients. The median decrease for potassium was 0.3?mmol/L. Digoxin concentration reduced from 3.8 to 0?nmol/L post-Fab. There was a rebound observed in the free digoxin concentration in 25 patients but none had associated clinical deterioration. Conclusions: One to two vials of anti-digoxin Fab initially bound all free digoxin confirming Fab efficacy. However, this was associated with only a moderate improvement in HR and potassium, suggesting bradyarrhythmia and hyperkalaemia may be from other co-morbidities.     

An amino acid-based peritoneal dialysis fluid buffered with bicarbonate versus glucose/bicarbonate and glucose/lactate solutions: an intraindividual randomized study.

OBJECTIVE: In order to study acute metabolic changes and peritoneal transport, amino acids as osmotic agent and bicarbonate as buffer were tested as new agents in peritoneal dialysis (PD) solutions. DESIGN: In a prospective, cross-over, randomized, intraindividual study, we investigated the acute metabolic changes following the application of three different PD fluids: (1) a 1% amino acid-based PD solution buffered with bicarbonate (34 mmol/L) (Amino/Bic); (2) a 1.5% glucose anhydrous-containing bicarbonate-buffered solution (34 mmol/L) (Glu/Bic); and (3) a conventional 1.5% glucose anhydrous-based dialysis solution with lactate (35 mmol/L) (Glu/Lac). SETTING: University medical center. PATIENTS: Ten nondiabetic patients stable on continuous ambulatory peritoneal dialysis (time on dialysis, 42.5 +/- 21.5 months) were treated and monitored with the test solutions over a 6-hour dwell.Three different study days followed in a randomized order for each patient (interval of 1-3 weeks). Blood and dialysate samples were taken at 0.25, 0.5, 1, 2, 4, and 6 hours. Immediately after the 1-hr dwell (and after sampling), the patients received a standardized breakfast, thereby simulating usual food intake. RESULTS: Following the application of Amino/Bic a significant increase in plasma amino acids occurred, with peak levels (maximum 250% increase) after either the 1-hr or the 2-hr dwell. Before taking the standard meal (0.5 hr, 1 hr), the mean serum glucose level with Amino/Bic was 8% +/- 13% lower than with Glu/Bic (p = 0.06) and 14% +/- 8% lower than with Glu/Lac (p < 0.01). This difference was still significant after the standard breakfast and also for the whole dwell (average serum glucose 0.5-6 hr: Amino/Bic, 91 +/- 6 mg/dL; Glu/Bic, 100 +/- 8 mg/dL; Glu/Lac, 102 +/- 7 mg/dL; p < 0.01 MANOVA). The serum insulin profiles did not differ between the fluids. A transperitoneal protein- and amino acid-related nitrogen loss of 0.49 +/- 0.18 g and 0.48 +/- 0.12 g per dwell was measured using Glu/Bic and Glu/Lac, while a positive balance of 1.80 +/- 0.43 g was achieved with Amino/Bic. The parameters of acid-base status (pH, HCO3, pCO2) remained nearly unchanged in the blood, irrespective of the solution used, while dialysate values differed markedly. No significant differences with respect to ultrafiltration (Amino/Bic, -68 +/- 199 mL/6 hr; Glu/Bic, -51 +/- 89 mL/6 hr; Glu/ Lac, -2 +/- 134 mL/6 hr) and peritoneal creatinine clearance (Amino/Bic, 4.9 +/- 0.6 mL/min; Glu/Bic, 5.1 +/- 0.6 mL/min; Glu/ Lac, 4.8 +/- 0.5 mL/min) were measured. CONCLUSIONS: Our results demonstrate that ultrafiltration and small solute clearance over a 6-hour dwell with a 1% Amino/Bic solution were comparable to those of 1.5% Glu/Bic and 1.5% Glu/Lac. Reduced serum glucose concentrations were found with Amino/Bic and this fluid compensated the transperitoneal protein-nitrogen loss of about three glucose dwells. Bicarbonate buffering (34 mmol/L) did not change blood acid-base status combined with either glucose or amino acids.