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Objectives: Propofol-based sedation may increase hemodynamic instability by decreasing vascular tone and venous return. Incremental exogenous catecholamines doses may be required to counteract such effects, aggravating the deleterious effects of sympathetic overstimulation. α-2 adrenergic agonists have been reported to decrease norepinephrine requirements in experimental septic shock. The aim of the present study is to test the hypothesis that switching from sedation with propofol to the α-2 agonist dexmedetomidine may decrease norepinephrine doses in septic shock., Design: Prospective open-label crossover study., Settings: University hospital, ICU., Patients: Thirty-eight septic shock patients requiring norepinephrine to maintain adequate mean arterial pressure and needing deep sedation with propofol and remifentanil to maintain a Richmond Agitation-Sedation Scale score between -3 and -4., Interventions: An initial set of measurements including hemodynamics, norepinephrine doses, and depth of sedation were obtained during sedation with propofol. Propofol was then replaced by dexmedetomidine and a second set of data was obtained after 4 hours of dexmedetomidine infusion. Sedation was switched back to propofol, and a final set of measurements was obtained after 8 hours. A Richmond Agitation-Sedation Scale score between -3 and -4 was maintained during the study period., Measurements and Main Results: Norepinephrine requirements decreased from 0.69 ± 0.72 μg/kg/min before dexmedetomidine to 0.30 ± 0.25 μg/kg/min 4 hours after dexmedetomidine infusion, increasing again to 0.42 ± 0.36 μg/kg/min while on propofol 8 hours after stopping dexmedetomidine (p < 0.005). Dexmedetomidine dosage was 0.7 ± 0.2 μg/kg/hr. Before and after dexmedetomidine infusion, sedative doses remained unchanged (propofol 2.6 ± 1.2 vs 2.6 ± 1.2 mg/kg/hr; p = 0.23 and remifentanil 1.27 ± 0.17 vs 1.27 ± 0.16 μg/kg/hr; p = 0.52, respectively). Richmond Agitation-Sedation Scale was -4 (-4 to -3) before, -4 (-4 to -3) during, and -4 (-4 to -4) after dexmedetomidine (p = 0.07)., Conclusions: For a comparable level of sedation, switching from propofol to dexmedetomidine resulted in a reduction of catecholamine requirements in septic shock patients.

Objective: To evaluate the efficacy and safety of liberal fluid resuscitation of adults with severe malaria. DESIGN, SETTING, PATIENTS, AND METHODS: Twenty-eight Bangladeshi and Indian adults with severe falciparum malaria received crystalloid resuscitation guided by transpulmonary thermodilution (PiCCO) in an intensive care setting. Systemic hemodynamics, microvascular indices and measures of acidosis, renal function, and pulmonary edema were followed prospectively., Results: All patients were hypovolemic (global end-diastolic volume index<680 mL/m) on enrollment. Patients received a median (range) 3230 mL (390-7300) of isotonic saline in the first 6 hours and 5450 mL (710-13,720) in the first 24 hours. With resuscitation, acid-base status deteriorated in 19 of 28 (68%), and there was no significant improvement in renal function. Extravascular lung water increased in 17 of 22 liberally resuscitated patients (77%); eight of these patients developed pulmonary edema, five of whom died. All other patients survived. All patients with pulmonary edema during the study were hypovolemic or euvolemic at the time pulmonary edema developed. Plasma lactate was lower in hypovolemic patients before (rs=0.38; p=0.05) and after (rs=0.49; p=0.01) resuscitation but was the strongest predictor of mortality before (chi-square=9.9; p=0.002) and after resuscitation (chi-square=11.1; p<0.001) and correlated with the degree of visualized microvascular sequestration of parasitized erythrocytes at both time points (rs=0.55; p=0.003 and rs=0.43; p=0.03, respectively). Persisting sequestration was evident in 7 of 15 patients (47%) 48 hours after enrollment., Conclusions: Lactic acidosis--the strongest prognostic indicator in adults with severe falciparum malaria--results from sequestration of parasitized erythrocytes in the microcirculation, not from hypovolemia. Liberal fluid resuscitation has little effect on this sequestration and does not improve acid-base status or renal function. Pulmonary edema--secondary to increased pulmonary vascular permeability--is common, unpredictable, and exacerbated by fluid loading. Liberal fluid replacement of adults with severe malaria should be avoided.

Objective: Conflicting data exist on the renal effects of hydroxyethyl starch preparations. The aim of the present study was to evaluate the impact of balanced crystalloids, as well as 0.9% saline-based and balanced 6% tetrastarch solutions, on renal function and ultrastructural morphologic correlates of acute kidney injury in an established model of ovine endotoxemic shock., Design: Randomized, controlled, experimental study., Setting: Animal research facility of a university hospital., Subjects: A total of 31 awake instrumented sheep., Interventions: The animals were subjected to continuous endotoxin infusion (Salmonella typhosa) at incremental doses until the mean arterial pressure was <65 mm Hg and arterial lactate was ≥ 2 mmol·L⁻¹ or (if arterial hypotension was absent) arterial lactate was ≥ 4 mmol·L⁻¹. The subjects were then randomized to receive no fluid resuscitation (control group, n = 5) or blinded infusion of a balanced crystalloid (n = 9), 0.9% saline-based (n = 8), or balanced 6% hydroxyethyl starch 130/0.4 (n = 9) up to a maximum dose of 50 mL·kg⁻¹, followed by open-label infusion of balanced crystalloid. Animals surviving the 12-hr intervention period were deeply anesthetized and killed. Kidney samples were taken immediately for transmission electron microscopic analyses. Additional specific experiments were performed to take kidney samples ex vivo., Measurements and Main Results: Endotoxemia was associated with arterial hypotension and capillary leakage. Fluid resuscitation established a hypotensive-hyperdynamic circulation in all resuscitated animals without significant hemodynamic differences among groups. Plasma creatinine and urea concentrations were higher in both hydroxyethyl starch groups as compared to the crystalloid group (creatinine, 1.2 ± 0.1 and 1.4 ± 0.3 vs. 0.8 ± 0.1 mg·dL⁻¹; urea, 21 ± 1 and 21 ± 2 vs. 17 ± 2 mg·dL⁻¹; p < .05 for 0.9% saline-based and balanced tetrastarch vs. crystalloids at 8 hrs). In contrast, kidney function, as measured by creatinine clearance and cumulative creatinine excretion, was similar between the colloid and crystalloid treatment groups (creatinine clearance at 8 hrs, 122 ± 18 and 108 ± 31 vs. 107 ± 13 mL·min⁻¹·m⁻²; creatinine excretion per hour alive, 283 ± 29 and 264 ± 19 vs. 291 ± 24 mg·hr⁻¹; p > .05 for 0.9% saline-based and balanced tetrastarch vs. crystalloids), whereas kidney function deteriorated markedly in control animals. The electron microscopic tubular injury score was lower in hydroxyethyl starch-treated animals as compared to the crystalloid group. Vacuolar tubular cell alterations were present in all groups. The percentage of intact microvilli brush borders was significantly higher in sheep treated with either hydroxyethyl starch solution as compared to the other groups., Conclusions: The present study provides evidence that renal function, as measured by creatinine clearance and cumulative creatinine excretion as well as ultrastructural tubular integrity, is preserved with the use of 6% tetrastarch solutions despite increases in plasma levels of renal retention variables in ovine endotoxemic shock.

Objective: Citrate anticoagulation is an excellent alternative to heparin anticoagulation for critically ill patients requiring continuous renal replacement therapy. In this article, we provide a safe and an easy-to-handle citrate anticoagulation protocol with variable treatment doses and excellent control of the acid-base status., Design: Prospective observational study., Setting: University hospital., Patients: One hundred sixty-two patients with acute renal failure requiring renal replacement therapy were enrolled in the study., Intervention: A continuous venovenous hemodialysis-based citrate anticoagulation protocol using a 4% trisodium solution, a specially designed dialysate fluid, and a continuous calcium infusion were used. The study period was 6 days. Hemofilters were changed routinely after 72 hours of treatment. The patients were grouped according to body weight, with patients below 60 kg body weight in group 1, patients with at least 60 kg and up to 90 kg body weight in group 2, and patients with a body weight of above 90 kg in group 3. Dialysate flow was adapted according to body size and matched approximately 2 L/hr for a patient with average body size. Blood flow, citrate flow, and calcium flow were adjusted according to the dialysate flow used., Measurements and Main Results: Median filter run time was 61.5 hours (interquartile range: 34.5-81.1 hours). Only 5% of all hemofilters had to be changed because of clotting. The prescribed treatment dose was achieved in all patients. Acid-base and electrolyte control were excellent in all groups. In the rare cases of metabolic disarrangement during citrate anticoagulation, acid-base values were rapidly corrected by modifying either the dialysate flow or alternatively the blood flow rate. Eight patients (5%) developed signs of citrate accumulation indicated by an increase of the total calcium >3 mmol/L or a need for high calcium substitution., Conclusions: We provide a safe and an easy-to-handle citrate anticoagulation protocol that allows an excellent acid-base and electrolyte control in critically ill patients with acute renal failure. The protocol can be adapted to patients' need, allowing a wide spectrum of treatment doses.

Objectives: Mechanical ventilation during critical care can cause structural and functional disturbances in the lung with subsequent release of proinflammatory mediators, termed ventilator-induced lung injury (VILI). VILI progressively provokes decreased efficiency of gas exchange with subsequent hypoxic pulmonary vasoconstriction leading to cardiopulmonary alterations, such as pulmonary hypertension and right heart failure. We therefore aimed to evaluate whether inhalation therapy with levosimendan, a calcium-sensitizer with pulmonary vasodilating properties, could attenuate VILI and improve short-term survival in a rat experimental model., Design: Experimental animal model., Setting: University hospital., Subjects: Forty male Sprague-Dawley rats., Interventions: Rats were randomly treated as follows (n = 8, each group): 1) inhalation of the solvent only before induction of VILI, no further intervention; 2) inhalation of 240 microg of levosimendan before VILI induction; 3) inhalation of 24 microg of levosimendan before VILI induction; 4) intravenous administration of 24 microg/kg levosimendan before VILI induction; 5) control group with surgical preparation only. All groups were observed for 4 hrs., Measurements and Main Results: After 4 hrs following induction of VILI, levels of interleukin-1beta and macrophage inflammatory protein-2 in plasma and bronchoalveolar lavage fluid were analyzed by enzyme-linked immunosorbent assay. Nitric oxide release from alveolar macrophages was measured by Griess assay. Content of matrix metalloproteinase-2 and matrix metalloproteinase-9 in bronchoalveolar lavage fluid was analyzed by gelatin zymography. Inhalation of 240 microg of levosimendan significantly improved survival after 4 hrs and mean arterial blood pressure compared with VILI only. Additionally, inhalation of 240 microg and infusion of 24 microg/kg levosimendan significantly reduced the release of interleukin-1beta, the nitric oxide release from alveolar macrophages, macrophage inflammatory protein-2 in plasma, and the macrophage inflammatory protein-2 and matrix metalloproteinase-9 content in bronchoalveolar lavage fluid compared with VILI only., Conclusions: Our study demonstrates that prophylactic inhalation of 240 microg of levosimendan improves survival and reduces release of inflammatory mediators in our experimental model of VILI. This might affect the clinical prophylaxis and treatment of VILI.

Objective: We hypothesized that nitric oxide derived from the neuronal nitric oxide synthase (NOS) is responsible for much of the injury resulting from skin burn and smoke inhalation. Therefore, we aimed to examine the effects of selective neuronal NOS inhibition on cardiopulmonary functions and cellular injury in sheep with acute respiratory distress syndrome secondary to combined burn and smoke inhalation injury., Design: Prospective, randomized, controlled laboratory experiment., Setting: Investigational intensive care unit., Subjects: A total of 22 chronically instrumented adult ewes., Interventions: Sheep were randomly assigned to either healthy controls (sham), injured controls (40% third-degree flame burn; 48 breaths of cotton smoke), or an injury group treated with the specific neuronal NOS inhibitor 7-nitroindazole (1 mg x kg(-1) x hr(-1)) from 1 hr postinjury to the end of the 48-hr study period. Hypoxic pulmonary vasoconstriction was assessed as decrease in left pulmonary blood flow in response to single-lung hypoxic challenges (100% nitrogen) at baseline, 24 hrs, and 48 hrs., Measurements and Main Results: The combination injury contributed to a approximately 90% loss of hypoxic pulmonary vasoconstriction and was associated with significant pulmonary shunting and death of one animal. The increase in nitrate/nitrite plasma levels in injured controls (12 hrs: 17 +/- 2 vs. 6 +/- 1 microM in sham animals; p < .001) was linked to increases in inducible NOS messenger RNA and 3-nitrotyrosine formation in lung tissue (48 hrs: 22 +/- 1 vs. 0.8 +/- 0.3 nM in sham animals; p < .001). 7-Nitroindazole treatment prevented the injury-associated changes in inducible NOS messenger RNA, nitrate/nitrite, and 3-nitrotyrosine, thereby attenuating the loss of hypoxic pulmonary vasoconstriction and improving gas exchange. In addition, 7-nitroindazole decreased lung tissue concentrations of hemoxygenase-1 and ameliorated myocardial depression, airway obstruction, pulmonary edema, ventilatory pressures, and histopathologic changes seen in injured controls., Conclusions: The present study provides evidence that neuronal NOS-derived nitric oxide plays a pivotal role in the pathogenesis of acute respiratory distress syndrome resulting from combined burn and smoke inhalation injury.

Objective: To test whether fluid resuscitation with normal saline or 4% albumin is associated with differential changes in acid-base status and serum electrolytes., Design: Nested cohort study., Setting: Three general intensive care units., Patients: Six hundred and ninety-one critically ill patients., Interventions: Randomization of patients to receive blinded solutions of either 4% human albumin or normal saline for fluid resuscitation., Measurements and Main Results: Albumin was given to 339 patients and saline to 352. At baseline, both groups had a similar serum bicarbonate, albumin, and base excess levels. After randomization, bicarbonate and base excess increased significantly and similarly over time (p < .0001). On multivariate analysis, fluid resuscitation with albumin predicted a smaller increase in pH (p = .0051), bicarbonate (p = .034), and base excess (p = .015). The amount of fluid was an independent predictor of pH (p < .0001), serum chloride (p < .0001), calcium (p = .0001), bicarbonate (p = .0002), and base excess (p < .0001) on the first day of treatment. In patients who received >3 L of fluids in the first 24 hrs, albumin administration was associated with a significantly greater increase in serum chloride (p = .0026). Acute Physiology and Chronic Health Evaluation II score and the presence of sepsis also independently predicted changes in several electrolytes and acid-base variables., Conclusions: When comparing albumin and saline, the choice and amount of resuscitation fluid are independent predictors of acid-base status and serum electrolytes. When large volumes are given, albumin administration leads to a higher chloride concentration. However, overall differences between the types of fluid are minor, whereas the volume of fluid administered is a much stronger predictor of such changes, which are also influenced by illness severity and the passage of time.

Objective: This study was performed to evaluate the effects of 0.9% saline (SAL), 0.9% saline + sodium bicarbonate + mannitol (SAL/BIC/MAN), and hypertonic saline-dextran (HSD) on hemodynamic variables, tissue blood flow, and oxidant injuries in experimental traumatic rhabdomyolysis (TR) in rats subjected allogeneic muscle extract infusion., Design: Prospective, randomized, experimental., Setting: Physiology experiment laboratory., Subjects: Male Sprague-Dawley rats, weighing 250-300 g., Interventions: All groups (n = 8 each) underwent femoral artery and vein catheterization. The animals in the TR, SAL, SAL/BIC/MAN, and HSD groups received an infusion of 2 mL of autologous muscle extract for 60 mins. After autologous muscle extract infusion, the SAL and HSD groups received 30 mL/kg 0.9% saline for 30 mins or 4 mL/kg HSD for 5 mins, respectively. The SAL/BIC/MAN group received 30 mL/kg 0.9% saline for 30 mins plus a bolus of 1 g/kg mannitol and a bolus of 2 mEq/kg sodium bicarbonate diluted in 1 mL of saline. At 2 hrs of autologous muscle extract infusion, erythrocyte flows in liver and kidney were measured by using a laser Doppler flowmeter. Then, blood samples and kidney and liver biopsies were taken to measure levels of glutathione and malondialdehyde., Measurements and Main Results: TR caused decreases in mean arterial pressure, tissue blood flow, and tissue glutathione and an increase in malondialdehyde. Rats in the HSD group had significant metabolic acidosis. SAL resuscitation did not correct tissue blood flow and prevent oxidant injury. HSD increased tissue blood flow, mean arterial pressure, and liver and kidney glutathione and decreased serum, liver, and kidney malondialdehyde. SAL/BIC/MAN resuscitation corrected all oxidant damage variables but did not increase tissue blood flow. SAL/BIC/MAN preserved serum malondialdehyde and liver glutathione better than the HSD did., Conclusions: HSD prevented oxidant injury and restored tissue blood flow but increased metabolic acidosis that followed autologous muscle extract infusion. SAL/BIC/MAN seems to be more effective than HSD in decreasing oxidant injury. Further research on the effects of the solute overload and metabolic acidosis due to HSD resuscitation on renal function in experimental rhabdomyolysis is warranted.

Objectives: MalPEG-hemoglobin, 4 g/dL (MP4), is a hemoglobin-based oxygen carrier with a low hemoglobin concentration, low P50 (oxygen half-saturation pressure of hemoglobin), high colloid osmotic pressure, and high viscosity. This study evaluated resuscitation with MP4 in anesthetized swine hemorrhaged 250 mL by controlled withdrawal, followed by a 5-mm tear in the abdominal aorta., Design: Randomized, unblinded., Setting: Academic animal laboratory., Subjects: Anesthetized male and female Swedish Landrace pigs., Interventions: Four groups of pigs (n = 7 each) were randomized after hemorrhage by aortic tear to receive 250 mL of MP4, Ringer's acetate, 10% pentastarch, or 4 g/dL of stroma-free hemoglobin, followed by aortic repair and transfusion of 250 mL of autologous blood. End points were 20-hr survival, hemodynamic variables, and acid-base status., Measurements and Main Results: Measurements included continuous aortic, pulmonary arterial, and central venous pressures, cardiac output by thermodilution, arterial and venous blood gases; electrolytes; lactate; base excess; oxygen delivery, consumption, and extraction ratio; hematocrit; hemoglobin; and urine output. Body weight (24-27 kg) and hemorrhage volume (26-33 mL/kg) were similar in the four groups. The nadir of mean arterial pressure (22-28 mm Hg) and the increase in lactic acid (5-8 mEq/L) after hemorrhage were similar in all groups, indicating equivalent shock in the four groups. Survival was greatest in the MP4-treated animals (six of seven) compared with Ringer's acetate (two of seven), 10% pentastarch (one of seven), and stroma-free hemoglobin (two of seven) and was accompanied by an improved recovery of arterial pressure, cardiac output, and lactate. Total hemoglobin concentration was equivalent in all groups. Arterial pressure did not increase above baseline values, and systemic vascular resistance was unchanged following administration of MP4, indicating the lack of peripheral vasoconstriction. Mortality in Ringer's acetate, stroma-free hemoglobin, and 10% pentastarch treated animals was associated with deteriorating acid-base status, low urine output, and hyperkalemia., Conclusion: These data demonstrate that restoration of oxygen delivery with a small volume of MP4 yields significant recovery from hemorrhage without systemic vasoconstriction.

Objective: To evaluate the magnitude and cause of metabolic acidosis after infusion of 7.5% sodium chloride 6% dextran 70., Design: Randomized, prospective clinical study., Setting: University hospital., Patients: Two groups of 14 patients each, undergoing repair of abdominal aortic aneurysm., Interventions: Patients were randomly assigned to receive either 250 mL of hypertonic saline dextran (HSD) or a conventional fluid regimen with 250 mL of hydroxyethyl starch in normal saline solution (H-NS) during the period of aortic clamping. Additionally, normal saline was used in both groups to reach a target pulmonary artery occlusion pressure of 15-18 mmHg. pH, Paco2, and serum concentrations of sodium, potassium, magnesium, calcium, chloride, lactate, albumin, and phosphate were measured. Strong ion difference was calculated as (sodium + potassium + magnesium + calcium) - (chloride + lactate). The amount of weak plasma acid was calculated., Measurements and Main Results: The infusion of HSD resulted in an immediate large increase in serum sodium (19 mmol/L) and chloride (22 mmol/L), whereas the infusion of H-NS led only to mild increases in serum sodium (3 mmol/L) and chloride (6 mmol/L). Both HSD and H-NS caused concomitant and equal decreases in the amount of weak plasma acid, strong ion difference, and pH (7.28-7.30). The reduction of bicarbonate was also identical and proportional to the extent of dilution due to infusion of HSD and H-NS. This induced metabolic acidosis was corrected spontaneously in both groups 24 hrs after surgery., Conclusion: Both the intravenous administration of 7.5% sodium chloride and the conventional fluid regimen with saline-based 6% hydroxyethyl starch solution resulted in a metabolic acidosis of equal extent. This suggests dilution of plasma buffers or a decrease in strong ion difference to be the primary cause of metabolic acidosis.

Objectives: The primary objective was to evaluate the relationship between high-dose lorazepam and serum propylene glycol concentrations. Secondary objectives were a) to document the occurrence of propylene glycol accumulation associated with continuous high-dose lorazepam infusion; b) to assess the relationship between lorazepam dose, serum propylene glycol concentrations, and propylene glycol accumulation; and c) to assess the relationship between the osmol gap and serum propylene glycol concentrations., Design: Prospective, observational study., Setting: Tertiary care, medical intensive care unit., Patients: Nine critically ill adults receiving high-dose lorazepam (> or =10 mg/hr) infusion., Interventions: Cumulative lorazepam dose (mg/kg) and the rate of infusion (mg.kg(-1).hr(-1)) were monitored from initiation of lorazepam infusion until 24 hrs after discontinuation of the high-dose lorazepam infusion. Serum osmolarity was collected at 48 hrs into the high-dose lorazepam infusion and daily thereafter. Serum propylene glycol concentrations were drawn at 48 hrs into the high-dose lorazepam infusion, and the presence of propylene glycol accumulation, as evidenced by a high anion gap (> or =15 mmol/L) metabolic acidosis with elevated osmol gap (> or =10 mOsm/L), was assessed at that time., Measurements and Main Results: The mean cumulative high-dose lorazepam received and mean high-dose lorazepam infusion rate were 8.1 mg/kg (range, 5.1-11.7) and 0.16 mg.kg(-1).hr (-1)(range, 0.11-0.22), respectively. A significant correlation between high-dose lorazepam infusion rate and serum propylene glycol concentrations was observed (r =.557, p =.021). Osmol gap was the strongest predictor of serum propylene glycol concentrations (r =.804, p =.001). Propylene glycol accumulation was observed in six of nine patients at 48 hrs. No significant correlation between duration of lorazepam infusion and serum propylene glycol concentrations was observed (p =.637)., Conclusion: Propylene glycol accumulation, as reflected by a hyperosmolar anion gap metabolic acidosis, was observed in critically ill adults receiving continuous high-dose lorazepam infusion for > or =48 hrs. Study findings suggest that in critically ill adults with normal renal function, serum propylene glycol concentrations may be predicted by the high-dose lorazepam infusion rate and osmol gap.

Objective: To compare resuscitation with 0.9% saline with Hextend, a synthetic colloid in a balanced electrolyte solution, in terms of acid-base status and survival time in an experimental model of septic shock in the rat., Design: Randomized, open-label, controlled experiment., Setting: University research laboratory., Subjects: Sixty adult, male Sprague-Dawley rats., Intervention: Animals were studied for 12 hrs after intravenous infusion of Escherichia coli endotoxin (20 mg/kg). Animals were volume resuscitated to maintain a mean arterial pressure >60 mm Hg using either 0.9% saline (n = 25), Hextend (n = 25), or lactated Ringer's (n = 10)., Measurements: Arterial blood gases and electrolytes were measured before and after resuscitation (0, 180, 360, and 540 mins after endotoxin infusion). Survival time was measured, up to 12 hrs., Results: Mean survival time among animals treated with saline or Ringer's was 45% less compared with Hextend-treated animals: 391 +/- 151 mins and 362 +/- 94 mins vs. 567 +/- 140 mins, respectively, p <.0001. Overall survival (at 12 hrs) was 0% with saline or Ringer's vs. 20% with Hextend, p =.05. After resuscitation with saline, arterial standard base excess and plasma apparent strong ion difference were both significantly lower (-19.3 +/- 5.2 vs. -12.1 +/- 5.7, p <.001, and 23.0 +/- 6.2 vs. 30.3 +/- 2.9, p <.0001, respectively) and plasma Cl(-) was significantly higher (123 +/- 7 vs. 115 +/- 3 mmol/L, p <.0001) compared with Hextend. Resuscitation with Ringer's solution resulted in a standard base excess, and Cl(-) between that of saline and Hextend (-15.4 +/- 3.1, and 117 +/- 3, respectively)., Conclusion: Compared with 0.9% saline, volume resuscitation with Hextend was associated with less metabolic acidosis and longer survival in this experimental animal model of septic shock.

Objectives: To determine the relationship between the strong ion difference (SID) of a diluting crystalloid and its metabolic acid-base effects on in vitro blood dilution., Design: Prospective in vitro study., Setting: University research laboratory., Subjects: Normal human blood., Interventions: Three solutions were prepared, each with [Na] 140 mmol/L. [Cl-] for solutions 1, 2, and 3 was 120, 110, and 100 mmol/L, respectively, the other anion being HCO3-. SID values were thus 20, 30, and 40 mEq/L, respectively. Serial dilutions of well-oxygenated fresh venous blood were performed anaerobically by using each of solutions 1-3 as well as 0.9% saline (SID = 0 mEq/L) and Hartmann's solution (SID = -4 mEq/L)., Measurements and Main Results: Blood gas and electrolyte analyses were performed before and after each dilution. Apart from dilutions with solution 3 (crystalloid SID 40 mEq/L) during which plasma SID did not change, plasma SID decreased during hemodilution. In contrast, base excess increased during hemodilution with solutions 3 and 2 (crystalloid SID 40 mEq/L and 30 mEq/L, respectively) and decreased only with the remaining three solutions. The relationships between hemoglobin concentrations and both plasma SID and whole blood base excess throughout dilution were linear, with slopes proportional to the SID of the diluent in each case. Linear regression revealed that the SID of crystalloid producing a zero base excess/hemoglobin concentration slope during blood dilution (i.e., no change in metabolic acid-base status) is 23.7 mEq/L., Conclusions: On in vitro hemodilution, there is a simple linear relationship between diluent crystalloid SID and the rate and direction of change of plasma SID and whole blood base excess. Direct extrapolation to in vivo situations such as acute normovolemic hemodilution and large volume correction of extracellular fluid deficits requires experimental confirmation.

Objective: To compare the effects of heparin or sodium citrate used to anticoagulate indwelling arterial catheters on acid-base and electrolyte measurements., Design: Randomized controlled trial., Setting: Medical-surgical university-affiliated intensive care unit., Subjects: Twenty patients with indwelling arterial catheters., Interventions: Patients were randomly allocated to have ten 1-mL aliquots of blood sampled serially from an arterial catheter maintained with either heparin or sodium citrate. A sample then obtained by arterial puncture provided true measurement values. Acid-base and electrolyte measurements of whole blood were obtained from each sample by means of a Coming 860 analyzer., Measurements and Main Results: Contamination with sodium citrate lowered ionized calcium and pH but increased glucose and Pco2. Heparin produced negligible effects on those measurements. When sodium citrate was used, reliable measurements were not obtained for ionized calcium, pH, and glucose, even after 9 mL of blood had been discarded. However, reliable P(CO2) measurements were obtained after 2 mL of blood was discarded., Conclusions: Sodium citrate used to maintain arterial catheters can contaminate blood samples. The result of that contamination can mimic severe hypocalcemia, metabolic acidosis, and mild hyperglycemia. Failure to recognize the effects of sodium citrate on acid-base and electrolyte measurements may lead to changes in treatment that could affect patient outcome adversely.

Objective: To investigate the potential of specific angiotensin II subtype 1 (AT1) receptor blockade to modify the mesenteric hemodynamic response to acute hypovolemia and retransfusion., Design: Prospective, randomized, controlled experimental study., Setting: University-affiliated animal research laboratory., Subjects: Fasted, anesthetized, ventilated, juvenile domestic pigs of both sexes., Interventions: Acute, graded hypovolemia by 20% and 40% of the total estimated blood volume followed by retransfusion in control animals (CTRL; n = 10) and animals pretreated with the AT1 receptor blocker candesartan (CAND; n = 10)., Measurements and Main Results: Invasive monitoring of arterial and central venous blood pressures, cardiac output, portal venous blood flow, and jejunal mucosal blood flow. Blood gases were repeatedly analyzed to calculate oxygen delivery and consumption. Thirty minutes after each level of hypovolemia at 20% and 40%, cardiac output was decreased in CTRL animals from a baseline of 2.9 +/- 0.1 to 1.8 +/- 0.2 and 1.1 +/- 0.2 L/min, with no differences compared with CAND animals. Cardiac output was restored to 3.0 +/- 0.3 L/min 30 mins after retransfusion in CTRL animals, with no significant intergroup differences. Baseline portal venous blood flow (Q(MES)) and jejunal mucosal perfusion (PU(JEJ)) were greater in CAND animals compared with CTRL animals. During graded hypovolemia, CAND animals maintained Q(MES) and PU(JEJ) at significantly higher levels compared with CTRL animals, particularly after 40% hemorrhage (+221% and + 244%, respectively, relative to the mean values in CTRL animals). The same pattern was observed after retransfusion. Moreover, the calculated mesenteric critical oxygen delivery was significantly greater in CTRL animals (74 mL/min) compared with CAND animals (34 mL/min). No animals died in the CAND group, whereas four animals died during 40% hypovolemia or retransfusion in the CTRL group., Conclusions: Specific AT1 blockade before acute hypovolemia significantly ameliorated mesenteric and, in particular, jejunal mucosal hypoperfusion. In addition, cardiovascular stability was improved, and mortality in conjunction with acute hypovolemia and retransfusion could be completely avoided. These findings support a fundamental role of the renin-angiotensin system in the mesenteric response to acute hypovolemia and indicate a substantial interventional potential for candesartan in conjunction with circulatory stress.

Objectives: a) To determine the relationship of acid-base balance (pH, PCO2) of blood samples from the intraosseous and the mixed venous route during prolonged cardiopulmonary resuscitation; b) to compare the effect of separate infusions of epinephrine, fluid boluses, or sodium bicarbonate through the intraosseous sites on the acid-base status of intraosseous and mixed venous blood during cardiopulmonary resuscitation; and c) to compare pH and Pco2 of intraosseous and mixed venous blood samples after sequential infusions of fluid, epinephrine, and sodium bicarbonate through a single intraosseous site., Design: Prospective, randomized study., Setting: Animal laboratory at a university center., Subjects: Thirty-two mixed-breed piglets (mean weight, 30 kg)., Interventions: Piglets were anesthetized and prepared for blood sampling and cardiopulmonary resuscitation. After anoxic cardiac arrest, ventilation was resumed and chest compression was resumed. Blood gas samples from the pulmonary artery and both intraosseous sites were obtained simultaneously at baseline, at cardiac arrest, and at 5, 10, 15, 20, and 30 mins of cardiopulmonary resuscitation for group 1 (control group) and after drug (epinephrine and sodium bicarbonate) and saline infusions via one of the intraosseous cannulas in groups 2 through 5., Measurements and Main Results: We found no differences between intraosseous and mixed venous pH and Pco2 during periods of <15 mins of cardiopulmonary resuscitation. However, this relationship was not maintained during prolonged cardiopulmonary resuscitation and after bicarbonate infusion. After large volume saline infusion, the pH and Pco2 of mixed venous and intraosseous blood were similar. During epinephrine infusion, the relationship between intraosseous and mixed venous pH and Pco2 was similar to that found in the control group., Conclusions: The intraosseous blood sample could be used to assess central acid-base balance in the early stage of arrest and cardiopulmonary resuscitation of <15 mins. However, during cardiopulmonary resuscitation of longer duration, drug infusions may render the intraosseous site inappropriate for judging central acidosis.

Objective: To assess the effects of lidocaine on the hemodynamic and inflammatory responses to Escherichia coli endotoxemia in rabbits., Design: Prospective, randomized, controlled experimental study., Setting: University laboratory., Subjects: Twenty-seven female Japanese rabbits, anesthetized with urethane and ventilated mechanically., Interventions: Animals were randomly assigned to one of three groups: a) endotoxemic control group (n = 9), receiving intravenous Escherichia coli endotoxin (0.5 mg/kg bolus) via the mesenteric vein; b) laparotomy control group (n = 9), treated identically to the endotoxemic control group, except for substitution of 0.9% saline for endotoxin; and c) lidocaine-treated group (n = 9), treated identically to the endotoxemic controls and additionally, intravenous lidocaine (3 mg/kg bolus, followed by infusion at 2 mg/kg/hr) was administered immediately after endotoxin, Measurements and Main Results: We compared hemodynamics, blood gases, and microscopic findings of lung tissue obtained at necropsy in each group. Laparotomy alone had a minimal effect on the parameters and findings. Endotoxin injection decreased mean systolic arterial pressure from 135 +/- 6 (SD) to 95 +/- 25 mm Hg (p < .05) and increased the mean base deficit from -1.2 +/- 1.8 to -14.4 +/- 4.2 mmol/L (p < .05), and caused the infiltration of neutrophils into the lungs. Lidocaine administration abolished the hypotension and attenuated the increase the base deficit to -9.5 +/- 2.1 mmol/L (p < .05) and the cellular infiltration in comparison with endotoxemic controls., Conclusions: Lidocaine attenuated the hemodynamic and inflammatory responses to endotoxemia in rabbits. Findings suggest that lidocaine administration may prevent the development of hypotension and metabolic acidosis during endotoxemia.

Background and Methods: Calcium-channel blockers may attenuate vasospasm after transient ischemia and improve organ blood flow after resuscitation. Our aim was to assess the effect of diltiazem on systemic oxygen delivery and consumption, hemodynamics, electroencephalogram (EEG), and organ blood flow after restoration of spontaneous circulation. After a 3-min period of asphyxial cardiac arrest, 14 pigs (20 to 27 kg) were randomly allocated to treatment with either diltiazem (0.1 mg/kg bolus followed by an iv infusion of 0.025 mg/min/kg over 120 mins) or placebo, given at 5 mins after successful resuscitation. Organ blood flow was measured using tracer microspheres 120 mins after resumption of spontaneous circulation., Results: Median systemic oxygen delivery index values at 30, 60, and 120 mins after restoration of spontaneous circulation were 18.2 mL/min/kg (range 14.8 to 20.7), 16.8 mL/min/kg (13.2 to 20.8), and 19.6 mL/min/kg (16.9 to 21.0), respectively, in the diltiazem group and 13.1 mL/min/kg (11.2 to 14.6), 11.9 mL/min/kg (10.3 to 13.3), and 14.7 mL/min/kg (11.4 to 17.2), respectively, in the control group (p less than .05 for all three comparisons). At the same points in time, median systemic oxygen consumption indices were 3.2 mL/min/kg (range 2.2 to 3.7), 2.1 mL/min/kg (1.9 to 3.0), and 2.6 mL/min/kg (1.8 to 3.8) in the diltiazem group and 2.8 mL/min/kg (2.1 to 4.0), 2.7 mL/min/kg (1.7 to 4.3), and 2.3 mL/min/kg (1.6 to 3.8) in the placebo group (NS). Diltiazem enhanced the postarrest recovery of EEG total power. Right and left cerebral blood flow 120 mins after restoration of spontaneous circulation was significantly (p less than .01) higher in the diltiazem group in comparison with the control group., Conclusions: Diltiazem causes an increase in systemic oxygen delivery index by promoting vasodilation, but it does not change systemic oxygen consumption index in comparison to placebo treatment. It may be that an impairment in local autoregulation and/or in oxidative metabolism at the cellular or subcellular level was the reason why diltiazem did not improve these derangements. The observed increase in cerebral blood flow and in EEG recovery may be beneficial to the brain after a period of asphyxia.

Unlabelled: BACKGROUND AND HYPOTHESIS TESTED: The effects of adenosine (100 micrograms/kg/min; n = 7) were examined during rodent cardiopulmonary resuscitation (CPR). Change in coronary artery perfusion pressure, end-tidal PCO2, and arterial acid-base status of anesthetized, male, Sprague-Dawley rats were compared with CPR controls (0.9% sodium chloride; n = 7) and with sham controls (n = 9). Sustained ventricular fibrillation was induced and precordial chest compression was followed by defibrillation., Results: After 6 mins of cardiac arrest, six (86%) of seven adenosine-treated animals were resuscitated after adenosine infusion and four (57%) of seven control animals were resuscitated after sodium chloride infusion. During chest compression, coronary artery perfusion pressure was 7 +/- 2 mm Hg after adenosine, but was 22 +/- 3 mm Hg in the controls (p less than .01). Parallel decreases were observed in mean aortic pressure. Arterial and end-tidal PCO2 significantly (p less than .01) decreased after adenosine. These changes contrasted with a second control group of nine identically prepared animals which, in the absence of ventricular fibrillation and subsequent chest compression, demonstrated no changes in hemodynamic, respiratory, or blood gas variables., Conclusions: Adenosine decreased coronary artery perfusion pressure. However, despite marked reductions in coronary artery perfusion pressure, survival was not compromised after adenosine infusion in this rodent model of CPR.

Objective: A recent report suggested that, for hypotensive patients, tissue acidemia is best monitored by simultaneous estimates of arterial pH, mixed venous pH, and bicarbonate. This method of detecting tissue acidemia may therefore apply to fulminant hepatic failure patients, who are known to have a high frequency of covert tissue hypoxia. In the present study, both arterial pH and mixed venous pH and bicarbonate were compared in 22 patients with fulminant hepatic failure. Blood samples were drawn from the pulmonary artery and radial artery and this blood was analyzed to determine oxygen delivery and consumption. The arterial pH, mixed venous pH, and bicarbonate were compared using an oxygen flux test to determine the optimal method of demonstrating tissue hypoxia in this group of patients., Design: A prospective study., Setting: The Liver Unit of our institution., Patients: Patients (n = 22) with fulminant hepatic failure admitted between January 1989 and January 1990., Interventions: Patients were studied before and after an infusion of prostacyclin., Measurements and Results: The findings of this study suggest that pH and bicarbonate differences in arterial and mixed venous blood samples were not indicative of tissue hypoxia in patients with fulminant hepatic failure. By contrast, measurement of oxygen consumption after the infusion of prostacyclin, with the demonstrated increase in oxygen uptake, provided a more accurate indication of covert tissue hypoxia., Conclusions: In critically ill patients with a hyperdynamic circulation, such as those patients with fulminant hepatic failure, an oxygen flux test remains the best method of determining the presence of covert tissue hypoxia.

The cardiopulmonary consequences of hemorrhagic hypovolemia and the subsequent administration of ketamine were evaluated in eight dogs; five additional dogs served as controls. Heart rate (HR), systemic vascular resistance, breathing rate, minute ventilation (VE), PaO2, alveolar-arterial oxygen tension gradient, and oxygen extraction ratio increased, while arterial and pulmonary pressures, CVP, cardiac output, oxygen transport, PVO2 PaCO2, mixed venous oxygen content, bicarbonate, and base deficit decreased in response to hypovolemia. Ketamine administration was associated with a significant increase in HR, arterial and pulmonary BP, and PaCO2, and a significant decrease in VE (transient), PaO2 (transient), and pH. Ketamine supported cardiovascular function well, did not impair tissue oxygenation, and caused only transient respiratory depression in these hypovolemic dogs.

The effects of hydrochloric acid (HCl) administration were studied in 15 critically ill patients whose metabolic alkalosis caused a significant alkalemia (pH 7.50 to 7.58) unresponsive to sodium and potassium chloride administration. Arterial pH and bicarbonate and chloride concentrations normalized after a 6- to 12-h mean infusion of 200 +/- 54 mmol of .25 N HCl. There were no deleterious vascular, hematologic, or metabolic side-effects. HCl administration was associated with an increase in mean PaO2 from 94 +/- 21 to 121 +/- 31 torr (p less than .001). This increase was comparable in patients breathing spontaneously and those treated with controlled mechanical ventilation, and was attributed at least in part to a decrease in pulmonary shunt. These results indicate that .25 N HCl, infused at the rate of 100 ml/h into the superior vena cava, can correct metabolic alkalosis safely and rapidly. The persistence of the beneficial effects of this treatment on arterial oxygenation remains to be confirmed.

CO2 kinetics during CPR was investigated in 15 anesthetized piglets. BP, blood gases, and acid-base balance were monitored through catheters in the carotid artery and a central vein, as well as in cerebrospinal fluid. Cardiac arrest was induced by a transthoracic direct current shock. CPR was begun immediately by artificial ventilation and simultaneous external chest compressions. Epinephrine was administered after 8 min of CPR. One group (n = 5) of animals received no buffer treatment while another (n = 5) received an infusion of 75 mmol sodium bicarbonate and a third group (n = 5) received an equivalent amount of tris-buffer mixture. The results of these experiments, as well as previously described circulatory variables during CPR, were analyzed using a computer model describing the CO2 kinetics of the pig. Our main finding was that PaCO2 was positively correlated to cardiac output during CPR; improved cardiac output during CPR resulted in more efficient tissue CO2 elimination and was associated with increased survival rates. PaCO2 was also somewhat reduced by efficient alveolar hyperventilation. The arterial PCO2 and pH did not reflect the acid-base balance in peripheral tissues. During CPR, bicarbonate and tris-buffer mixture both quickly passed through the blood-brain barrier. When buffer treatment is indicated during CPR, a buffer which does not increase tissue PCO2 may be the drug of choice.