Hemoglobin mass and hemoglobin concentration

blood measurement method

In clinical medicine, no distinction is being been made between hemoglobin mass (Hb-mass) and hemoglobin concentration ([Hb]). While [Hb] represents the amount of hemoglobin in 100ml (or one liter) of blood, Hb-mass represents the total amount of hemoglobin circulating in the human body. Typical values for [Hb] in healthy women and men are 14.0g/100ml and 15.0g/100ml, respectively, while Hb-mass values are ~ 500g and ~750g, respectively. If the liquid amount of blood (i.e., plasma volume) changes the relative amount of [Hb] also changes. Plasma volume changes can occur in the short-term due to sweating or overhydration but also can occur because of many diseases (see below). This means that [Hb] often does not represent the true amount of hemoglobin in a human body. Therefore, in the case of many diseases, determining Hb-mass is extremely important to initiate a more individualized therapy and to avoid false interventions. Even though [Hb] is a frequently used valuable determined parameter in routine practice, measuring Hb-mass is gaining importance for answering scientific and clinical questions. It is our task to establish the measurement of Hb-mass and blood volume in routine clinical practice.

Hemoglobin concentration only represents the amount of hemoglobin in a certain amount of blood and does not consider total blood volume. On the contrary, Hb-mass represents the total amount of hemoglobin.

Blood volume overload and hypovolemia

Blood volume overload or a deficiency of blood (hypovolemia) contributes to the mortality of high-risk patients. Particularly in situations such as surgery, critical care, or transfusion, the outcome of a critical illness can be influenced by an abnormal blood volume status. This might be due to a direct lesion of blood pressure, organ perfusion, or functional damage. Furthermore, dosing to reach adequate drug concentration levels is uncertain in abnormal blood volumes. Patients with heart, kidney, and liver failure usually present with large blood volume variations (Perel, 2017; Otto et al., 2017), reaching the greatest volume expansion during septic shock. Studies in which invasive blood volume monitoring is performed show that the outcome of the illness is improved in patients with severe cardio-circulatory or vascular disease; polytrauma; shock; sepsis; heart, lung, or kidney failure; or patients undergoing a large resection or ablative surgery (Shoemaker et al., 1988). Despite these findings, routine monitoring of individual total blood volume during critical periods has not been established since invasive methods are too expensive and time-consuming.

Routine implementation of the optimized CO-rebreathing method will allow for screening total blood volume changes in risk patients and, therfore, will be an enormous step towards individualized diagnostics and treatment.

Anemia

Anemia is a decrease in the concentration of hemoglobin in the blood. Hemoglobin is the oxygen-transporting protein that is found in red blood cells (erythrocytes). Suffering from anemia means that the oxygen transport capacity of blood is reduced. Typical symptoms are a worsened ability to concentrate, easily fatiguing, recurring headaches, and a massive decrease in performance. 

Worldwide, around 10% of the population (i.e., 700 million people) suffer from anemia. Anemia is diagnosed when Hb-concentration in 100ml of blood is less than 13.0g in men and 12.0g in women. However, in various diseases, anemia can be misdiagnosed when the reduction of Hb-concentration is not due to a deficiency of hemoglobin but due to an increase of the liquid phase of the blood (i.e., blood plasma). This increase in plasma volume occurs in most patients with liver failure (50-95%) and a large percentage of patients with heart failure (34-61%; Otto et al., 2017). 

The same problem occurs in patients who are admitted to the intensive care unit. After some days in intensive care, approximately 60% of them are diagnosed with anemia, often due to a plasma volume increase, known as “dilutional anemia.” Since this artifact cannot be detected using common testing methods, dilutional anemia is often treated with dangerous blood transfusions that are not necessary and often lead to dangerous blood volume overload.

Analyzing the absolute amount of hemoglobin and plasma volumes with the optimized CO-rebreathing method will save patients from having an enormous number of fluid overload-related complications, non-effective drug treatments, and unnecessary blood transfusions. 

Heart failure

Heart failure of various origins is very often (34% – 61%; Otto et al., 2017) accompanied by anemic conditions which are usually treated with erythropoietin and iron supplementation. However, in about 30% of these cases, low hemoglobin concentration is not caused by a reduced number of erythrocytes but by an expansion of plasma volume. This is called “dilution anemia” (see Anemia for further explanation). If dilution anemia is treated with conventional methods, volume overload of the cardiovascular system, which leads to fatal complications such as ischemic heart attack or stroke, can occur.

With the optimized CO-rebreathing method, a distinction can be made between true anemia and dilution anemia within a few minutes (Otto et al., 2017; Plumb et al., 2020). An outstanding clinical study has shown that determining Hbmass, blood volume, and subsequent individualized therapy, a process that is called “blood volume guided treatment,” reduced the 365-day mortality rate by 86% and re-admission to the clinic by 56% (Strobeck et al., 2018). Massen et al. (2014) show that the optimized CO-rebreathing method is a diagnostic method also very well-tolerated by elderly patients.

The determination of total Hb-mass in heart failure patients will reveal pseudo-anemic conditions in approx. 30% of them. This revelation with lead to improved therapeutic measures.

Liver disease

Anemia is a common hematological abnormality (prevalence between 50 and 94%) that affects patients with chronic liver disease (see Anemia). There are different etiologies of anemia due to gastrointestinal bleeding and enlargement of the spleen. In a recent study, Otto et al. (2017) showed increased plasma volumes in 80% of chronic liver disease patients, underlining the necessity of determining Hb-mass and blood volume to prevent the misdiagnosis of an anemic condition. Determining Hbmass can prevent the use of inadequate treatments using erythropoietic agents and can lead to a specific, individualized treatment being carried out using adequate fluid reduction.

The determination of total Hb-mass in heart failure patients will reveal pseudo-anemic conditions in approx. 30% of them. This revelation with lead to improved therapeutic measures.

Surgery

IIn the clinical setting, hemoglobin concentration ([Hb]) is frequently used as a rough estimate of blood volume reduction. However, when using [Hb] to assess blood loss during surgical procedures, a severe problem arises (Otto et al., 2013). Since a loss of blood reduces the amount of hemoglobin and plasma in the same ratio, [Hb] remains relatively constant during the acute incident. Only hours later, when increased plasma volume compensates for the loss of red cells, can a decrease in [Hb] be detected. However, a direct measurement of total Hb-mass during surgery can reveal an acute blood loss, allowing for a quick and adequate treatment with a blood transfusion. Currently, there is no non-invasive routine method available that allows for the direct quantification of Hb-mass during surgery.

 Integrating the optimized CO-rebreathing method into the ventilation apparatus during surgery would allow on-time screening of Hb-mass to immediately reveal occult blood loss.

Chronic kidney disease/dialysis

Renal insufficiency is a disease that, with increasing severity, leads to a reduction of and, in the end stage, a complete cessation of erythrocyte formation. By administering recombinant erythropoietin or related substances, hemoglobin concentration ([Hb]) is adjusted to a tolerable value of approx. 12 g/dL. However, since frequent fluctuations in blood volume occur throughout the progression of this chronic disease, hemoglobin levels cannot be adequately adjusted by monitoring [Hb] concentration alone. In these cases, additionally determining Hb-mass and blood volume would make it possible to adjust individually optimized hemoglobin content and thus prevent volume overloading.

If the life of a patient with end-stage renal insufficiency can only be preserved using dialysis treatment, the biggest challenges are to detect fluctuations in blood volume and to withdraw the individually-required amount of fluid from the body during dialysis. So far, only indirect methods that lead to imprecise volume status results, such as weighing patients before and after dialysis, are used in routine medicine.

A pilot study shows that it is possible to use the optimizes CO-rebreathing method to control fluid balance during dialysis and thereby prevent cardiovascular complications.

References

Perel A: Iatrogenic hemodilution: a possible cause for avoidable blood transfusions? Crit Care 2017, 21:291.

Otto JM, Plumb JOM, Clissold E, Kumar SB, Wakeham DJ, Schmidt W, Grocott MPW, Richards T, Montgomery HE: Hemoglobin concentration, total hemoglobin mass and plasma volume in patients: implications for anemia. Haematologica 2017, 102:1477-1485.

Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee TS. Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest. 1988 Dec;94(6):1176-86. doi: 10.1378/chest.94.6.1176.

Plumb JOM, Otto JM, Kumar SB, Wright M, Schmidt W, Grocott MPW, Montgomery HE. Application of the optimized carbon monoxide rebreathing method for the measurement of total haemoglobin mass in chronic liver disease. Physiol Rep. 2020 Mar;8(6):e14402. doi: 10.14814/phy2.14402.

Strobeck JE, Feldschuh J, Miller WL. Heart Failure Outcomes with Volume-Guided Management. JACC Heart Fail. 2018 Nov;6(11):940-948. doi: 10.1016/j.jchf.2018.06.017.

Massen L, Heinrich C, Preßler A, Wachsmuth NB, Prommer N, Schmidt W. CO rebreathing method for determining blood volumes in heart failure patients. Dtsch Z Sportmed. 2014, 65 (7-8), 225.

Otto JM, Montgomery HE, Richards T. Haemoglobin concentration and mass as determinants of exercise performance and of surgical outcome. Extrem Physiol Med. 2013 Nov 26;2(1):33. doi: 10.1186/2046-7648-2-33.