Michael Booke

Inhaled prostaglandin E1 for treatment of acute lung injury in severe multiple organ failure

Acute lung injury is characterized by hypoxemia due to pulmonary ventilation/perfusion-mismatching. IV administered prostaglandin E1 (PGE1), a vasodilator with a high pulmonary clearance, has been studied in acute lung injury. Inhalation of the vasodilators nitric oxide and prostacyclin improved oxygenation by selective dilation of the pulmonary vasculature in ventilated lung areas. In the present study, PGE1 inhalation was used for treatment of acute lung injury. Fifteen patients with acute lung injury defined as PaO2/fraction of inspired oxygen (FIO2) <160 mm Hg were treated with PGE1 inhalation in addition to standard intensive care. The drug was continuously delivered via a pneumatic nebulizer. Acute physiology and chronic health evaluation system II and multiple organ failure scores were (mean +/- SEM) 33 +/- 2 and 10 +/- 0.3, respectively. Inhaled PGE1 was administered for 103 +/- 17 h at a dose of 41 +/- 2 [micro sign]g/h. The PaO2/FIO2 ratio increased from 105 +/- 9 to 160 +/- 17 mm Hg (P < 0.05) and to 189 +/- 25 mm Hg (P < 0.05) after 4 h and 24 h, respectively. PGE1 inhalation decreases in mean pulmonary artery pressure and central venous pressure were not statistically significant. Mean arterial pressure, pulmonary capillary wedge pressure, cardiac output, and heart rate remained unchanged. Intensive care unit mortality was 40%. The present data suggest that inhaled PGE (1) is an effective therapeutic option for improving oxygenation in patients with acute lung injury. Whether inhaled PGE1 will increase survival in acute lung injury should be investigated in a controlled prospective trial. Implications: In patients with severe acute lung injury and multiple organ failure, inhaled prostaglandin E1 improved oxygenation and decreased venous admixture without affecting systemic hemodynamic variables. Controlled clinical trials are warranted. (Anesth Analg 1998;86:753-8)

Fat elimination during intraoperative autotransfusion: an in vitro investigation.

Intraoperative autotransfusion of scavenged blood is an established method to reduce the need for perioperative homologous blood transfusion.However, if fat particles contaminate blood suctioned from the wound site, no reliable method is available to remove them during the washing and concentration of the recycled blood. A new generation of autotransfusion devices (e.g., continuous autotransfusion system [CATS]), based on separation chambers used in cell separators or plasmapheresis devices, allows continuous procession of the collected blood, in contrast with the discontinuous process used in conventional autotransfusion devices such as the Cell Saver 5. Theoretically, the continuous system should be more efficient than the discontinuous system in eliminating fat. Outdated, 36-day-old packed red blood cells, 600 mL, were mixed with 500 mL of lactated Ringers solution and 200 mL of soya oil. Soya oil was used because it has a fatty acid composition similar to that of fat found in bone marrow. The blood mixture was then washed and concentrated by using either the CATS or the Cell Saver 5. Six samples were processed by each device. The CATS eliminated the soya oil (200 mL) completely, whereas the Cell Saver 5 delivered 30.3 +/- 7.8 mL soya oil into the retransfusion bag. The new generation of autotransfusion devices allows complete removal of fat particles. Implications: Autotransfusion devices serve to wash and retransfuse blood scavenged from the wound site. However, they cannot completely remove fat particles. This in vitro investigation showed that a new device completely removes fat particles and thus prevents retransfusion of fat. (Anesth Analg 1997;85:959-62)

Nitric oxide synthase inhibition versus norepinephrine for the treatment of hyperdynamic sepsis in sheep.

OBJECTIVES To investigate the effects of Nomega-mono-methyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthesis, on hemodynamics, oxygen transport, and regional blood flow in an ovine model of hyperdynamic sepsis and to compare these effects with the responses to norepinephrine. DESIGN Prospective, nonrandomized, controlled experimental study with repeated measures. SETTING Investigational intensive care unit at a university medical center. SUBJECTS Twenty-five female, healthy, adult sheep of the Merino breed, divided into three groups: nine control sheep; eight sheep treated with L-NMMA; and eight sheep treated with norepinephrine. INTERVENTIONS All sheep were chronically instrumented. After a 5-day recovery period, a continuous infusion of live Pseudomonas aeruginosa (2.5 x 10(6) colony-forming units/min) was started and maintained for the remainder of the experiment. After 24 hrs of sepsis, eight sheep received L-NMMA (7 mg/kg/hr), eight sheep received norepinephrine, and nine sheep received the vehicle alone (0.9% saline). The norepinephrine dosage was continuously and individually adjusted to achieve the same increase in blood pressure as was observed in a matched sheep of the L-NMMA group. MEASUREMENTS AND MAIN RESULTS After 24 hrs of sepsis, all sheep developed a hyperdynamic circulatory state with increased cardiac indices and reduced arterial pressures, and systemic vascular resistances. L-NMMA reversed the hyperdynamic circulation, causing an increase in arterial pressure by peripheral vasoconstriction. Norepinephrine led to an increase in blood pressure by augmenting cardiac indices, leaving the systemic vascular resistance unaffected. The norepinephrine dose needed to keep the blood pressure high had to be continuously increased, reflecting the reduced vascular responsiveness to catecholamines during sepsis. Renal blood flow remained unaffected by all treatment forms. Norepinephrine and L-NMMA led to a dramatic increase in urine production. Blocking the nitric oxide synthase with L-NMMA did not interfere with the hosts pulmonary ability to clear bacteria, nor did treatment with norepinephrine. CONCLUSIONS Blocking nitric oxide synthase had a marked vasoconstrictive effect. Both norepinephrine and L-NMMA increased arterial pressure without reducing renal blood flow, leading to an improved renal function.

Nitric oxide synthase inhibition versus norepinephrine in ovine sepsis: effects on regional blood flow.

Hypotension is a serious problem in septic patients. We investigated regional perfusion in several organs during treatment of hyperdynamic sepsis in sheep. Sepsis was induced and maintained for the entire experiment with a continuous infusion of live Pseudomonas aeruginosa. Treatment with either norepinephrine or the nitric oxide synthase inhibitor Lω-mono-methyl-arginine (l-NMMA) was begun after 24 h of sepsis and continued for 24 h. The norepinephrine dosage was adjusted to achieve the same increase in mean arterial pressure as that obtained by a fixed dose of l-NMMA (7 mg/kg/h). Blood flows were analyzed by the microsphere technique. Both compounds restored blood pressure effectively, but only L-NMMA caused a significant increase in systemic vascular resistance, concomitant with a significant fall in cardiac output. Sepsis caused an increase in myocardial blood flow and a redistribution of blood flow away from the pancreas and the stomach. Renal blood flow was not significantly elevated. During treatment with either compound, renal blood flow remained unchanged, despite a fall in cardiac output in the l-NMMA group. Unchanged renal blood flow combined with the restoration of arterial blood pressure caused a significant increase in urine output. Both l-NMMA and norepinephrine caused a redistribution of blood flow to the colon. Pancreatic blood flow was further reduced by l-NMMA but the oxygen extraction improved simultaneously, so that oxygen availability in the pancreas might have been unchanged. Because ischemic pancreatitis in sepsis is likely to trigger multiorgan failure, further investigations in that area are desirable.

Intraoperative Autotransfusion in Small Children: An In Vitro Investigation to Study Its Feasability

ntraoperative autotransfusion (IAT) of washed redblood cells is an established method to reduce peri-operative transfusion requirements (1). However,this technique is not used in small children because itis technically impossible to wash and hemoconcen-trate small volumes of salvaged blood. The processingof ,300 mL of salvaged blood is considered a contra-indication for IAT (2) because the smallest bowl avail-able for autotransfusion devices has a capacity of125 mL (Haemonetics Cell Saver 5 [HCS]; Haemonet-ics, Munich, Germany) and needs approximately300 mL of salvaged blood to be completely filled.New technology of autotransfusion devices may im-prove blood salvaging in small children: smaller bowls(capacity 55 mL) are now available (DIDECO Compact-A& Advanced; Sorin Biomedica, Puchheim, Germany). Anew generation of autotransfusion devices (CATS; Frese-nius AG, Bad Homburg, Germany) based on the technol-ogy of cell separators is also available. The CATS has awashing chamber in the shape of a double spiral and pro-cesses shed blood continuously (3).Since these new systems have become available, thelimitations of conventional IAT should be examined insmall children. Therefore, we performed an

Nitric oxide synthase inhibition during experimental sepsis improves renal excretory function in the presence of chronically increased atrial natriuretic peptide.

OBJECTIVE To test whether renal excretory function decreases after nitric oxide synthase inhibition during experimental hyperdynamic sepsis. DESIGN Prospective, randomized, controlled animal trial. SETTING Research laboratory at a large university medical center. SUBJECTS Chronically instrumented Merino breed ewes (n = 18). INTERVENTIONS Continuous infusion of Escherichia coli endotoxin (10 ng/kg/min) for the experimental period of 32 hrs. One group received a bolus of the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (25 mg/kg), after 24 hrs, and the remaining sheep were given the carrier, sodium chloride 0.9%. MEASUREMENTS AND MAIN RESULTS The sheep developed a hyperdynamic cardiovascular response characterized by a decrease in systemic vascular resistance index (p < .05), and an increased cardiac index (p < .05) by 24 hrs. The sheep retained fluid, with creatinine clearance decreasing in the presence of chronically increased atrial natriuretic peptide. After the administration of N omega-nitro-L-arginine methyl ester, systemic vascular resistance index and cardiac index returned to baseline values, fluid balance normalized, and glomerular filtration rate increased (p < .05), while the control animals continued to retain fluid and their creatinine clearance continued to decrease. The concentrations of atrial natriuretic peptide did not differ significantly between groups after N omega-nitro-L-arginine methyl ester administration. CONCLUSIONS In this ovine model of experimental hyperdynamic sepsis, renal excretory function decreases in the presence of chronically increased concentrations of atrial natriuretic peptide. Administration of the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester, reverses the vasodilatory state, thereby improving fluid balance and glomerular filtration.

Enhancement of axillary brachial plexus block anesthesia by coadministration of neostigmine

BACKGROUND AND OBJECTIVES The acetylcholinesterase inhibitor neostigmine has shown peripherally mediated analgesic action in recent preclinical and clinical studies. The present study investigates the effectiveness of adding neostigmine to a local anesthetic, mepivacaine, in patients receiving axillary brachial plexus block for upper extremity surgery. METHODS In a double-blind, randomized study 34 patients were assigned to the treatment group: Neostigmine (NM) (500 microg) + mepivacaine (M) (500 mg) (NM, n = 17) as drugs for the plexus block, or to control group: mepivacaine (500 mg) + saline (0.9%, 1 mL) (M, n = 17). RESULTS The onset and duration of sensory and motor block was similar in both groups. Patients receiving NM had significantly lower pain ratings [visual analogue scores (VAS): 14.7 +/- 9.9 vs 32.4 +/-23.5; P < .05] 24 hours after surgery, and a lower number of patients in the NM group needed supplemental analgesics during the first 24 hours postoperatively. No adverse events were recorded for either group. CONCLUSIONS Peripherally administered neostigmine improves postoperative analgesia in axillary brachial plexus block.

Effects of inhaled nitric oxide and nebulized prostacyclin on hypoxic pulmonary vasoconstriction in anesthetized sheep

OBJECTIVES Inhaled nitric oxide has been shown to be a selective pulmonary vasodilator, leading to reduced pulmonary arterial pressure and improved ventilation/perfusion ratio in the acute respiratory distress syndrome. This local pulmonary vasodilation theoretically can be achieved by the airway application of a short-acting vasodilator, such as prostacyclin. We hypothesized that nebulized prostacyclin has the same properties for selective pulmonary vasodilation as inhaled nitric oxide. DESIGN Prospective, experimental study in sheep. SETTING Investigational intensive care unit in a university hospital. SUBJECTS Six adult ewes of the Merino breed. INTERVENTIONS Sheep (n = 6) were surgically prepared for chronic study. After 5 days of recovery, the sheep had tracheostomies performed under anesthesia. Intubation with a modified Robert-Shaw tube allowed side-separated ventilation. The entire left lung was ventilated with pure nitrogen, whereas the right lung was ventilated with pure oxygen. Nitric oxide and prostacyclin were added in different concentrations to the nitrogen, with which the left lung was ventilated. MEASUREMENTS AND MAIN RESULTS The blood flows to the left and right lungs were measured with ultrasonic flow probes on the common and left pulmonary artery. Measurements were taken after each compound had been administered for 10 mins at a predefined dose. Both inhaled nitric oxide and nebulized prostacyclin caused effective, selective, dose-dependent pulmonary vasodilation. Inhaled nitric oxide was able to abolish hypoxic pulmonary vasoconstriction when insufflated into the animals at a concentration of 50 ppm of nitrogen, but 100 ppm of nitric oxide had no further effect. Prostacyclin, at a dosage of 10 micrograms/min, showed maximum pulmonary vasodilation, which could not be further increased by doubling the dosage. However, prostacyclin produced less dilation than high doses of nitric oxide, and its maximum pulmonary vasodilation was comparable with that effect obtained under ventilation with 20 ppm of nitric oxide. CONCLUSIONS Both drugs selectively dilated the pulmonary vasculature in ventilated alveoli. Prostacyclin nebulization is an excellent tool to reduce pulmonary hypertension and to improve the ventilation/perfusion ratio. Prostacyclin nebulization can be used without the highly sophisticated technical equipment that is needed for controlled nitric oxide inhalation, and may therefore become a new, noninvasive therapeutic approach for treatment of adult respiratory distress syndrome in hospitals that cannot provide nitric oxide inhalation.

The effects of propofol on hemodynamics and renal blood flow in healthy and in septic sheep, and combined with fentanyl in septic sheep.

Sepsis is characterized by myocardial depression and systemic vasodilation, both of which are most likely mediated by nitric oxide.Propofol inhibits nitric oxide synthase and may therefore be beneficial in sepsis. On the other hand, renal blood flow, known to be only minimally affected by propofol in healthy subjects, may be drastically reduced in septic individuals, because the renal microvasculature is known to be very sensitive to nitric oxide. In this study, the effects of propofol in healthy and in septic sheep, and in combination with fentanyl, were analyzed and compared with nonanesthetized septic sheep. In healthy sheep, propofol caused only minor hemodynamic changes. In septic sheep, however, hemodynamics deteriorated. Renal blood flow was reduced to 60% +/- 10% of the preseptic baseline and to 39% +/- 4% of the septic value. This reduction was selective, since the cardiac output decreased significantly less. These adverse effects of propofol on hemodynamics and renal blood flow were reduced when propofol was combined with fentanyl. (Anesth Analg 1996;82:738-43)

Early multiple organ failure after recurrent endotoxemia in the presence of vasoconstrictor-masked hypovolemia.

ObjectiveCritically ill patients who develop multiple organ failure during systemic inflammatory states are often predisposed to hypovolemia and vasoconstrictor therapy. Although numerous investigations have evaluated the sequelae of systemic inflammation, no data are available on the contribution of chronic vasoconstrictor-masked hypovolemia to organ dysfunction and morphology. DesignProspective, randomized laboratory investigation. SettingUniversity research laboratory. SubjectsEighteen adult chronically instrumented sheep. InterventionsThe animals were randomly assigned to one of three groups. In the norfenefrine-masked hypovolemia plus endotoxemia (NMH+ENDO) group, mean arterial pressures of 80 mm Hg were maintained by using the &agr;1-adrenergic catecholamine norfenefrine for 52 hrs during hypovolemia. Hypovolemia was induced by hemorrhage (about 23 mL·kg−1) until mean arterial pressures reached 40 mm Hg. Endotoxin (0.5 &mgr;g·kg−1) was then injected after 4, 16, 28, and 40 hrs. The NMH group received norfenefrine-masked hypovolemia but no endotoxin. In the ENDO group, recurrent endotoxemia was induced during normovolemia. Measurements and Main ResultsDespite profound differences in fluid management, cardiovascular filling pressures were not statistically different between groups. Endotoxemia induced norfenefrine-refractory shock (p < .05 vs. the other groups) and contributed to renal dysfunction only during vasoconstrictor-masked hypovolemia. Norfenefrine-masked hypovolemia caused disseminated cardiac cell necrosis independent of endotoxemia (p < .05 vs. ENDO). ConclusionsHypovolemia can be masked when volume status is monitored by filling pressures. In this new model of endotoxemia-associated multiple organ failure, chronic vasoconstrictor-masked hypovolemia turned systemic inflammation into a life-threatening condition with renal and cardiovascular failure. Cardiomyocyte necroses were caused by vasoconstrictor-masked hypovolemia but were unrelated to cardiovascular failure.