10. Iatrogenic anemia

Iatrogenic anaemia is a condition of lowered hematocrit and hemoglobin count resulting from large or frequent removal of blood samples, usually for laboratory testing (1). Anaemia is not so uncommon in critical care patients with almost 97% of patients becoming anaemic in an initial 8 days of admission (2). Iatrogenic anaemia due to blood drawn for diagnostic testing is modern age bloodletting which has been rationalized throughout medical practice (3). Diagnostic blood sampling can lead to severe anaemia leading to unintentional but definitive harm to the patients (4). The diagnostic phlebotomy related blood loss in critical care patients has been 40 to 70 ml per day which exceeds basal red cell formation rate of 15-20 ml/ day (5,6).

Apart from transporting gases, red cells contribute to vasoregulation at microvascular level through various mechanisms (7). The physiological functions of red cells, its rheology are altered in critically ill patients which contribute to poor prognosis. Anemia can impact mortality, morbidity and quality of life independently. It has been associated with increased mortality and hospitalization in patients with cardiac, renal and pulmonary ailments (2,8). The intensive care unit (ICU) patients with anemia has increased ventilator and admission days, increased risk of myocardial infarction and increased risk of death (2). Anemia has been traditionally treated with allogenic blood transfusions particularly in ICU settings which in turn is associated with infectious as well as non-infectious complications (9). Allogenic blood transfusion has been independently associated with poor patient outcomes (2).

Current Practices in various patient groups

Anaemia is a common comorbidity in intensive care patients with a reported prevalence of up to 98% and 40–50% of patient’s haemoglobin are < 9 g/dL). Allogenic blood transfusion due to iatrogenic anaemia further leads to increased complication rate, prolonged hospital stays, and increased mortality rate (10-12). Diagnostic blood loss in hospital setting is an independent risk factor for iatrogenic anaemia particularly in an ICU where prolonged hospital stay and relatively more diagnostic blood sampling place patients at higher risk (5,13,14). The diagnostic blood loss in a critical care setting has been reported from 9.8 ml to 377 ml per day in a recently published scoping review (11). Surgical patients had 17% more phlebotomy related blood loss particularly cardiothoracic ICUs have reported more frequent and higher daily blood loss when compared to medical ICUs and general ward patients (11, 15).

The widely recognised diagnostic blood loss practices are still prevalent and has not changed over years (15). Complete blood counts (CBC), coagulation, and blood gas analysis were the most frequently ordered investigations in a cardiac ICU (16). Blood sample draw for research purposes from ICU patients is also an area of concern for the development of iatrogenic anaemia. The guidelines to limit research sample blood draw neither specify for specific issues nor prescribes effective monitoring mechanism (17, 18). The neonatal and paediatric group patients are more vulnerable population due to relatively small blood volume and ineffective erythropoiesis in premature infants (19, 20). The patients with iatrogenic anaemia are reported to stay longer with increased number of ventilator days in paediatric intensive care unit (PICU) (19). The multiple variables can affect phlebotomy induced blood loss in PICU patients including blood draw site, number and type of test ordered and patient’s body weight (20). The diagnostic phlebotomy loss is not limited to critical care patients. It has been also reported from general ward patients requiring general medical care (21). The mean haemoglobin change was significant in medical and geriatric patients also (21, 22). The volume of blood sampling and baseline haemoglobin are the only two independent risk factors associated with iatrogenic anaemia in the ward patients, unlike ICU counterparts (23). The diagnostic phlebotomy has cost implications including both direct phlebotomy & test cost and indirect cost including blood transfusion, longer hospital stay, increased ventilator days and morbidity (15). The development of iatrogenic anaemia due to diagnostic phlebotomy can have significant financial to the patients and healthcare organizations (15, 24). 

One of the pillars for the patient blood management “minimizing blood loss” advocates for the minimization of phlebotomy. The Choosing wisely campaign is adopted across the world and many scientific societies has come up with recommendations for diagnostic testing to minimise iatrogenic anaemia (25). Choosing wisely campaign-based guidelines for minimization of diagnostic testing are mentioned at the end (25).

Strategies to prevent iatrogenic anaemia

a, Devices and techniques to minimize phlebotomy associated blood loss

Iatrogenic anaemia is not only associated with volume of blood sample collected but also with the conventional sample collection methods. The sample collection methods have not evolved in synchronization of modern testing platform resulting in estimated wastage of 25 million litres of blood in western world alone (26). The use of small volume tubes in place of routine tubes has been shown to reduce phlebotomy related total blood loss while maintaining laboratory test quality in studies including a stratus randomised controlled trial (27,28). The modern automated analysers are able to process test from small volume tubes but request for additional test on a low volume sample may be a challenge (29). Small volume tubes are still not widely adapted despite their availability with no additional cost, mostly attributed to the lack of high quality evidence but still evidence suggest that small volume tubes can prevent iatrogenic anaemia (27,30). The amount of blood draw can also be optimised by calculating minimum amount of blood required for investigations utilizing patient parameters like haematocrit, and laboratory instrument parameters such as minimum volume required for a specific test, dead volume etc.

This clinical decision support tool can achieve 36 to 56% of volume collected (31). Conventional blood draw from arterial or venous lines particularly central lines requires discard of initial volume which is usually mixture of crystalloid and blood. The volume of discard per sampling depends upon type of line especially internal volume of line and may range from 2 to 10 ml for each sampling and usually account for significant amount of blood loss in ICUs (29). Patients with major surgery particularly cardiac and vascular surgeries spend longer ICU and hospital stay which makes them more prone for diagnostic blood loss including discard volumes (32). Closed blood collection devices can help to reduce iatrogenic blood loss by allowing complete return of initial discard volume while maintaining closed system of blood sample collection (32). Closed blood collection devices are available from various manufacturers and few modified in-house devices have been reported (33,34). Apart from these devices, a push-pull protocol for blood sampling from central line to avoid blood loss during sampling without affecting test results can also be implemented. This method has been reported as safe and reliable by investigators (35,36). 

Despite reported effectiveness of above-mentioned devices and methods to reduce diagnostic blood sampling loss, these are not still part of standard diagnostic care plan across the world. This may be partly due to reported heterogeneity among studies resulting in uncertain clinical effect including blood transfusion, hospital or ICU stay duration, morbidity and mortality. The closed blood sampling devices may be costly to implement universally. The test validity, staff workload, equipment compatibility and insufficient sample for retest remains possible limiting factors for implementation of small volume tubes (27,37).

b. Use of point of care technique (POCT) devices and iatrogenic anaemia

The point of care test (POCT) devices are available for rapid analysis of small volume of blood to provide information about multiple analyses (38). These are being used for several years especially in the ICUs, operation theatres (OT) and emergency departments. The POCT devices can provide diagnostic test results in a shorter turnaround time (TAT) which can have impact on therapeutic interventions (39). POCT devices can also mitigate risk of pre-analytical error of conventional laboratory testing involving sample collection, storage and transport (38). In a prospective analysis of POCT devices in an adult ICU set up, the diagnostic blood loss was reduced while comparable test results were obtained (40). The introduction of POCT for electrolyte and bilirubin testing in a NICU resulted in 19% reduction in blood loss. There was 22% reduction in blood transfusion requirement after implementation of POCT (41, 42). The use of POCT devices may produce significant cost saving primarily due to consistent improvement in clinical care (39). Non-invasive testing using ex vivo or in vivo sensors can eliminate need for blood draw which has been established for pH, blood gas analysis and haemoglobin estimation in critical care services (29,43,44). Use of POCT devices for coagulation testing can guide transfusion and coagulation therapy resulting in reduced blood transfusion and associated adverse events (45). 

POCT were considered to improve diagnosis certainty, guide treatment, help education and empowering patients and improve relationship of patients with primary clinicians but accuracy of test results, higher cost and risk overreliance on POCT then clinical skills were major limitations in a systematic review (46). One must be very cautious when measurements are taken with single drop of blood with POCT devices as drop to drop variations may affect test accuracy of cellular component measurements. These should only be used when degree of variability is acceptable based on clinical conditions (47). 

Role of education in minimizing iatrogenic anaemia

Physicians in a currently existing complex healthcare system order diagnostic tests for treatment decisions, fearing to miss some important diagnostic clue, following protocols and guidelines, inadequate educational feedback, lack of awareness among clinician about cost of diagnostic test and sometimes based on the patient's desire (48,49). Sedrak MS reported routine habit, unawareness of cost, diagnostic uncertainty and fear of attending consultant as major contributing factor among general surgery and internal medicine residents for over ordering of laboratory tests (50).

Education of healthcare professionals for appropriate indications to order tests, for the cost of the tests, and for the use of electronic medical records to minimize laboratory test ordering have been reported to lower the number of tests ordered (51). Educating the residents about high value cost conscious care to laboratory ordering, coverage of waste produced by excessive laboratory ordering, through multitier approach including didactic lectures, verbal or email reminders and poster display have been shown to improve ordering practices of the residents (51-53). Educational interventions among nurses for phlebotomy blood loss, hospital acquired anaemia (HAA), use of blood conservation sampling devices (BCDS) has resulted in the reduction of phlebotomy associated blood loss but no effect HAA, mostly due to small sample size (54). 

Choosing wisely campaign-based guidelines for minimization of diagnostic testing

1. American society for advancement of blood bank and biotherapies

(Callum JL, Waters JH, Shaz BH, Sloan SR, Murphy MF. The AABB recommendations for the choosing wisely campaign of the American Board o Internal Medicine. Transfusion 2014; 54:2344–52.)

2. American society of haematology

Hicks LK, Bering H, Carson KR, Kleinerman J, Kukreti V, Ma A, et al. The ASH choosing wisely(R) campaign: five hematologic tests and treatments to question. Blood 2013; 122:3879–83.

3. Critical care societies Collaborative

Halpern SD, Becker D, Curtis JR, Fowler R, Hyzy R, Kaplan LJ, et al. An official American Thoracic Society/American Association of Critical-Care Nurses/American College of Chest Physicians/Society of Critical Care Medicine policy statement: the choosing wisely(R) top 5 list in critical care medicine. Am J Respir Crit Care Med 2014; 190: 818–26.

4. American Society of Anesthesiologists

Corwin HL, Gettinger A, Pearl RG, Fink MP, Levy MM, Abraham E, et al. The CRIT study: Anemia and blood transfusion in the critically ill—current clinical practice in the United States. Crit Care Med 2004; 32:39–52.

5. American Society for Clinical Pathology

Fowler AJ, Ahmad T, Phull MK, Allard S, Gillies MA, Pearse RM. Meta-analysis of the association between preoperative anaemia and mortality after surgery. Br J Surg 2015; 102:1314–24.

6. The Italian Society of Internal Medicine

Montano N, Costantino G, Casazza G, Sbrojavacca R, Lenti MV, Falsetti L, et al. The Italian Society of Internal Medicine choosing wisely campaign. Intern Emerg Med 2016; 11:1125–30.

7. The Society of Hospital Medicine

Bulger J, Nickel W, Messler J, Goldstein J, O’Callaghan J, Auron M, et al. Choosing wisely in adult hospital medicine: five opportunities for improved healthcare value. J Hosp Med 2013; 8:486–92.

8. Canadian Hematology Society

Hillis CM, Schimmer AD, Couban S, Crowther MA. The Canadian choosing wisely campaign: the Canadian hematology Society’s top five tests and treatments. Ann Hematol 2015; 94:541–5.