Summary: anemia at the time of surgery, even mild anemia, increases the risk of serious complications including death.

There is a large body of evidence that even borderline anemia has profound implications (see earlier posts). Anemia affects the ability of every cell in the body to do perform its functions by diminishing the amount of oxygen available. A study recently published in The Lancet documents the serious effects of anemia on surgical outcomes. The authors state:

“Preoperative anaemia is associated with adverse outcomes after cardiac surgery but outcomes after non-cardiac surgery are not well established. We aimed to assess the effect of preoperative anaemia on 30-day postoperative morbidity and mortality in patients undergoing major non-cardiac surgery.”

They analyzed data for 227,425 patients, of whom 69,229 had preoperative anaemia, undergoing surgery in 2008 from The American College of Surgeons’ National Surgical Quality Improvement Program database from 211 hospitals worldwide with reference to mortality and morbidity due to cardiac, respiratory, CNS, urinary tract, wound, sepsis, and venous thromboembolism complications. This was correlated with anaemia, defined as mild with a hematocrit or more than 29d% to 39% in men and 29 to 36% in women, or moderate-to-severe, less than 29% in both sexes. What did the data show?

“After adjustment, postoperative mortality at 30 days was higher in patients with anaemia than in those without anaemia; this difference was consistent in mild anaemia and moderate-to-severe anaemia. Composite postoperative morbidity at 30 days was also higher in patients with anaemia than in those without anaemia, again consistent in patients with mild anaemia and moderate-to-severe anaemia. When compared with patients without anaemia or a defined risk factor, patients with anaemia and most risk factors had a higher adjusted OR for 30-day mortality and morbidity than did patients with either anaemia or the risk factor alone.”

The preoperative diagnosis and treatment of anemia is rarely undertaken before surgery. Indeed, I often find on delving into the medical histories of complex chronic cases that anemia, whose causes can be a significant clue to unlocking a case, is ‘swept under the rug’. The authors state:

“Our findings should lead to a careful consideration of appropriate interventions aimed at correction of preoperative anemia in the most patients…At least in elective surgical cases, the treatment of preoperative anemia before surgical intervention should be strongly considered.”

This should be the standard of care for patients undergoing elective surgery. The authors conclude:

“Preoperative anaemia, even to a mild degree, is independently associated with an increased risk of 30-day morbidity and mortality in patients undergoing major non-cardiac surgery.”

Even mild anemia is a complicating factor, impediment to improvement, and important clue to underlying causation in many chronic conditions.

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Clinicians will wish to read the entire guidelines on managing iron deficiency anemia just published GUT (International Journal of Gastroenterology and Hepatology), but a few important points are worth noting here:

• “Any level of anaemia should be investigated in the presence of iron deficiency.”
• “Serum ferritin is the most powerful test for iron deficiency.”
• “Gastrointestinal (GI) blood loss from colonic cancer or gastric cancer, and malabsorption in coeliac disease are the most important causes that need to be sought.”
• “Upper and lower GI investigations should be considered in all postmenopausal female and all male patients where IDA has been confirmed unless there is a history of significant overt non-GI blood loss.”
• “All patients should be screened for coeliac disease.”
• “Colonoscopy has advantages over CT colography for investigation of the lower GI tract in IDA, but either is acceptable. Either is preferable to barium enema, which is useful if they are not available.”
• “In patients with recurrent IDA and normal OGD and colonoscopy results, Helicobacter pylori should be eradicated if present.”
• “Faecal occult blood testing is of no benefit in the investigation of IDA.”
• “Rectal examination is seldom contributory, and, in the absence of symptoms such as rectal bleeding and tenesmus, may be postponed until colonoscopy.”
• “Urine testing for blood is important in the examination of patients with IDA .”

Determining the cause and treating any type of anemia is of the highest importance—with even borderline anemia the ability of every cell in the body to function is impaired due to suboptimal oxygen delivery. There are a number of posts presenting studies on the depredations of mild anemia that can be seen by typing ‘anemia’ in the search box above.

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Earlier posts have offered evidence for the need to take even slightly low levels of hemoglobin very seriously. Now a research article just published in PLoS Medicine (Public Library of Science) reports that borderline anemia makes coronary artery disease significantly more lethal. The authors note:

“Coronary artery disease is the main cause of death in high-income countries and the second most common cause of death in middle- and low-income countries…Recent studies have suggested that low hemoglobin may be associated with mortality in patients with coronary artery disease. Therefore, using blood hemoglobin level as a prognostic biomarker for patients with stable coronary artery disease may be of potential benefit especially as measurement of hemoglobin is almost universal in such patients and there are available interventions that effectively increase hemoglobin concentration.”

They examined the data for 20,131 with stable angina and another 14,171 who had survived a first heart attack for an average of 3.2 years, correlating outcomes with hemoglobin values. Their findings are very important for clinicians and patients, who should inquire about their hemoglobin values, to bear in mind:

“For men with MI, the threshold value was 13.5 g/dl; the 29.5% of patients with haemoglobin below this threshold had an associated hazard ratio for mortality of 2.00 compared to those with haemoglobin values in the lowest risk range. Women tended to have lower threshold haemoglobin values (e.g, for MI 12.8 g/dl) but the shape and strength of association did not differ between the genders, nor between patients with angina and MI.”

In other words, hemoglobin below 13.5 g/dl in men and slightly lower in women doubled the risk of death. The authors conclude:

“There is an association between low haemoglobin concentration and increased mortality. A large proportion of patients with coronary disease have haemoglobin concentrations below the thresholds of risk defined here.“

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Even in developed nations iron deficiency is a common problem. An important clinical report just published in the journal Pediatrics examines the serious consequences, with recommendations for screening and supplementation. The authors state:

“Iron deficiency (ID) and iron-deficiency anemia (IDA) continue to be of worldwide concern…In industrialized nations, despite a demonstrable decline in prevalence, IDA remains a common cause of anemia in young children. However, even more important than anemia itself is the indication that the more common ID without anemia may also adversely affect long-term neurodevelopment and behavior and that some of these effects may be irreversible.“

The authors undertake a thorough revision and extension of the previous policy statement on ID and IDA in children last published in 1999, offering up-to-date guidelines for diagnosis and prevention in infants and toddlers aged 1 to 3. Clinicians reading this can peruse the study (the link above opens the paper in its entirety) for the specifics on acceptable hemoglobin levels and iron fortification. I encourage attention to the complications of iron deficiency, iron supplementation, and lead toxicity:

“Results of both animal and human studies have confirmed that IDA increases intestinal lead absorption…In contrast, iron supplementation in a child with IDA who also has lead poisoning without chelation therapy seems to increase blood lead concentrations and decrease basal lead excretion…Thus, in theory, selective rather than universal iron supplementation would be more likely to reduce lead poisoning and its potential harmful effects on these children.”

While lead toxicity is a problem for some, the effects of ID/IDA on neurodevelopment are universal:

“Results of a preponderance of studies have demonstrated an association between IDA in infancy and later cognitive deficits. Lozoff et al have reported detecting cognitive deficits 1 to 2 decades after the iron deficient insult during infancy.”

While the present science on this topic offers mixed evidence, the authors see fit to conclude:

“Given that iron is the world’s most common single-nutrient deficiency and there is some evidence of adverse effects of both ID and IDA on cognitive and behavioral development, it is important to minimize ID and IDA in infants and toddlers without waiting for unequivocal evidence.”

Their recommendations include these guidelines:

1. Breastfed infants should be supplemented with 1mg/kg per day of oral iron beginning at 4 months of age until appropriate iron-containing complementary foods (including iron-fortified cereals) are introduced in the diet.
2. Whole milk should not be used before 12 completed months of age.
3. The iron intake between 6 and 12 months of age should be 11 mg/day.
4. Toddlers 1 through 3 years of age should have an iron intake of 7 mg/day. For toddlers not receiving this iron intake, liquid supplements are suitable for children 12 through 36 months of age, and chewable multivitamins can be used for children 3 years and older.

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Oxygen is critical for brain function and iron is necessary to get it there. It’s worth re-visiting a study published six years ago in the journal Pediatrics that documents the profound effects of even intermittent hypoxia.

“A review of the evidence concerning the effect of chronic or intermittent hypoxia on cognition in childhood was performed by using both a systematic review of the literature and critical appraisal criteria of causality.”

The authors applied rigorous appraisal criteria to massive amounts of data narrowed down to 55 studies to resolve their findings:

“Adverse effects were noted at every level of arterial oxygen saturation and for exposure at every age level except for premature newborns.”

Their conclusions are emphatic:

“Adverse impacts of chronic or intermittent hypoxia on development, behavior, and academic achievement have been reported in many well-designed and controlled studies in children with CHD [congenital heart disease] and SDB [sleep-disordered breathing] as well as in a variety of experimental studies in adults…Because adverse effects have been noted at even mild levels of oxygen desaturation, future research should include precisely defined data on exposure to all levels of desaturation.”

Ferritin is the ‘storage’ form of iron in the bloodstream and one of the more reliable indicators of iron availability and utilization. Suboptimal ferritin can affect learning and behavior in two ways: by diminishing the oxygen-carrying capacity of the blood due to less hemoglobin, and by limiting the production of key neurotransmitters. The authors of a paper published in the journal Child Psychiatry & Human Development state:

“Our aim was to investigate the relation between behavioral symptoms and hematological variables which are related with iron deficiency and anemia, ferritin, hemoglobin, mean corpuscular volume (MCV), and reticulosite distribution width (RDW) in children and adolescents with pure Attention Deficit Hyperactivity Disorder (ADHD) or ADHD comorbid with other psychiatric disorders.”

The authors correlated results from the Conners Parent (CPRS) and Teacher Rating Scales (CTRS) the metrics for anemia and iron insufficiency. Their data showed that when ADHD was present with other problems (comorbidities) the association was pronounced:

“Comorbid ADHD subjects had lower mean hemoglogin and MCV. In the ADHD group in general, CPRS and CTRS Total scores were significantly negatively correlated with ferritin level. When only pure ADHD subjects were taken into account, the correlations did not reach statistical signifance. Overall, these results suggested that lower ferritin level was associated with higher behavioral problems reported by both parents and teachers. Presence of comorbid conditions might increase the effect of lower iron stores on behavioral measures.”

An interesting study published in the journal Sleep Medicine investigates the association of Restless Legs Syndrome (RLS) and iron deficiency on ADHD. The authors state:

“Increasing evidence suggests a significant comorbidity between attention-deficit/hyperactivity disorder (ADHD) and restless legs syndrome (RLS). Iron deficiency may underlie common pathophysiological mechanisms in subjects with ADHD plus RLS (ADHD+RLS). “

The data provided further evidence for the impact of iron deficiency on ADHD:

“The mean serum ferritin levels were significantly lower in children with ADHD than in the control group. There was a trend for lower ferritin levels in ADHD+RLS subjects versus ADHD. Both a positive family history of RLS and previous iron supplementation in infancy were associated with more severe ADHD scores.”

The authors offer useful advice to clinicians and parents in their conclusion:

“Children with ADHD and a positive family history of RLS appear to represent a subgroup particularly at risk for severe ADHD symptoms. Iron deficiency may contribute to the severity of symptoms. We suggest that clinicians consider assessing children with ADHD for RLS, a family history of RLS, and iron deficiency.”

Additional research published in Pediatrics documents further the adverse effect of intermittent hypoxia and snoring on childrens’ behavior. The authors’ objective:

“Sleep-disordered breathing is associated with impaired behavior and poor academic performance in children. We aimed to determine the extent of behavioral problems in snoring children, clarify the role of intermittent hypoxia, and test the reversibility of impaired behavior and poor academic performance.”

They included 1144 children in their study, correlating snoring, oxygen saturation with pulse oximetry, and impaired behavior using parental questionnaires and academic performance. The evidence was striking:

“HS [habitual snoring] was significantly associated with hyperactive and inattentive behavior , daytime tiredness , and sleepiness. These associations were independent of intermittent hypoxia. HS was also significantly associated with bad conduct, emotional symptoms , and peer problems.“

Moreover, although academic success did not make a big change when snoring ceased, hyperactive and inattentive behavior improved significantly. The authors conclude:

“We suggest that impaired behavior is a key feature of HS independent of intermittent hypoxia and improves when HS ceases.”

We can add to the above evidence another study published in the Archives of Pediatrics & Adolescent Medicine that also investigates the link between iron deficiency and ADHD. In addition to lower hemoglobin…

“Iron deficiency causes abnormal dopaminergic neurotransmission and may contribute to the physiopathology of attention-deficit/hyperactivity disorder (ADHD).”

Again we see serum ferritin levels correlating with the Conners’ Parent Rating Scale scores measuring severity of ADHD symptoms:

“The mean serum ferritin levels were lower in the children with ADHD…In addition, low serum ferritin levels were correlated with more severe general ADHD symptoms measured with Conners’ Parent Rating Scale…These results suggest that low iron stores contribute to ADHD and that ADHD children may benefit from iron supplementation.”

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Even borderline anemia needs attention because it reduces the functional capability of every cell in the body. Iron deficiency anemia can sometimes respond incompletely to iron supplementation for a variety of reasons. Data from the World Health Organization (WHO) suggest that Helicobacter pylori is the most common infection in the world, with research showing links to cardiovascular disease, stomach cancer and other diseases. This paper recently published in the Post Graduate Medical Journal was inspired by the observation that…

“Recent guidelines on iron deficiency anaemia (IDA) have confirmed the aetiological role of Helicobacter pylori (H pylori), but the relationship still remains controversial.”

The authors documented data from eight studies that showed improvement in IDA with increases in hemoglobin and serum ferritin after H. pylori eradication were superior to those seen when iron was given alone. Thus their conclusion:

“H pylori eradication therapy combined with iron administration is more effective than iron administration alone for the treatment of IDA.”

Note: Helicobacter pylori infection is most accurately diagnosed by either stool antigens or a breath test for exhaled gases (not blood or stool antibodies). I have seen excellent results confirmed by follow-up tests with an evidence-based antimicrobial botanical formula.

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Because anemia degrades the ability of the blood to carry oxygen to every cell in the body it has a profound and global affect on function, especially for the brain. Sadly, this is often ‘written off’ in older folks who miss out on the care they need.

Here’s a paper published in the journal Haematologica that opens with…

“Mild anemia is a frequent laboratory finding in the elderly usually disregarded in everyday practice as an innocent bystander.”

They took over three years to investigate the association of mild anemia with hospitalization and mortality in 7,536 subjects. Here’s what their data showed:

“The risk of hospitalization in the 3 years following recruitment was higher among the mildly anemic…Mortality risk in the following 3.5 years was also higher among the mildly anemic elderly…Similar results were found when slightly elevating the lower limit of normal hemoglobin concentration to 12.2 g/dL in women and to 13.2 g/dL in men.”

They conclude with this statement:

“After controlling for many potential confounders, mild grade anemia was found to be prospectively associated with clinically relevant outcomes such as increased risk of hospitalization and all-cause mortality.”

A study published not long ago in the journal Medicine also highlights the fact that even borderline anemia can have a big effect. First they note:

“The occurrence of anemia in older adults has been associated with adverse outcomes including functional decline, disability, morbidity, and mortality.”

In their study…

“Anemia was defined as hemoglobin <13 g/dL for men or <12g/dL for women.”

These levels are almost always ignored by most doctors. Here’s what their data showed:

“Anemia was associated with greater fatigue, lower handgrip strength, increased number of disabilities, and more depressive symptoms. Multivariate regression analysis…demonstrated strong associations for reduced hemoglobin, even within the “normal” range, and poorer health-related quality of life across multiple domains.”

Leading to the conclusion:

“Thus, anemia was independently associated with clinically significant impairments…Mildly low hemoglobin levels, even when above the World Health Organization (WHO) anemia threshold, were associated with significant declines in quality of life among the elderly.”

Another paper published in Current Opinion in Hematology begins with the familiar observation:

“Anemia is common in older adults and is an independent predictor for increased morbidity and mortality in several disease states. Older persons with anemia suffer hospitalization, physical decline, and disability at higher rates than those people without anemia.”

In their study they found that a third of the cases were due to nutritional deficiencies (!), a third from chronic disease, and a third were unexplained (more on that in a future post). They too found that it predicted diminished physical performance and mobility, and reported the same finding that clarifies how we should understand ‘low’:

“The data suggest that the risk of mortality and loss of mobility even extends to levels of hemoglobin normally considered low normal by WHO criteria….”

Practitioners take note of their parting comment:

“Anemia is a common modifiable predictor of poor medical outcome in older adults and, as such, should be actively managed.”

I’ll introduce one more paper published in the Public Library of Science (PLoS One) that focuses on the damage to cognition and mood caused by mild anemia. In this study mood (depression), cognition, attention, memory and quality of life were all quantified for 4,068 individuals. Here’s what their data showed:

“In univariate analyses, mild anemic elderly persons had significantly worse results on almost all cognitive, functional, mood, and QoL (Quality of Life) measures. In multivariable logistic regressions…mild anemia remained significantly associated with measures of selective attention and disease-specific QoL.”

As in other studies, when the reference range was narrowed to a more precise ‘functional’ level, the deleterious effect of mild anemia was clear:

“When the lower limit of normal hemoglobin concentration according to WHO criteria was raised to define anemia (+0.2 g/dL), differences between mild anemic and non anemic elderly persons tended to increase on almost every variable.”

Here’s the bottom line: mild anemia has a profoundly negative impact on every aspect of function and should be investigated diligently as to its cause and treated accordingly.

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Anemia, even low grade, should never be dismissed no matter the primary complaint because it affects the ability of every cell in the body to do its job. Iron deficiency has numerous causes. This fascinating paper recently published in Acta Hæmatologica describes the fairly common phenomenon of iron deficiency anemia (IDA) that does not respond to iron supplementation. The authors state: “Recent studies indicate that 20-27% of patients with unexplained IDA have autoimmune gastritis, about 50% have evidence of active H. pylori infection, and 4-6% have celiac disease. The implications for abnormal iron absorption of celiac disease or autoimmune gastritis are obvious.” [Helicobacter is an extremely common stomach infection and the cause of most gastric ulcers.]

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