Central Nervous System Monitoring

The primary objective of intensive care is to prevent and treat secondary brain injury (SBI) caused by hypotension, hypoxia, or hyperthermia. We will focus this chapter on traumatic brain injury (TBI) and our objective will be the treatment and prevention of SBI using a neuroprotective strategy to maintain cerebral perfusion in order to meet the brain’s oxygen and metabolic demands. Elevated intracranial pressure (ICP) is an important cause of SBI and associated with very poor outcome after TBI. Elevated ICP can be related to brain edema, vascular engorgement, cerebral contusion, or intracranial mass lesions. The prevention and control of raised ICP and the maintenance of cerebral perfusion pressure (CPP) are essential therapeutic goals after TBI. ICP monitoring has developed an essential role in the treatment of TBI, despite the incredible absence of class-1 studies and its use is only recommended by international consensus guidance [1].

ICP Monitoring
ICP is a very complex variable. Recent consensus (Brain Trauma Foundation) indication for ICP monitoring in TBI include: patients in coma (Glasgow Coma Scale score of 8 or less) with an abnormal head CT scan; patient in coma with a normal head CT scan but at least two other risk factors for elevated ICP (age over 40 years, pathologic motor posturing, systolic BP under 90 mmHg); and in other head injured patients at the physician’s discretion [2].
There is around a 60% chance of raised ICP in patients with these risk factors. Although there are again no class-1 studies, there is some clinical evidence supporting the use of ICP to assess prognosis after severe TBI, to guide therapeutic interventions, and to detect earlier intracranial mass lesions. ICP monitoring is accepted as a low-risk procedure, a decisive clinical decision-making tool, and a high-yield and cost-effective intervention during TBI management.

ICP cannot be precisely estimated from any specific clinical feature or CT finding and must be actually measured [2]. Different methods of ICP monitoring have been described (Table 12.1) but two methods are commonly used at the bedside intraventricular catheters and intraparenchymal catheter-tip micro-transducer systems. An intraventricular catheter, connected to a standard pressure transducer via a fluid filled catheter is the “gold standard” method for monitoring ICP. Ventricular catheters measure global ICP and have the additional advantages of allowing periodic external calibration, administration of drugs, and therapeutic drainage of cerebrospinal fluid (CSF). However, installation may be difficult and their use is complicated by an infection rate up to 11% [4]. Micro transducer-tipped ICP monitors can be located in the brain parenchyma or subdural space, either via a cranial access device (skull bolt) or during a neurosurgical procedure. They are almost as accurate as ventricular catheters and are reliable and easy to use at the bedside [1]. Their infection rates are much lower but the measured pressure may not be representative of true CSF pressure, due to the intraparenchymal pressure gradients that are very common after TBI [1]. In vivo calibration is not possible but the zeroing during surgical installation lies within a clinically acceptable range and is usually as low as 1 mmHg after 5 days of continuous use [1].

Table 1 Intracranial pressure monitoring catheters. Modified from [1]

Absence of Consensus
There is no general consensus on the benefits of ICP monitoring and intense variability in its application. There are also important differences between different centers regarding treatment modalities guided by ICP levels. In the USA, for instance, ICP monitors were placed in only 58% of patients who fulfilled established criteria for monitoring, and therapies to reduce ICP were routinely applied in those patients in whom ICP was not monitored [5]. In a survey carried out by the European Brain Injury Consortium, ICP monitoring was undertaken in only 37% of eligible patients [6] and, in a Canadian study of severe TBI, only 20% of neurosurgeons believed that outcome was affected by ICP monitoring [6]. The Latin American Brain Injury Consortium (LABIC) is now conducting a randomized controlled clinical trial (RCCT) comparing TBI patients with and without ICP monitoring.

Treatment of Intracranial Hypertension
High ICP and low CPP result in cerebral ischemia after TBI and are associated with increased mortality and worse outcome in survivors [7]. Consensus guidance recommends that ICP above 20–25 mmHg should be aggressively treated using a multimodal approach [3].

Sedation and Analgesia
Sedation and analgesia are two crucial components of TBI management [8]. They minimize pain, anxiety and agitation, reduce cerebral metabolic rate, and facilitate mechanical ventilation. Propofol is a widely used sedative agent because it reduces ICP, has profound cerebral metabolic suppressive effects, allows easy control of sedation levels and ICP, and permits rapid wake-up [8]. Other combinations of Midazolam, Fentanyl, and morphine are also very popular.

PaCO2 is a major determinant of cerebral vessel diameter, with its reduction causing cerebral vasoconstriction and therefore a reduction in cerebral blood volume and ICP. Although it has been widely used in the treatment of elevated ICP, it is thought that it can worsen regional ischemia, particularly in the first 24 h after TBI. The routine application of hyperventilation is discouraged and a PaCO2 target of 30–35 mmHg should be used in the first instance. Hyperventilation to lower levels should always be carried out in association with cerebral oxygenation monitoring to avoid cerebral ischemia. Acute hyperventilation is relatively safe only for short-term use (<30 min) and is effective in controlling severely raised ICP while a neurosurgery procedure is prepared. It can also be used in threatened or actual brain herniation.

Hyperosmolar Therapy
Mannitol in bolus (0.5 g/kg) effectively treats elevated ICP and improves outcome, although it has never been subject to an RCCT against placebo [9]. It has at least two mechanisms of action: its plasma-expanding effects causes an increase in cerebral microcirculatory flow and is responsible for the rapid onset of action, and its osmotic effect reduces cerebral edema by drawing water across the blood–brain barrier into the vascular space. Treatment driven by ICP increase is much more effective than treatment oriented by clinical signs [9]. Repeated administration could result in high osmolality (>320 mOsm/l), renal, and neurologic complications.
Hypertonic saline is very effective, even better than mannitol, and its actions are not related just to the hyperosmotic effects, but also to hemodynamic, vasoregulatory, endothelial, immunological, and neurochemical actions [10]. It is efficient in controlling ICP resistant to mannitol and is associated with fewer side effects. However, there are no large RCCTs comparing mannitol and hypertonic saline. Furthermore, there are many concentrations available (1.7–29.2%) and the optimal concentration to lower elevated ICP has not been defined [11]. Based on our own data, we suggest a 3 ml/kg loading bolus in a 7.5% concentration.

Moderate Hypothermia
Moderate hypothermia (33–35°C) has efficient neuroprotective effects in animal studies but human trials have been disappointing, mainly because of infection. We must control this morbidity, which is not that simple, before using it again in humans. In addition, high temperatures are associated with worse outcomes after TBI and are the most important cause of secondary brain injury. Core temperature and cerebral temperature should be continuously monitored and pyrexia must be prevented and aggressively treated.

Barbiturates lower ICP by many mechanisms and, although there is no good evidence that they improve outcome after TBI [12], there has been a resurgence of interest in the use of high-dose barbiturate therapy for the treatment of refractory intracranial pressure [13]. Hypotension is a frequent complication of treatment, and drug accumulation leads to delayed recovery and difficulties in rapid clinical assessment when the drug is discontinued. Continuous EEG monitoring can be used to titrate barbiturate infusion and minimize side effects.

Neurosurgical Procedures
The removal of an expanding intracranial mass lesion is the goal of neurosurgical treatment after TBI. An external ventricular catheter allows drainage of CSF and, because intracranial compliance is reduced, removal of even small CSF volumes can result in a dramatic decrease in ICP. Decompressive craniectomy is an extensive procedure where a large area of the skull vault is removed, and the dura is opened wide to allow brain expansion, with a consequent ICP reduction. There is divided opinion on the relative benefits and risks of the operation [14]. Our group strongly recommends this method, but it must be performed in a small window of time (<8 h after TBI) and the duraplasty must be large and wide to be effective. This controversial issue is currently being addressed by an RCCT—the Rescue ICP study (www.rescueicp.com).

Like all difficult cases and diseases this issue has many controversies and we will address each one.

What is the Target ICP?
Although it is very well recognized that raised ICP correlates with higher risk of mortality and morbidity, not all patients with intracranial hypertension have poor outcome [15]. There is therefore a fundamental dilemma about which patients should be treated and at what ICP level. Furthermore, recent evidence suggests that the duration of intracranial hypertension and its fast response to treatment could be better predictors of neurological outcome than isolated and absolute ICP values [16]. It has also recently been demonstrated that brain resuscitation after TBI based exclusively on control of ICP levels and CPP does not prevent cerebral hypoxia in more than 20% of patients [17]. This is unsurprising because monitoring of ICP and CPP does not tell the whole story. They are global measurements and sometimes a small but very important cerebral region is suffering very much without global modifications. It is impossible to know in an individual patient whether the targeted ICP or CPP is enough to allow the brain’s metabolic demands to be met at a particular moment in time [1]. There is preliminary evidence that therapy directed towards maintenance of brain tissue oxygenation as well as ICP and CPP is associated with reduced mortality after TBI [18].

Does ICP Monitoring and Management Improve Outcome?
In a retrospective study, an “aggressive” management protocol was associated with decreased risk of mortality and shorter length of hospital stay, although there were no differences in functional status in survivors after discharge [5]. Another large retrospective study also concluded that ICP monitoring was associated with significantly decreased mortality [18] but two surveys [19, 20] and one prospective study [21] did not show benefits from ICP monitoring. In general, all studies demonstrated that the use of ICP increased intensity of treatment without clear evidence of improvement in outcome [1].

Complications of Treatment
Conventional approaches to the management of TBI have concentrated on a reduction in ICP to prevent secondary cerebral ischemic injury, but there has been a shift in emphasis from primary control of ICP to a multifaceted approach of maintenance of CPP >70 mmHg and brain protection [1]. The Brain Trauma Foundation now recommends that the CPP target after severe TBI should lie between 50–70 mmHg [3] instead of the previous suggested value >70 mmHg. The previous aggressive attempts to maintain CPP >70 with volume overload and vasopressors caused a fivefold increase in the occurrence of acute lung injury.

Multimodal Monitoring
In addition to the evidence that the control of ICP and CPP may improve outcome after severe TBI, it is also possible that targeting treatment only towards changes in these two variables might be inappropriate because, when changes do occur in these measurements, irreversible ischemic brain damage may already have occurred [1]. So, besides the pressures, it is also necessary to monitor the adequacy of cerebral perfusion, such as measurements of cerebral oxygenation (jugular venous oximetry and brain tissue oxygen tension) and metabolic status (cerebral micro dialysis). Monitoring of several variables simultaneously, the multimodal monitoring (MM), allows cross validation between monitors, artifact rejection, and greater confidence in making the right clinical decision. Developments of MM have allowed a movement away from rigid physiological target setting after TBI toward an individually tailored, patient-specific approach. This new vision provides early warning of impending brain ischemia, prevents secondary brain injury, and guides targeted therapy.

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3. The Brain Trauma Foundation (2007) The American Association of Neurological Surgeons. The joint section on neurotrauma and critical care. J Neurotrauma 24:S1–S106
4. Beer R, Lackner P, Pfausler B, Schmutzhard E (2008) Nosocomial ventriculitis and meningitis in neurocritical care patients. J Neurol 255:1617–1624
5. Bulger EM, Nathens AB, Rivara FP, Moore M, MacKenzie EJ, Jurkovich GJ (2002) Management of severe head injury: Institutional variations in care and effect on outcome. Crit Care Med 30:1870–1876
6. Smith M (2004) Neurocritical Care: Has it come of age? Br J Anesth 93:753–755
7. Balesteri M, Czosnyka M, Hutchinson P (2006) Impact of intracranial pressure and cerebral perfusion pressure on severe disability and mortality after head injury. Neurocrit Care 4:8–13
8. Citerlo G, Cormio M (2003) Sedation in neurointensive care: Advances in understanding and practice. Curr Opin Crit Care 9:120–126
9. Wakai A, Roberts I, Schierhalt G (2007) Mannitol for acute traumatic brain injury. Cochrane Database Syst Rev CD001049
10. Himmelsecher S (2007) Hypertonic saline solutions for treatment of intracranial hypertension. Curr Opin Anaesthesiol 20:414–426
11. White H, Cook D, Venkatesh B (2006) The use of hypertonic saline for treating intracranial hypertension after traumatic brain injury. Anesth Analg 102:1836–1846
12. Roberts I (2000) Barbiturates for acute traumatic brain injury. Cochrane Database Syst Rev CD000033
13. Helmy A, Vizcaychipi M, Gupta AK (2007) Traumatic brain injury: Intensive care management. Br J Anaesth 99:32–42
14. Hutchinson PJ, Kirkpatrick PJ (2004) Decompressive craniectomy in head injury. Curr Opin Crit Care 10:101–194
15. Resnick DK, Marion DW, Carlier P (1997) Outcome analysis of patients with severe head injuries and prolonged intracranial hypertension. J Trauma 42:1108–1111
16. Treggiari MM, Schutz N, Yanez ND, Romand JA (2007) Role of intracranial pressure values and patterns in predicting outcome in traumatic brain injury: A systematic review. Neurocrit Care 6:104–112
17. Stiefel MF, Udoetuk JD, Spiotta AM et al (2006) Conventional neurocritical care and cerebral oxygenation after traumatic brain injury. J Neurosurg 105:568–575
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19. Stocchetti N, Penny KI, Dearden M (2001) Intensive care management of head-injured patients in Europe: A survey from the European brain injury consortium. Intensive Care Med 27:400–406
20. Sahjpaul R, Girotti M (2000) Intracranial pressure monitoring in severe traumatic brain injury—Results of a Canadian survey. Can J Neurol Sci 27:143–147
21. Cremer OL, van Dijk GW, van Wensen E, Brekelmans GJ et al (2005) Effect of intracranial pressure monitoring and targeted intensive care on functional outcome after severe head injury. Crit Care Med 33:2207–2213

Cancer in Children

Pediatric oncology represents only a small fraction of the discipline of oncology. How-ever, the numerous advances in the diagnosis and treatment of childhood cancer have resulted in significant improvements in survival. Approximately 75% of all children diagnosed with malignant neoplasms will survive more than 5 years (Smith & GloecklerReis, 2002).

Cardiovascular Disease

Cardiovascular diseases (CVD), which include stroke, hypertension (HTN), arrhythmias, coronary heart disease (CHD), and heart failure (HF) are major contributors to mortality and morbidity. Although the most prevalent form of CVD is HTN, the majority of CVD deaths are attributed to CHD. The prevalence and incidence of CHD increase dramatically with age and CHD is the leading cause of death in the elderly, with 84% of all CHD deaths in those 65 years of age or older (American Heart association [AHA],2001).

Heart Failure in the Critically ill Older Patient

Heart Failure in the Critically ill Older Patient

Heart failure (HF) is a clinical syndrome that usually develops after sufficient myocardial cell damage has occurred to impair ventricular contractility or relaxation. To maintain tissue and organ viability, the neurohumoral axis is activated. Neurohumoral activation is adaptive initially; however, with time, sustained neurohumoral activation produces symptomatic and progressive HF. There is no cure for HF, although with recent advances in treatment, prognosis can be improved, hospitalizations prevented, and quality of life enhanced. These improvements, however, are modest in most patients (Cleland et al., 2006; Koelling, Chen, Lubwama, L’Italien, & Eagle, 2004; Shahar & Lee, 2000).

Urinary Incontinence in Critically Ill Older Adults

Over 317,000 older adults fracture their hips annually (“HCUP facts and figures,” 2005) and are hospitalized for medical management and surgical repair. Older adults represent 38% of discharged patients from nonfederal hospitals and have greater risks from hospitalization than younger patients (R. M. Palmer, 2006).

Pressure Ulcer Prevention and Management

The cost of pressure ulcers is high, both in terms of suffering caused to the patient and the financial burden on society and the patient (Bennett, Dealey, & Posnett, 2004; Edwards, 1994; Hopkins, Dealey, Bale, Defloor, & Worboys, 2006; Langemo, Melland, Hanson, Olson, & Hunter, 2000; Nixon et al., 2006; Thomson & Brooks, 1999). Pressure ulcer prevalence ranges from 2.3 to 28% in long-term-care facilities (Coleman, Martau, Lin, &Kramer, 2002; Lahmann, Halfens, &Dassen, 2005). Incidence figures on intensive care wards vary between 8 and 40% (National Pressure Ulcer Advisory Panel, 2001). Prevention of pressure ulcers is important from the viewpoint of the patient, care provider, and society.

Wound Healing in the Elderly

Healing wounds is a complicated process and an understanding of the normal function of the skin layers and wound-healing cascade is vital to good outcomes. As people age, changes occur to the skin layers as well as to wound-healing phases that delay or impede the healing process. Complicating the wound-healing process is the fact that a large number of hospitalized elderly will be diagnosed with one or more medical conditions that will also affect wound healing. The combination of these skin layer and wound-healing phase changes in the elderly coupled with medical conditions, including cardiac and respiratory illnesses and diabetes makes it very difficult or impossible to heal chronic wounds such as pressure, arterial, venous, and diabetic ulcers.
This chapter lists the demography of the elderly and the background and significance of wounds. A description of normal skin layers and functions along with the changes that occur as people age follows. The normal wound-healing cascade and changes that occur with the elderly population are then presented. Finally, the influences of poor tissue perfusion, malnutrition, and infection on wound healing are described.
Background and Significance
The treatment of chronic wounds costs Americans billions of dollars annually and a 10% increase in cost for the treatment of chronic wounds is projected per year (Administration on Aging, 2003). Millions of people are affected by one or more chronic wounds each year (Mustoe, O’Shaughnessy, & Kloesters, 2006; Pittmam, 2007). Pressure ulcers, venous stasis ulcers, and diabetic ulcers comprise most of the chronic wounds (Mustoe et al., 2006). The prevalence of chronic wounds is a concern. One hundred and twenty of 100,000 persons between the ages of 45 and 64, 150 of 100,00 persons between the ages of 65 and 74, and 800 of 100,000 persons over the age of 75 have a chronic wound (Pittman, 2007). Three and a half percent of the population 65 years and older have a venous stasis ulcer. The reoccurrence rate of venous stasis ulcers is approximately 70% (Hess & Kirsner, 2003). Seventeen million people have been diagnosed with diabetes. Approximately 15% of those diagnosed with diabetes will develop a diabetic ulcer (Hanft, Temar, & Williams, 2002; Hess & Kirsner). A lower extremity amputation will be necessary in 15 to 20% of those who have a diabetic ulcer and these numbers are predicted to increase as more people are diagnosed with diabetes (Hanft et al.; Hess & Kirsner).
The most common ulcer to occur in the critical care elder is pressure ulcers. The National Pressure Ulcer Advisory Panel (NPUAP) suggests incidence rates of hospitalacquired pressure ulcers range within 0.4 to 38% (NPUAP, 2001). However, the higher incidence rates of 20 to 38% are found in the critical care areas of the hospital. These elders are most vulnerable because of their comorbid conditions. Moreover, there is ample evidence to suggest these ulcers occur very early (within 72 hours) during the critical care stay. The NPUAP suggests that mortality rates are as high as 60% for elders with pressure ulcers within 1 year of hospital discharge. It should be noted that the ulcer may not cause the demise of the elder, but rather is an indicator of the decline in health status posthospitalization.
The prevalence of facility-acquired pressure ulcers reported by the NPUAP in acute-care facilities ranges from 10 to 18%. Patients over the age of 70 account for 70% of hospital-acquired pressure ulcers (Thomas, 2001). Estimated costs of treating patients with pressure ulcers in 2004 dollars are $9.1 to $11.6 billon annually (Zulkowski, Langemo, Posthauer, & NPUAP, 2005. Treatment cost per pressure ulcer was $20,900 to $151,700 dollars (Zulkowski et al.). As of October 1, 2008, the Centers for Medicare and Medicaid Services will no longer pay for any hospital-acquired stage III or stage IV pressure ulcer. Thus, it will be imperative for hospitals to identify and heal these ulcers early in their development.
Skin Layers and Function
The skin is the body’s largest organ; it forms a protective barrier from the external environment and at the same time maintains internal homeostasis (Wysocki, 2007). The thickness of skin varies from 0.5 mm to 6 mm (Wysocki). Skin weighs approximately 6 pounds or is equal to 15% of the entire body mass for an adult (Wysocki). The skin has several functions, including: (a) protection against pathogens, (b) protection against trauma, (c) protection against ultraviolet radiation, (d) thermoregulation, (e) skin immune system, (f) sensation, (g) metabolism of vitamin D, (h) communication, (i) regeneration of new skin cells, (j) elimination of waste products, and (k) expression
of emotions (Allwood & Curry, 2000; Doughty & Sparks-DeFriese, 2007; Langemo & Brown, 2006). The skin is divided into three main layers known as the epidermis, dermis, and subcutaneous. The epidermis and dermis layers are separated by the basement membrane.
The epidermis is avascular and receives oxygen and nourishment by diffusion. Langerhans cells are found in the epidermis and are responsible for identification, uptake, development, arrangement of soluble antigens, and sensitization of T lymphocytes (Wysocki, 2007). The epidermis contains glucose, carbohydrates, and enzymes for energy (Allwood & Curry, 2000). The body’s ability to access this energy is crucial to wound healing. The epidermis contains five layers, including: (a) stratum corneum, (b) stratum lucidum, (c) stratum granulosum, (d) stratum spinosum, and (e) stratum germinativum (Allwood & Curry; Wysocki). The description and function of the epidermis layers are listed in Table.1 (Allwood & Curry; Wysocki).

Table·1 Functions of the Epidermis Layers
Epidermis Layers
Description and Function
Stratum corneum
Top layer (.02 mm to .5 mm) Composed of dead keratinocytes Flat cells without nuclei Cells shed continually Cells consist of keratin (a tough, fibrous, insoluable protein) Protects from external stimulus entering the body Averts water loss
Stratum lucidum

Established in thick epidermis of the palms of the hands and soles of the feet One to five cells deep Transparent layer Cells are nonviable Consists of prekeratin filament and protein Protects from friction by the toughness of the layer
Stratum granulosum

Granular layer One to five cells deep Diamond shaped not flattened Contains proteins to help organize the keratin filament
Stratum spinosum

Spinous layer Contains the desmosome, which is a cell–cell junction Polyhedral Produces involucrin (precursor to cornified envelopes) Contains new keratin filaments
Stratum germinativum

Basal layer
Single layer of basal keratinocytes Respond to extracellular matrix, growth factors, hormones, and vitamins As cells leave the basal layer differentiation begins Consists of Rete ridges that assist in the adherence of the epidermis to the dermis Melanocytes for skin pigmentation

The dermis layer is the thickest part of the skin ranging from 2 mm to 4 mm deep (Wysocki, 2007). The dermis contains cells, nerves, skin appendages, and blood vessels. The dermis layer is divided into two layers known as the papillary dermis and reticular layer. The papillary dermis is responsible for the nourishment and oxygenation of the viable cells of the epidermis (Allwood & Curry, 2000; Wysocki). The reticular layer contains hair follicles, nerve sensory endings, sweat glands, and sebaceous glands. The reticular layer of the dermis is accountable for the skin’s sturdiness and strength (Allwood & Curry).
Two primary proteins found in the dermis are collagen and elastin. Collagen is a structural protein that is matured by secreted tropocollagen from dermal fibroblasts and an extracellular course (Allwood & Curry, 2000; Wysocki, 2007). The dermis consists of type I fiber-forming collagen, which provides the skin’s tensile strength (Wysocki). Elastin is a protein that is fiber forming, which provides elastic recoil to the skin (Allwood & Curry; Wysocki). Elastin forms structures similar to a coil or spring that can be stretched and returned to its original shape (Wysocki).
Three main cell types found in the dermis are fibroblasts, macrophages, and mast cells. Their functions are listed in Table.2 (Allwood & Curry; Wysocki).
The subcutaneous layer contains loose connective tissue. This layer connects the dermis to the muscle (Allwood & Curry, 2000). This layer provides vascularization, insulation, energy stores, mobility of the skin, and cushioning for underlying structures (Wysocki, 2007).
Table·2 Cell Type and Function
Cell Type

·        Most abundant cell
·        Forms connective tissue
·        Secretes growth factors


·        Derived from tissue monocytes from bone marrow precursor cells
·        Most important cell due to their adaptability
·        Secrete growth factors, cytokines, and immune molecules
·        Antibacterial effects
·        Coagulation
·        Angiogenesis
·        Tissue remodeling
·        Phagocytosis of debris and foreign bodies
·        Vital in reabsorption and recycling of tissue and their components
·        Participate in immune response
·        Critical in wound healing
Mast cell

·        Found surrounding vascular connective tissue
·        Mainly in the papillary layer and subcutaneous tissue
·        Secrete proteins
·        Responsible for the release of histamines with injury, infection, and exposure to allergens
·        Numerous in subacute and chronic inflammatory diseases
·        Phagocytosis

Skin Layer Function Changes in the Elderly
All three of the skin layers are present as people age but changes occur within these layers that affect wound healing. The changes to the epidermis, dermis, and subcutaneous layer begin in the third decade of life and these changes continue over many years (Allwood & Curry, 2000; Doughty & Sparks-DeFriese, 2007). Some of these changes are visible in the second decade of life as a result of excessive exposure to sunlight (Montagna & Carlisle, 1979). Major changes are evident at approximately 70 years old (Doughty &Sparks-DeFriese). The epidermal and dermal junction flattens, which increases shear-injury risk (Pittman, 2007). Changes that occur within the three skin layers are described in Table.3 (Allwood & Curry; Baranoski, 2001; Gosain & DiPietro, 2004; Doughty & Sparks-DeFriese; Johnson, 1996; Montagna & Carlisle; Pittman; Roberts, 2007; Vohra & McCollum, 1994; Witkowski & Parish, 2000).
Repair Mechanisms
Repair occurs by two different mechanisms. The first mechanism is regeneration, which is tissue repair. The second mechanism is scar tissue formation or connective tissue repair. The mechanism for repair depends on the depth of the tissue damage. Partial thickness, which involves the epidermis and dermis layers, heals by regeneration. Full thickness, which extends past the dermis layer, heals by connective tissue repair.

Table·3 Skin Changes in the Elderly
Layer Changes
Epidermal layer

·        Epidermal turnover time increases, which delays wound healing time
·        The barrier protection function is deceased, which increases the risk for irritation and breakdown of the skin
·        A decrease in the amount of Langerhans cell production increases the risk of cancer and infection
·        A decrease in Langerhans cell production decreases immunity properties of the skin
·        Melanocytes are decreased as well as an abnormal production of melanocytes, which decrease protection against ultraviolet radiation Reduction in sensation, which increases the risk for trauma and injury
Dermal layer

·        Dermis decreases in thickness and appears flatter and thinner
·        Decrease in the number of sweat glands: hypothermia and heat stoke are more likely
·        Decreased vascular components, approximately 35% of vertical capillary loops
·        Blood vessels are more pronounced
·        Skin elasticity decreases, which is related to age and sun damage
·        Collagen appears to be unwinding and elastin appears to be lysing
·        Wrinkling and sagging occur
·        Decreased skin turgor is apparent
·        Structure is irregularly shaped
·        Dehydration of skin
·        Decreased macrophage production
·        Decreased inflammatory response
·        Decrease in mast cells and melanocytes, which affects allergic reactions
·        Healing time is delayed
·        Bruising and purpura are evident

·        Decreased amount of subcutaneous fat layer
·        Decrease in thermoregulation
·        Decreased insulation to extremities
·        Decreased skin fold breadth
Normal Wound-Healing Cascade
The normal wound-healing cascade is a complex process that is activated the instant damage occurs to the skin. Knowledge of normal wound-healing phases is essential for the clinician in order to understand the changes that occur as people age. The normal wound-healing cascade and the cell functions will be described in the following sections.
Some literature combines the vascular response and inflammatory phase because homeostasis occurs simultaneously with the inflammatory phase (Ayello et al., 2004). Homeostasis is achieved when vasoconstriction of the blood vessels occurs and platelets arrive at the wound. A blood clot is formed by the platelets to hinder blood loss Hess & Kirsner, 2003). Blood clotting is started by commencement of a proteolytic cascade that produces thrombin and fibrin (Knighton, Fiegel, Doucette, Fylling, & Cerra, 1989; Shultz & Mast, 1998). Thrombin works together with platelets to create alpha granule release of platelet growth factors (Knighton et al.). Fibrin creates the blood clot, which consists of fibrin, red blood cells, and platelets (Knighton et al., Shultz & Mast). The blood clot is a new matrix that seals the wound and protects it from bacterial invasion and water loss (Mast & Schultz, 1996). Following this initial response, vasodilatation and increased capillary permeability occur, which causes leakage of plasma (Ayello et al., Schultz et al., 2003).
Platelet degranulation provides the first signals to begin the wound-healing cascade. Alpha granule of the platelets contain growth factors, which are: (a) platelet derived growth factors (PDGF), (b) insulin-like growth factor-1 (IGF-1), (c) epidermal growth factors (EGF), (d) fibroblast growth factor (FGF), and (e) transforming growth factor-Β (TGF-Β) (Schultz et al., 2003). These growth factors are released from platelets and leave the wound, migrating into the surrounding tissue and blood vessels (Mast & Schultz, 1996). Growth factors release signals to inflammatory cells as a response to injured cells (Hess & Kirsner, 2003). Growth factors stimulate production, movement, and delineation of wound cells that include epithelial cells, fibroblasts, and endothelial cells (Ayello et al., 2004). This begins the inflammatory phase of wound healing, which is catabolic. Growth factors and functions are described in Table.4 (Morykwas & Argenta, 1997; Okan, Woo, Ayello, & Sibbald, 2007; Woo, Ayello, & Sibbald, 2007).
Growth Factors and Functions
Growth Factors
Platelet derived growth factors (PDGF)
Derived from platelets, fibroblasts, keratinocytes, and macrophages
·        Deposition of extracellular matrix
·        Angiogenesis
·        Fibroblast and immune cell initiation
·        Increases collagen synthesis
·        Increases TIMP synthesis
·        Decreases MMP synthesis
Insulin-like growthfactor-1 (IGF-1)
Derived from fibroblasts, neutrophils and macrophages
·        Stimulation of keratinocytes and fibroblasts
·        Initiation of endothelial cell
·        Angiogenesis
·        Collagen synthesis
·        Deposition of extracellular matrix
·        Metabolism of cells
Epidermal growth factors (EGF)
Derived from fibroblasts, keratinocytes and macrophages
·        Stimulation and movement of keratinocytes
·        Deposition of extracellular matrix
Fibroblast growth factor (FGF)
Derived from fibroblasts, endothelial cells, and macrophages
·        Deposition of extracellular matrix
·        Angiogenesis
·        Initiation of endothelial cell
·        Stimulation and movement of keratinocytes
Transforming growth factor-B (TGF-Β)
Derived from platelets, fibroblasts, and macrophages
·        Chemoattractant to fibroblasts
·        Deposition of extracellular matrix
·        Increases collagen synthesis
·        Increases TIMP synthesis
·        Decreases MMP synthesis

Inflammatory Phase
The first cells to arrive to the wound and initiate phagocytosis are polymorphonuclear neutrophils (PMN) (Hess & Kirsner, 2003). These are blood-borne cells that protect the host from bacteria and infection. Neutrophils release tumor necrosis factor-a (TNFa) and interleukins IL-2 and Il-4, which are proinflammatory cytokines that work at the site of injury (Mast & Schultz, 1996). Neutrophils also release matrix metalloproteinase eight (MMP-8), which consists of neutrophil elastase and neutrophil collagenase (Schultz & Mast, 1998). The purpose of MMP-8 is to remove the damaged extracellular matrix, which is replaced with new extracellular matrix (Schultz & Mast). This action allows for the wound-healing cascade to continue in a proper sequence. The number of neutrophils present decreases dramatically within 72 hours after the initial injury has occurred.
Monocytes are crucial in the inflammatory phase. Monocytes are blood-borne cells that are attracted to the wound by complement-derived peptides (C5a), degradation products from fibronectin, and TGF-Β (Knighton et al., 1989). Monocytes mature into macrophages within 24 to 48 hours after the injury has occurred (Hess & Kirsner, 2003; Knighton et al.).
Macrophages are considered the most important of the wound cells because they are involved in all phases of wound healing (Frenkel et al., 2002). Macrophages replace neutrophils in the wound and are responsible for several actions during the inflammatory phase. They initiate phagocytosis, which breaks down dead cells and the damaged matrix (Hess & Kirsner, 2003). Macrophages are bactericidal and promote angiogenesis (Ayello et al., 2004).
Macrophages secrete more growth factors and signal for additional macrophages and monocytes to respond to the wound as a result of their chemoattractant properties (Schultz et al., 2003). Macrophages secrete proinflammatory cytokines that attract inflammatory cells into the wound from the surrounding blood vessels (Frenkel et al., 2002). The proinflammatory cytokines are TNF-a ´ and interleukins IL-1, IL-6, and IL-8. IL-1 and TNF-a ´ rouse vascular endothelial cells to express cell bonding (Schultz & Mast, 1998). The IL-1 and TNF-a ´ are mitogenic with fibroblasts, MMP expression is up regulated, and tissue inhibitors of metalloproteinases (TIMPs) are down regulated (Schultz & Mast). The vascular cells construct IL-8 as a response to IL-1 and TNF-a ´ to express cell bonding on the inflammatory cells (Schultz & Mast). IL-6 is responsible for fibroblast production and protein synthesis (Schultz et al., 2003). Amino acids and sugars are converted from macromolecules by macrophages for wound healing (Hess & Kirsner, 2003).
Mast cells are derived from the dermis. One function of these cells is local inflammation, which increases the sensation of pain. Another function of the mast cell is to increase vascular permeability. Histamines, prostaglandins, leukotrienes, and enzymes are released by mast cells.
Proliferative Phase
The next phase of wound healing is the proliferative phase or the connective tissue phase, which is anabolic. This phase can last for several weeks (Hess & Kirsner, 2003). During the proliferative phase, the number of inflammatory cells decreases and is replaced by fibroblasts, endothelial cells, and keratinocytes (Ayello et al., 2004). Macrophages are mediators for the initiation of the proliferative phase (Frenkel et al., 2001). The proliferative phase is initiated by the stimulation of the movement of fibroblasts, epithelial cells, and vascular endothelial cells to begin the healing of the wound by the formation of granulation tissue (Schultz et al., 2003). Cell movement and production persist as a temporary matrix is created, which contains fibrin and fibronectin (Ayello et al.; Schultz et al.). Granulation tissue replaces the temporary matrix as it fills the wound cavity. Granulation tissue provides a moist surface for cell migration. A decrease in wound dimension occurs as the wound edges contract together, lessening the wound-surface dimension as the wound fills with granulation tissue. Granulation tissue is vastly vascular and damage to this tissue occurs easily. Granulation tissue contains fibroblasts, keratinocytes, macrophages, immature collagen, endothelial cells, and new blood vessels (Hess & Kirsner, 2003).
Approximately 5 days after injury fibroblasts arrive to the wound. Fibroblasts secrete PDGF, IGF-1, bFGF, TGF-a , and keratinocyte growth factor (KGF). Fibroblasts stimulate production of cells, creation of extracellular proteins, and formation of new blood vessels (Ayello et al., 2004; Schultz & Mast, 1998). Fibroblasts produce and release collagen, a major connective tissue protein, as well as elastin and proteoglycans molecules (Ayello et al.). Fibroblasts initiate the production of collagen, which gives the tissue strength and composition (Hess & Kirsner, 2003). Fibroblasts do not perform phagocytosis so dead cells and a damaged matrix impede the migration of these cells.
Keratinocytes are the main cells of the epidermal layer and travel from the wound edges for epithelialization (Hess & Kirsner, 2003; Woo et al., 2007). Epithelialization is the last step in the proliferative phase. Keratinocytes form scar tissue as they travel and reproduce across the wound bed only with the existence of healthy granulation tissue (Hess & Kirsner). Growth factors and cytokines synthesized by keratinocytes are TGF-a ˆ , TNF-a ´ , and Il-1/A, which stimulate cell production, extracellular protein formation, and angiogenesis (Mast & Schultz, 1996). Keratinocyte’s five main functions are to (a) assist with proliferation of cells, (b) attract other cells to the wound, (c) provide antibacterial properties, (d) initiate epithelialization, and (e) signal transduction activity (Woo et al., 2007).
Endothelial cells promote development of new blood vessels quickly, which are necessary for nutrition for the new tissue. These cells stimulate fibrinolysis, breaking down the temporary matrix so fibroblast movement and collagen synthesis can occur. The growth factors synthesized by endothelial cells are vascular endothelial growth factors (VEGF), bFGF and PDGF (Mast & Schultz, 1996).
Maturation Phase
The final phase is the maturation phase or the remodeling phase. This phase can take months to years and is catabolic. Collagen fibers are the main substance in the wound and fiber collection increases creating a thick collagenous arrangement. Fibroblasts, MMPs, TIMPs, and TGF are vital to organizing, remodeling, and maturing the collagen fibers (Hess & Kirsner, 2003). Fibroblasts stimulate production of collagen, elastin, proteoglycans, MMPs, and TIMPs (Mast & Schultz, 1996). This action persists until the tensile strength of scar tissue is approximately 80% of normal tissue (Hess & Kirsner). Apoptosis or programmed cell death decreases fibroblast and capillary density (Ayello et al., 2004). Scar tissue decreases and the appearance of the scar tissue becomes less red and flat over time (Ayello et al.). This is known as the remodeling of the scar.
Wound Healing Alterations in Animal Models
Ashcroft, Horan, andFerguson (1997)
Rate of healing is dependent on the cause, depth, and site of injury
Absence or presence of comorbidities affects wound healing Age-related changes were noted in the rate and quality of wound healing
A delay in inflammatory response was noted due to monocytes/macrophage and B-lymphocyte migration
Decrease in the number of cytokines released or a damaged migration response
Decreased action of macrophages Decrease in plasma fibronectin, which could affect attachment and migration of cells A delay of epithelialization was observed
Quirinia and Viidik (1991)
Ischemia affects wound healing more significantly in older rats then younger rats
Repair of vascular components should be a priority intervention Ischemia is more harmful during the beginning stages of wound healing Ischemic wounds are more susceptible to infections that impair the inflammatory phase
Swift, Burns, Gray, andDiPietro (2001)
Neutrophil migration was unchanged in excisional wounds but macrophagemigration was significant
Increase in the number of macrophages but the action of the macrophages was decreased
A reduction in phagocytosis as well as the amount of damaged matrix that was affected
Reduction of signaling from cell surface Macrophage secretion of VEGF for angiogenesis was reduced T-cell migration is delayed as well as altered actions of the cells Inflammatory and proliferative responses are significantly reduced with chemokine-production alterations
Wound-Healing Cascade Changes in the Older Adult
Changes in the rate of healing time have been reported in the literature among the fetus, children, adults, and the elderly (Stotts & Wipke-Tevis, 2001). The woundhealing process is greatly affected when elders have one or more medical conditions.
As a person ages, wounds heal slower as well as become chronic because of a delayed inflammatory phase when one or more chronic diseases are present (Stotts & WipkeTevis). This can be attributed to changes within the wound-healing cascade as well as the influence of chronic disease and medications that affect tissue perfusion (Gusenoff, Redett, &Nahabedian, 2002; Langemo &Brown, 2006; Stotts &Wipke-Tevis). Malnutrition and infection contribute to impeded wound healing in the elderly (Gusenoff et al.; Stotts & Wipke-Tevis).
Wound-healing studies are limited with human subjects for ethical reasons. Researchers have established that changes occur during the wound-healing cascade, which include (a) an increase of adherence of the platelets to the endothelium; (b) increase of the release of alpha-granules by platelets; (c) a decreased amount of nitric acid by endothelial cells; (d) a decrease of neutrophils; (e) decrease in the response from keratinocytes, fibroblasts, and endothelial cells; and (f) a decrease in collagen (Allwood & Curry, 2000; Doughty & Sparks-DeFriese, 2007). The existence of a direct correlation between animal models and human models is unknown (Swift, Burns, Gray, & DiPietro, 2001). However, three studies using animal models describe changes that occur within the wound-healing cascade, these are described in Table.5 (Ashcroft, Horan, & Ferguson, 1997; Quirinia & Viidik, 1991; Swift et al.). Other researchers have observed that injecting activated monocytes/macrophages into wounds increases the healing rate of pressure ulcers in the elderly and spinal cord injured (Frenkel et al., 2001, 2002).
The most important factor in aiding the wound-healing process in elders in critical care is increasing tissue perfusion. This can be incredibly challenging for critically ill elders who have hemodynamic challenges. The wound cannot heal without sufficient blood supply. Intrinsic factors such as anemia, diabetes, cardiovascular disease, hypotension, chronic obstructive pulmonary disease, low blood protein levels, high temperature, and smoking can increase demand for oxygen and the metabolic rate (Doughty & Sparks-DeFriese, 2007; Grey, Harding & Enoch, 2006; Stotts & Wipke-Tevis, 2001). Severe anemia affects tissue perfusion, which decreases the oxygen transportation capability of the blood (Langemo & Brown, 2006; Phillips, 1999; Stotts & Wipke-Tevis). Macrovascular and microvascular changes in the circulatory system in diabetic patients reduce tissue perfusion (Baranoski, 2006; Phillips, 1999). Patients with cardiovascular disease who have low ejection fractions have a reduction in tissue perfusion and low capillary closing (Calianno, 2000). An elevation of 1 degree in body temperature increases oxygen demand and metabolic rate by 10% (Andrychuk, 1998).
Oxygen requirements vary depending on the wound-healing phase. The inflammatory phase has the highest requirement (Doughty & Sparks-DeFriese, 2007). Bactericidal activity is more effective with higher oxygen levels (Doughty & Sparks-DeFriese). Improved collagen synthesis and tensile strength are reported with higher levels of oxygen (Doughty & Sparks-DeFriese). The proliferative phase requires lower oxygen levels (Doughty & Sparks-DeFriese). A degree of hypoxia in the wound can enhance angiogenesis (Doughty & Sparks-DeFriese).
Certain medications that are prescribed to treat chronic diseases can affect the skin layers and wound-healing cascade (Doughty &Sparks-DeFriese, 2005). Corticosteroids impede regeneration of the epidermis and collagen synthesis (Allwood & Curry, 2000; Baranoski, 2006; Tashkin, Murray, Skeans, & Murray, 2004; Torres & Stadelmann, 2006). Antibiotics, corticosteroids, and hormones can change the skin’s protective barrier function. The inflammatory response is affected by other medications such as analgesics, antihistamines, and nonsteroidal antiinflammatory agents (Doughty & Sparks-DeFriese). Antihypertension, vasoactive medications and diuretics may cause hypotension and dehydration of the skin (Andrychuk, 1998). Chemotherapy medications may interrupt the cell cycle and production of cells (Andrychuk).
Malnutrition and a lack of hydration impede wound healing (Cutting & Cardiff, 1994; Ratliff & Bryant, 2004; Stotts & Wipke-Tevis, 2001). Low protein serum levels are linked with delayed wound healing (Calianno, 2000; Grey et al., 2006). Collagen synthesis is reduced with low blood protein levels so tissue is thinner, which impedes wound healing (Phillips, 1999; Torres & Stadelmann, 2006). Functions of protein include reproduction of cells, construction of antibodies, alteration of the wound, creation of blood vessels, and promotion of collagen synthesis (Andrychuk, 1998). Adequate intake of protein, calories, fat, vitamins, and minerals are vital for suitable nutrition for wound healing (Stechmiller, 2003; Stotts & Wipke-Tevis, 2001). Dehydration is also correlated with wound healing because of drying of the skin (Posthauer, 2006).
Bacteria from surrounding skin contaminate the wound within 24 hours (Mustoe et al., 2006). High levels of bacteria in wounds can delay or impede wound healing (Cutting & Cardiff, 1994; Ovington, 2001). Chronic wounds are contaminated with bacteria (McGuckin, Goldman, Bolton, & Salcido, 2003; Ovington, 2002). Patients can present with fevers; tachycardia, hypotension, delirium, leukocytosis, or high glucose levels, which affect tissue perfusion and oxygen demands (McGuckin et al.). High quantities of bacteria are found in chronic wounds, which result in a prolonged inflammatory phases (Dow, Browne, & Sibbald, 1999). Inflammatory cells are constantly released, neutrophils continue to migrate to the wound, and thrombosis and vasoconstriction persist (Dow et al.; Falanga, 2002). A reduction in oxygen in a wound results in production of bacteria, damage of tissue, and reduction of platelets (Dow et al). Infected wounds have increased drainage, which alters the production and function of wound cells (Falanga). Extracellular matrix proteins are damaged by proteases that are found in the exudate (Falanga). Copious amounts of drainage can affect growth factors as well as fibroblasts and keratinocytes, which are necessary for wound healing (Falanga).
The management principles to consider in healing wounds in critical care are multifactorial. Thus, you have to understand the unique needs of the critically ill older adult. Assessing the patient as a whole and not simply the whole in the patient is critical. However, several management principles should be considered in wound healing in older adults (Brem & Lyder, 2004). The use of support surfaces to offload pressure (alternating air mattresses, low-air-loss mattresses or air-fluidized mattresses) is critical. Further, the use of frequent turning (every 1 to 2 hours) is beneficial. The removal of debris and/or necrotic tissue in the wound bed, as this may lead to wound infection is necessary. If infection is noted, it is imperative to use silver dressings or to implement IV antibiotics. The use of cleansing solutions or debridement may be very helpful in removing wound debris and/or necrotic tissue. Meeting the nutritional requirements for the critically ill older adults is important as wounds heal with a positive nitrogen balance. If too much protein is lost healing will be delayed as low protein stores lead to negative nitrogen balance, which will further delay healing. Finally, the principle of moist wound healing should be employed. Wounds heal faster when they are moist. Too much exudate may macerate surrounding tissue and if the wound is too dry, granulation tissue will not proliferate.
Figure. 1 
Deep tissue injury pressure ulcer.

Deep tissue injury pressure ulcer

Assessment of the pressure ulcer in the intensive care unit revealed a 5 cm x 5 cm x 0 cm ulcer with a thick yellow brown necrotic area. There was no odor or drainage. The edges were not demarcated. The periulcer tissue was indurated with erythema
Initial treatment included chemical and sharp debridement of thick yellow brown tissue. Bone was revealed in the base of the wound and osteomyelitis was diagnosed. The tissue in the base of the wound was pale pink with edema. Negative pressure wound therapy was started with silver foam dressing once the necrotic tissue was removed and antibiotic therapy was initiated. Patient had a myocutaneous flap placed 2 weeks later.
The patient was unable to receive his heart transplant until the sacral pressure ulcer healed. He eventually received the heart transplant and was discharged home.

Figure·2 Stage IV pressure ulcer.
Stage IV pressure ulcer

Wound healing is a complex process that is affected as people age. Researchers have shown that changes occur within the skin layers and wound-healing cascade that can slow the healing process. These changes can be complicated by chronic disease, medications, nutrition, and infection, which makes it very difficult or impossible to heal chronic wounds such as pressure, arterial, venous, and diabetic ulcers. It is critical for clinicians caring for critically ill older adults to understand the wound-healing processes to optimize treatment.
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