Over the last weeks, the description, pathology, and standard care for the 4 most typical wound types (arterial, venous, diabetic, and pressure) have been presented; however, sometimes in spite of the best care using these guidelines, a wound still does not progress. At that point, it is helpful to go back to the two basic questions: Why does the patient have this wound? and Why is the wound not healing? Answering the first question often requires the clinician to think outside the box - maybe it looks typical, but in actuality is a rare or atypical wound. Or maybe there are undiagnosed or undetected contributing factors that have not yet been addressed. This week we will briefly discuss those factors that impede wound healing, and hereafter we will discuss a myriad of atypical wound etiologies.
Infection The presence of significant bacteria in a wound, enough to affect the ability of the cells to reproduce and synthesize new tissue, is often not visible to the eye. Bactericidal agents released by phagocytic cells have consequences on the host tissue, damaging it and creating the chronic pro-inflammatory state that is present in a chronic wound. The effect of the microbes on the wound bed is dependent upon the type of bacteria, the number of colony-forming units (CFUs) per gram of tissue, and the host immune system. Signs of critical colonization (presence of replicating bacteria with significant numbers to affect the wound healing process) are the following: friable granulation tissue, increased exudate, deterioration of the wound bed, increased size of the wound, odor, and failure to respond to standard care. It has been suggested that erythema > 2 cm from the wound edge may be an indication of infection (defined for most bacteria as 105 CFUs per gram of tissue) and is an indication for systemic antibiotics, in which case a culture to determine drug specificity may be indicated. This concern would require communication and collaboration with the medical/infection specialist.
Medication Certain medications are known to interfere with the healing process, including steroids, non-steroidal anti-inflammatory drugs (NSAIDs), anticoagulants, antirejection medications, and chemotherapy. The role of steroids in suppressing the inflammatory healing process is one that often requires a fine balancing act – how minimal a dosage can the patient take without causing exacerbation of the underlying pathology requiring the steroids? Typically, daily dosages of steroids >10 mg/day will stall the healing response. Again, this takes collaboration with the immunology specialist. The role of NSAIDs in suppressing the inflammatory response is especially significant when given in large doses and for longer periods of time. Patients who are taking significant amounts may be advised to use other medications to mitigate pain so that the healing process can advance, as in the case of the patient with the wound in the attached photo. She was taking 800 mg of Motrin per day for pain from the venous wound, and when the wound stalled with standard care, she was willing to eliminate the NSAIDs. Within two weeks the wound was re-epithelializing at the edges and progressed to full closure.
Hyperglycemia Patients with poorly controlled diabetes will have difficulty healing a wound of any etiology, not just a diabetic foot ulcer. Recommended glucose levels for healing, as established by the American Diabetes Association, are 90-130 mg/dL, or hemoglobin A1C <7%. Counseling is advised for any patient who is having difficulty maintaining these levels of glucose control. In addition, for at risk patients who are having wound healing issues, closer examination of glycemic levels may be helpful, and may even lead to the detection of undiagnosed diabetes.
Protein-energy malnutrition (PEM) 20-25 kcal/kg/day and 60-70 grams of protein are required for normal daily activities, depending on age and size; however, healing of post-surgical incisions, large open wounds, burns, and injured tissue may require calorie and protein amounts 30-50% above normal. Albumin, pre-albumin, transferrin, and retinal binding protein levels are measurable lab values that have been used to detect malnutrition, but each has its limitations. The Academy of Nutrition and Dietetics and the American Society for Parenteral and Enteral Nutrition released a joint consensus statement which proposes that 2 or more of the following criteria constitutes a diagnosis of malnutrition:
- Insufficient energy intake
- Weight loss
- Loss of muscle mass
- Loss of subcutaneous fat
- Localized or generalized fluid accumulation that may mask weight loss
- Diminished functional status as measured by hand-grip strength.
Malnutrition may be obvious in the elderly, chronically ill, or indigent population; however, others who are at risk for delayed healing due to PEM include vegan/vegetarians and long-distance runners or athletes who exercise for long periods each day, thus utilizing the metabolic resources for exercise and leaving none for the healing process. Discussing diet and protein intake should be a part of the evaluation of every patient with a non-healing wound.
Stress Having a wound of any size can be stressful, painful, and frightening, especially if it is not healing. That stress, however, can impede the healing process by modulating the immune system. Higher levels of cortisol associated with stress will diminish the expression of pro-inflammatory cytokines needed to initiate and progress wound healing. Strategies to mitigate stress include education and preparation of the patient (especially before treatment), relaxation exercises, topical and systemic pain management, cognitive therapy, physical exercise, and social support.
Social Habits Smoking and vaping are known to impede healing by several mechanisms, including vasoconstriction with reduced blood supply, and thereby decreased nutrients and oxygen, to the injured tissue. In addition, the carbon monoxide associated with cigarettes binds to hemoglobin and thereby decreases the oxygen content of the blood, nicotine decreases fibrinolytic activity and augments platelet adhesion, and hydrogen cyanide impairs cellular oxygen metabolism. Any patient who has an open wound or who is anticipating surgery should be advised to cease smoking in order to optimize wound healing.
Alcohol abuse has also been shown to inhibit all phases of wound healing, and specifically decreases fibroblast migration and angiogenesis during proliferation, and decreases Type 1 collagen production with increased protease activity during remodeling, resulting in weaker extracellular matrix. Heavy drinkers (defined as > 4 drinks/day or 14/week for males, 3 drinks/day or 7/week for females) also have higher rates of hospital-acquired and surgical site infections.
Other factors that influence one’s ability to heal, such as arterial insufficiency and edema, have been discussed previously, but must also be considered when a patient’s wound is not progressing with standard care.
More information on factors that impede wound healing can be found at the following site:
Hamm RL, Luttrell T. Factors that impede wound healing. In Hamm R (Ed), Text and Atlas of Wound Diagnosis and Treatment: 2nd edition. New York: McGraw Hill Education. 2019, 321-346. Available at.
 Collins N, Friedrich L. Appropriately diagnosing malnutrition to improve wound healing. Wound Clin. 2016;10(11):10-12.
 Radek KA, Ranzer MJ, DiPietro LA. Brewing complications: the effect of acute ethanol exposure on wound healing. J Leukoc Biol. 2009;86:1125-1134.