Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-10-15
2002-03-12
Gitomer, Ralph (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S059000, C514S060000, C424S009100, C600S431000
Reexamination Certificate
active
06355624
ABSTRACT:
This invention relates to methods for measuring the plasma volume of a human or animal and to compounds for use in such methods.
The adequate oxygenation of tissue depends on cardiac output, the concentration of haemoglobin and total circulating blood volume (BV). The concentration of haemoglobin is often expressed as the Haematocrit (Hct) or packed cell volume (PCV). At a given cardiac output, both haematocrit and total circulating blood volume are important determinants of tissue oxygenation. A low haematocrit means a low oxygen carrying capacity and a low blood volume leads to under perfusion of some tissue in order to maintain the oxygenation of others such as brain and cardiac muscle. The estimation of blood volume is therefore an important measurement in patients with threatened tissue oxygenation. Total blood volume (BV) is the sum of red cell volume (RCV) and plasma volume (PV) and they are related to the whole body haematocrit (Hct) by the following relationship:
Hct
=
RCV
PV
+
RCV
=
RCV
BV
Equation (1)
It is known to assess the plasma volume (and thus indirectly the blood volume) using the plasma protein, albumin. Albumin has been labelled with various dyes, including Evans Blue (T1824) and Indocyanin Green, as well as being radio-labeled with iodine. A known amount of the labelled albumin is injected into the bloodstream and then a dilution analysis technique used to determine the volume of distribution of albumin. However, we have noted that, especially in sick patients, equating the volume of distribution of albumin to plasma volume is unsatisfactory in that the albumin also equilibrates into Interstitial water and also “leaks” at a rate of about 5% per hour and increasing to 15% per hour in patients with septic shock. The albumin space exceeds true plasma volume and this is exaggerated when capillary integrity is impaired. The “excess” volume of distribution of labelled albumin reflects mainly extravasation of the albumin simultaneously with its equilibration in the plasma in the circulation, in critically ill patients.
Accordingly, in present hospital practice worldwide, surgical resuscitation after blood loss is managed without accurate knowledge of measured blood volume. Likewise, intensive care patients who are dependant on respiratory support are managed without accurate knowledge of blood volume, but instead surrogate indicators of blood volume may be used such as clinical appraisal and intravascular pressure and flow measurements. These are only very generally related to the amount of blood in the circulation and it is possible for sick patients, including surgical cases or victims of trauma and the newborn, to have a deficiency of more than half the blood in their circulation.
Without any realistic possibility of routine measurement of plasma volume and thus total circulating blood volume, the effects of intravenous infusions used to attempt correction are hard to assess. Lack of this information seriously limits clinical monitoring and appraisal of the circulation of the most critically ill patients, as well as of less seriously sick patients who have undergone elective surgery.
The consequences of lack of knowledge of the circulating blood volume include management of patients who are hypo-volaemic with adverse effects on lung function and gastrointestinal tract, hepatic and renal perfusion by blood. In our own experience and observation, hypo-volaemia is extremely widespread in critically ill patients and goes undetected by present means of clinical evaluation and laboratory measurement.
Other methods of blood volume measurement are available which require the use of radioactive isotopes or non-radioactive “labels” to determine the amount of red cells and plasma in the circulation. Such methods include measuring red cells by monitoring dilution of cells labelled with radioactive chromium or technetium, or with non-radioactive biotin. Plasma is routinely measured from dilution of radiolabelled albumin. All of these measurements are expensive in expertise, time and financial cost and they do not lend themselves to widescale application. Furthermore, most of the standard methods are unsuitable for use in women in the childbearing age group or in children.
Accordingly, there is a need for a method of blood volume assessment with a more widely applicable and speedy methodology, which is less prone to error in critically ill patients and which can be implemented at relatively low cost and for 24 hours every day. Whilst the traditional methods of blood volume measurement using radiolabelled albumin are reasonably accurate in healthy patients, as noted above we have found that the accuracy declines considerably in sick patients, who are usually in most need of accurate blood volume measurement.
We describe below methods of determining the plasma volume of a human or animal, which methods comprise introducing into the bloodstream of the human or animal, labelled material comprising a modified or unmodified starch, or derivatives or mixtures thereof, and thereafter determining the concentration of said labelled material, thereby to determine the plasma volume.
In the course of our experiments we have found that, in sick patients, the plasma volume determined by use of labelled albumin is higher than that using labelled starches of somewhat larger molecular size We believe that this is due to the increased capillary permeability in sick patients arising from damage to the vascular endothelium, with albumin extravasating into the interstitial space which accounts for about 25% of the water volume of a normal adult. This has severe implications not only for the accuracy of any measurements of plasma volume using labelled albumin, but also for the use of albumin as a volume expander in patients undergoing major surgical procedures. A rapid and profound increase in systemic capillary permeability is now known to accompany all acute inflammatory states including major surgery, ischaemia and reperfusion injury, trauma, thermal injury, bacteraemia, and acute pancreatitis.
The problem with albumin infusion as a volume therapy stems from the ease with which albumin moves from the vascular compartment to the interstitium, even in health, and the loss of vascular endothelial integrity in disease. Of the 275 grams of albumin in a normal adult, 60% is to be found in the interstitial space, with 5 grams or more every hour moving across the normal vascular endothelium. This rate of leakage dramatically increases in any severe inflammatory condition leading to hypoalbuminaemia and interstitial oedema. Intravenous infusions of albumin, given in an attempt to correct blood loss during an acute inflammatory episode such as trauma, major surgery or their complications, are not only ineffective because albumin rapidly leaks out of the vascular compartment, but also worsen interstitial oedema, with each gram of albumin ‘binding’ 18 grams of water. The blood in the underfilled circulation, depleted of plasma and red blood cells, gives misleadingly ‘normal’ haemoglobin and haematocrit values, suggesting that red blood cell replacement has been adequate even though may be a deficit of up to 20-30% and typically 1.5-2.5 litres in an adult patient. The interstitial oedema and the inadequate red cell mass compromise both pulmonary gas exchange and tissue oxygen delivery. Hypovolaemia leads to reflex vasoconstriction, and splanchnic ischaemia, risking bacterial translocation and ineffective function of the reticuloendothelial system.
This clinic ‘ITU’ (Intensive Therapy Unit) syndrome of ‘symmetrical’ red cell and plasma depletion with hypovolaemia, hypoalbuminaemia and interstitial oedema yet normal haematocrit and haemoglobin is clinically unrecognizable until its late stages which may herald organ failures. Conventional management of hypovolaemia advocating albumin infusions without blood transfusion does not provide a sustained increase in intravascular volume since, in the ‘sick’ ITU patient with damaged vascular endothelium, albumin rapidly moves out of the vascular compartment and e
Jones John Gareth
Wardrop Charles Alexander James
Wusteman Frederick Stephen
Chaudhry Mahreen
Gitomer Ralph
University Wales College of Medicine
Young & Thompson
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