Organ perfusion

Medical appHcations of PFC emulsions for organ perfusion and intravenous uses have received much attention in recent years. The first commercial blood substitute (Fluosol DA 20%, trademark of the Green Cross Corp.) employed perfluorodecalin, and improved, second generation products based on this PFC, or perfluorooctylbromide, are now under development (20,21). The relatively high oxygen dissolving capabiHty of PFCs undedies these appHcations (see Blood, artificial). 

Verapamil (Table 1), the first slow channel calcium blocker synthesized to selectively inhibit the transmembrane influx of calcium ions into cells, lowers blood pressure in hypertensive patients having good organ perfusion particularly with increased renal blood flow. Sustained-release verapamil for once a day dosing is available for the treatment of hypertension. Constipation is a prominent side effect. Headache, dizziness, and edema are frequent and verapamil can sometimes cause AV conduction disturbances and AV block. Verapamil should not be used in combination with -adrenoceptor blockers because of the synergistic negative effects on heart rate and contractile force. 

Use when an appropriate fluid challenge fails to restore adequate hemodynamics and organ perfusion or in the face of life-threatening shock when fluid challenge is in progress. Should be utilized in patients who have been adequately fluid resuscitated... 

ECF depletion tends to occur acutely. In this setting, rapid and aggressive fluid replacement is required to maintain adequate organ perfusion. Because ECF depletion is generally due to the loss of isotonic fluid (proportional losses of sodium and water), major disturbances of plasma osmolality... 

Acidosis occurs during cardiac arrest because of decreased blood flow and inadequate ventilation. Chest compressions generate only about 20% to 30% of normal cardiac output, leading to inadequate organ perfusion, tissue hypoxia, and metabolic acidosis. Furthermore, the lack of ventilation causes retention of carbon dioxide, leading to respiratory acidosis. The combined acidosis reduces myocardial contractility and may cause arrhythmias because of a lower fibrillation threshold. 

Cardiac index and blood pressure must be sufficient to ensure adequate organ perfusion, as assessed by alert mental status, creatinine clearance sufficient to prevent metabolic azotemic complications, hepatic function adequate to maintain synthetic and excretory functions, a stable heart rate and rhythm, absence of ongoing myocardial ischemia or infarction, skeletal muscle and skin blood flow sufficient to prevent ischemic injury, and normal arterial pH (7.34 to 7.47) with a normal serum lactate concentration. These goals are most often achieved with a cardiac index greater than 2.2 L/min/m2, a mean arterial blood pressure greater than 60 mm Hg, and PAOP of 25 mm Hg or greater. 

Norepinephrine is a potent a-adrenergic agent (0.01 to 3 mcg/kg/min) that is useful as a vasopressor to restore adequate blood pressure after failure to restore adequate blood pressure and organ perfusion with... 

Stretch GL, Nation RL, Evans AM and Milne RW (1999) Organ Perfusion Techniques in Drug Development. Drug Develop Res 46 pp 292-301. 

Buffers and Media for Tissue and Ceil Culture and Organ Perfusion... 

Dopamine (Intropin) [Vasopressor/Adrenergic] Uses Shortterm use in cardiac decompensation secondary to X contractility when no hypovolemia is present T organ perfusion (at low dose) Action Renal dose 2-5 mcg/kg/min Inotropic dose 5-10 mcg/kg/min Pressor dose >10 mcg/kg/min Dose Adults Peds. 5-20 mcg/kg/min by cont inf, start at 5 and T by 5 mcg/kg/min to 20 mcg/kg/min max to effect (mix 400 mg in 250 mL D5W to make 1600 mcg/mL) (see Table 1-3) Caution [C, ] Contra Pheochromocytoma (adrenal gland tumor), VF, sulfite sensitivity Disp Inj 40, 80, 160 mg/mL, premixed 0.8, 1.6, 3.2 mg/mL SE Tach, vasoconstriction, X BP, HA, N/V, dyspnea Notes >10 mcg/kg/min 1 renal perfusion Interactions T Effects W/ a-blockers, diuretics, ergot alkaloids, MAOIs, BBs, anesthetics, phenytoin 1 effects W/ guanetliidine EMS Correct hypovolemia before use use microdrip set or inf pump check soln- discolored... 

The most frequent adverse reactions associated with the administration of proleukin include fever, chills, fatigue, malaise, nausea and vomiting. It has also been associated with capillary leak syndrome (CLS). CLS is defined as a loss of vascular tone and effusion of plasma proteins and fluids into the extravascular space. This leads to hypotension and decreased organ perfusion, which may cause sudden death. Other side effects include anaphylaxis, injection site necrosis and possible autoimmune and inflammatory disorders. 

Whereas sophisticated studies require the technology to be available in-house in preparation e.g. of slices or performing an organ perfusion study (see also chapter on Perfused Organs), others can be performed with cells (Li 1999) or fractions commercially available or easily prepared. A typical preparation scheme for preparation of subcellular fractions by differential centrifugation is given in Figure 3. 

Glucose begins to spill into the urine as the proteins responsible for reclaiming it from urine reach maximum capacity. As glucose is excreted in the urine, it takes a great deal of body water with it, resulting in dehydration. Dehydration further concentrates the blood and worsens the increased osmolality of the blood. Severe dehydration forces water out of cells and into the bloodstream to keep vital organs perfused. This shift of intracellular water into the bloodstream occurs at a cost, as the cells themselves need the water to complete chemical reactions that allow the cells to function. 

The next level of in vitro systems employed is the use of isolated perfused skin flap preparations that are surgically prepared vascularized skin flaps harvested from pigs and then transferred to an isolated organ perfusion chamber. This model allows absorption to be assessed in skin that is viable and anatomically intact and that has a functional microcirculation. Studies conducted to assess the percutaneous absorption of drugs and pesticides in this model compared to humans show a high correlation. Validation of these in vitro methods is a prerequisite for regulatory acceptance. 

Any change observed in an in vitro or organ perfusion system should be considered supplemental. Isolated findings of studies that use these systems are insufficient to characterize an agent as causing reproductive toxicity. 

Nasal absorption studies can be carried out in mainly two types of animal models the whole-animal model and the isolated organ perfusion model. 

Extensive burn injuries produce a systemic response that pulls fluid from the vascular system into the interstitial space. This is exacerbated in burns greater than 20% TBSA by a significant capillary leak into the microvasculature and generalized edema. Without proper treatment, intravascular fluid loss and hypovolemic burn shock result. This is why immediate initiation of fluid resuscitation is important. A successful fluid resuscitation will maintain intravascular volume and organ perfusion until capillary membrane integrity is restored (approximately 24 to 48 hours postinjury). 

Blood flow (oxygen delivery) rather than blood pressure is of the greatest immediate importance for the function of vital organs. A reasonable blood pressure is needed to ensure organ perfusion but peripheral vasoconstriction may maintain a normal mean arterial pressure despite a very low cardiac output. Under these circumstances, blood flow to vital organs will be inadequate and multiple organ... 

For example, the hypothesis that DCLHb would improve blood pressure, organ perfusion, and mortality was tested in a rodent model of sepsis. Administration of this tHb to moribund, septic rats immediately reversed the decreased MAP, increased systemic vascular resistance (SVR) and by 24 h, significantly elevated perfusion to vital areas (intestines, heart, and brain) as compared to albumin-treated animals. In addition, areas that did not display an increase in perfusion also did not demonstrate any deficits, suggesting that they were being adequately perfused. 

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