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The Journal of Bone and Joint Surgery (American). 2006;88:2060-2068. doi:10.2106/JBJS.F.00049 © 2006 The Journal of Bone and Joint Surgery, Inc.
Postoperative Delirium After Hip Fracture
1 Department of Orthopaedic Surgery, University of Minnesota, 2450 Riverside
Avenue South, Suite R200, Minneapolis, MN 55454. E-mail address:
benbeckyr{at}yahoo.com
The authors did not receive grants or outside funding in support of their
research for or preparation of this manuscript. They did not receive payments
or other benefits or a commitment or agreement to provide such benefits from a
commercial entity. No commercial entity paid or directed, or agreed to pay or
direct, any benefits to any research fund, foundation, educational
institution, or other charitable or nonprofit organization with which the
authors are affiliated or associated.
A hip fracture is sustained by 250,000 Americans every year1, and that number is expected to double by 20402. The most frequent complication associated with hip fracture in elderly patients is postoperative delirium3, with a prevalence ranging between 5% and 61%, depending on the patient population1,3-8. Delirium is often undetected, misdiagnosed, or undertreated9-11. However, this condition has severe consequences for the patient4,5,11. The focus of this article is to provide an overview of current knowledge regarding the outcomes, pathogenesis, diagnosis, prevention, and treatment of postoperative delirium in elderly patients treated for a hip fracture.
For the purposes of this article, delirium and acute confusional states are synonymous. Delirium consists of a "disturbance of consciousness.... with reduced ability to focus, sustain, or shift attention." There is also "a change in cognition... or the development of a perceptual disturbance that is not better accounted for by a preexisting, established, or evolving dementia."12 The diagnostic criteria for delirium have been established by the American Psychiatric Association (Table I)12. It is important to be aware of, and to use, these criteria because many of the signs and symptoms of delirium are also associated with conditions such as dementia, depression, and psychosis. Table II summarizes some of the distinguishing characteristics of these diagnoses13.
Deep vein thrombosis and the subsequent risk of death from pulmonary embolus have received a great deal of attention in the orthopaedic literature. The morbidity and mortality associated with postoperative delirium are far greater than those associated with deep vein thrombosis6, and yet postoperative delirium has received very little attention in the orthopaedic literature. Gustafson et al. studied 111 consecutive patients who had undergone surgery for a femoral neck fracture6. They evaluated the patients for preexisting dementia and, with use of the DSM-III6 (Diagnostic and Statistical Manual of Mental Disorders, Third Edition), examined them preoperatively and postoperatively for the development of delirium. Sixty-eight (61%) of the 111 patients became acutely confused: 33% were in an acute confusional state preoperatively and another 28% were in an acute confusional state postoperatively. Gustafson et al. followed all patients for six months after the operation and found a significant difference in the length of the stay in the hospital (p < 0.05) as well as in postoperative complications such as urinary incontinence (p = 0.0005), feeding problems (p = 0.05), and decubitus ulcers (p = 0.01). In addition, patients with delirium had an increased likelihood of dying or being placed in a nursing home for the first time, and they were less likely to regain their prefracture walking level. In a similar study, Marcantonio et al. evaluated 126 consecutive patients, more than sixty-five years old, who had sustained a hip fracture1. They examined them preoperatively, daily after the operation, and at one and six months postoperatively. Delirium developed in 41% (fifty-two) of the 126 patients; it persisted in fifteen patients at one month and in three patients at six months. Patients who had delirium had a significantly greater decline in activities of daily living (odds ratio, 2.6; 95% confidence interval, 1.1 to 6.1), a significantly greater decline in walking ability (odds ratio, 2.6; 95% confidence interval, 1.03 to 6.5), and a significantly higher rate of death or new placement in a nursing home (odds ratio, 3.0; 95% confidence interval, 1.1 to 8.4) during the follow-up period than those without delirium. In addition, patients whose delirium persisted had worse outcomes in those categories than patients whose delirium resolved. Edelstein et al. followed 921 patients for the development of delirium after hip fracture5. Although they reported a much lower prevalence (5.1%) than the authors mentioned above, they examined the patients for delirium at only one point in time after the operation and they selected healthier patients with their inclusion and exclusion criteria. They did show that patients with delirium had a significant increase in the length of the overall hospital stay (p < 0.001) and increased mortality (p = 0.02) at one year. In addition, their patients were less likely to regain their prefracture level of walking (p = 0.03) and activities of daily living (p < 0.001). Medically ill elderly individuals in whom delirium develops during hospitalization have an increased chance of dying during that hospitalization (an 11% rate of death in the first month after discharge and a 25% rate within six months12). The above reports document the substantial impact of delirium on patient outcomes, with increased rates of mortality or new nursing home placement postoperatively and longer, more expensive14 hospital stays. Prolonged delirium is also a risk factor for the development or worsening of dementia. Finally, delirium is upsetting for the patient and their loved ones. For all of these reasons, delirium requires our attention.
The pathogenesis of delirium is not fully understood. Part of the difficulty in studying delirium stems from the fact that it is transient and may often have multiple underlying causes15-19. Delirium has been considered to be a generalized, nonspecific dysfunction of the higher cortical processes because electroencephalograms of delirious patients have shown diffuse slowing16,18. However, studies of animals15 as well as studies of lesions in patients who have sustained a stroke or traumatic brain injury and functional brain imaging in humans18 offer insight regarding which areas of the brain and which neurotransmitters are primarily affected.
Similar to specific tracts in the spinal cord, there are tracts within the brain that are involved in our higher cortical functioning. These tracts are best thought of as parallel yet integrated circuits19,20. Wakefulness, attention, mood, and sleep appear to require sustained coherent activity in these various corticothalamic networks. These neural networks seem to be uniquely sensitive to the metabolic and other changes that are thought to generate delirium. Areas in the parietal and temporal cortices related to attention as well as in the reticular activating system in the brainstem are also affected18-23. Within the brain, there are a number of neurotransmitters that are responsible for overall brain function15-18,24. There are two major neurotransmitters: gamma-aminobutyric acid, which is inhibitory, and glutamate, which is excitatory. There are also four modulatory neurotransmitters that are very important in brain function and dysfunction: acetylcholine, dopamine, serotonin, and norepinephrine. Psychiatrists target these modulatory neurotransmitters with various psychotropic medications in order to treat psychiatric illnesses25-27. Alterations in each of these neurotransmitters have been found in patients with delirium15-19. In addition, these neurotransmitter systems are not mutually exclusive but interact extensively24. A decrease in acetylcholine and an increase in dopamine appear to have important roles in the development of delirium15,17,19. Decreased acetylcholine is also found in dementia28. Acetylcholine is important in arousal, attention, memory, and rapid eye movement (REM) sleep, all of which can be affected during delirium15,17,19. Delirium can be induced experimentally by administering anticholinergic drugs, and it can be reversed by administering physostigmine (a cholinergic agent) or antipsychotic medications such as haloperidol19. Furthermore, serum levels of anticholinergic activity, which are usually measured only in research settings, are increased during delirium, and higher levels correlate with greater cognitive impairment. Dopamine, on the other hand, is thought to change reciprocally with acetylcholine15,19; intoxication with dopamine can induce delirium19. The use of postoperative opiates can contribute to delirium by increasing dopamine activity while decreasing acetylcholine levels19. Hypoglycemia or hypoxia also can result in decreased levels of acetylcholine and, in susceptible individuals, delirium19,29,30. Finally, anything that causes an inflammatory response, such as infection, trauma, or operative intervention, causes the release of cytokines15,17. Cytokines, which include interleukins, tumor necrosis factor (TNF), and interferon-alpha, also increase dopamine levels and decrease acetylcholine levels15,17,31. The impact of aging on the brain also needs to be considered17. With aging, there are morphologic changes in the brain, including a decrease in overall volume, a decrease in the number and volume of neurons, and a loss of dendrites and synapses. In addition to these morphologic changes, there are hormonal changes, such as an increased basal level of cortisol. Also, there is an overall decrease in the level of acetylcholine as a result of a decrease in choline acetyl transferase activity, which is important in acetylcholine synthesis, combined with no change in acetylcholinesterase, the enzyme responsible for acetylcholine breakdown. This decrease in acetylcholine contributes to the memory impairment that occurs with aging and, in a more pronounced way, with Alzheimer's dementia. Lastly, there is an increase in the basal release of dopamine. The result of these age-related changes is a decreased brain reserve for handling metabolic and other stresses. The impact of various risk factors on the levels of acetylcholine and dopamine is summarized in Figure 15,17,32,33.
Diagnosing delirium requires a high index of suspicion, with an understanding that delirium will develop in nearly 50% of patients who have sustained a hip fracture. Use of the DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) criteria (Table I) or an instrument such as the CAM (Confusion Assessment Method) algorithm (Table III)11,16 at the bedside increases the likelihood of making the correct diagnosis7,11,15,34. The CAM, which is based on DSM-III-R criteria, has been validated in a number of settings11,15,34. It has high sensitivity and specificity and can be administered in approximately two to five minutes11,15. As part of the assessment for symptoms of delirium, it is important to understand the patient's baseline level of cognitive and other functioning. If the patient is not displaying symptoms of delirium on admission, baseline cognitive functioning can be assessed at that time with use of the Mini-Mental State Examination35. This simple examination is easy to administer and should be part of the preoperative evaluation36. Baseline functioning can also be determined by interviewing family members and reviewing medical records.
Symptoms such as agitation, delusions, or hallucinations are easy to observe but are present in only a minority of cases4. The more common, or core, symptoms are reduced clarity of awareness of the environment with a reduced ability to focus, shift, or sustain attention and cognitive changes such as memory loss, disorientation, or changes in language, including rambling, incoherent, or difficult-to-follow speech7. These findings can be more subtle and in part account for missed diagnoses. Also, recognizing delirium as it is developing may be helpful37. Disorientation and urgent calls for attention by the patient are the most predictive prodromal changes38. When a diagnosis of delirium is being considered during the perioperative period for a patient with a hip fracture, it is important to keep in mind the differential diagnosis of alcohol withdrawal, delirium tremens, or fat emboli syndrome39,40. These conditions will be discussed only briefly because they are not the focus of this article. Alcohol withdrawal occurs primarily in heavy drinkers (more than five drinks per day). It is essential to obtain a history regarding alcohol (or other substance) abuse from the patient and family members in order to be alert to the possibility of alcohol or other withdrawal syndromes. Withdrawal symptoms generally begin five to ten hours after the last drink, peak within forty-eight to seventy-two hours, and subside within five to seven days, although they can last longer. Postoperative pain medication can mask withdrawal symptoms as can concurrent illness or an operation39. Alcohol withdrawal is characterized by symptoms of autonomic hyperactivity such as diaphoresis; tachycardia; systolic hypertension; hand and body tremors; transient tactile, auditory, or visual hallucinations; anxiety; nausea and vomiting; psychomotor agitation; and occasionally seizures. A patient undergoing alcohol withdrawal is alert, oriented, aware of his or her environment, and able to attend. In patients with delirium tremens, alcohol withdrawal is complicated by frank delirium39. Fat emboli syndrome occurs within twenty-four to forty-eight hours following femoral neck fracture in 0.5% to 3% of individuals. It is characterized by pulmonary distress, changes in mental status, and a petechial rash in nondependent areas such as the axillae, the anterior surface of the neck, the chest, the area around the navel, and the conjunctiva and oropharynx. There can also be fever, tachycardia, jaundice, renal changes, and retinal changes40.
Often, delirium is preventable or its severity can be lessened, but unfortunately there is no single intervention that has been shown to prevent delirium1,7,37. Instead, reducing the incidence and severity of delirium relies on optimizing the medical and surgical care of the patient1,7,37 in order to maximize neuronal functioning. If delirium does develop, treatment then centers on supportive care and identifying and addressing the underlying cause or causes1,41. Most surgeons direct the postoperative pain control for their patients. Opiates can contribute to delirium by increasing dopamine levels and decreasing acetylcholine levels16,19. However, Morrison et al. demonstrated that delirium can also be associated with too little pain control3. They used multiple logistic regression analysis to identify risk factors in a study of 541 patients with a hip fracture. Severe pain significantly increased the risk of delirium (risk ratio, 9; 95% confidence interval, 1.8 to 45.2). In addition, delirium was more likely to develop in patients who received <10 mg of parenteral morphine sulfate equivalents per day than it was in patients who received more analgesia (risk ratio, 5.4; 95% confidence interval, 2.4 to 12.3). Finally, patients who received meperidine (Demerol) were at increased risk for the development of delirium compared with those who received other opioid analgesics (risk ratio, 2.4). This was probably due to the anticholinergic effects of meperidine. The type of anesthesia administered does not appear to affect the development of delirium. In the same study by Morrison et al.3, there was no significant difference between the delirium rates associated with regional and general anesthesia. Gustafson et al.6 showed a trend toward increased delirium with spinal anesthesia; however, it was not significant. They found that a drop in blood pressure below 80 mm Hg was more important, and this more commonly occurred with spinal anesthesia. Approximately 90% of their patients who had this decrease in blood pressure went on to have delirium6,33. Edelstein et al.5 reported a higher prevalence of delirium with general anesthesia and postulated that that higher prevalance may be due to cerebral hypoxia during general anesthesia. However, it appears that the ability to maintain oxygen delivery to the brain during surgery is more important than the type of anesthesia administered. Other investigators have concentrated more on optimizing the perioperative medical care of patients with a hip fracture in an attempt to decrease the prevalence of delirium. The intervention reported by Gustafson et al.33 consisted of preoperative and postoperative geriatric assessments as well as aggressive management of perioperative conditions and postoperative complications. The prevalence of delirium decreased from 61.3% in their observational cohort to 47.6% in their intervention group (p < 0.05). The prevalence of severe delirium was also significantly lower in their intervention group (30% compared with 7%) (p < 0.0001). The hospital stay decreased from seventeen to eleven days (p < 0.001), and rates of postoperative complications such as urinary retention, decubitus ulcers, and severe falls all decreased. Milisen et al.42 evaluated the impact of increased involvement by nurses on delirium in a prospective, randomized study of two groups of sixty patients with a hip fracture. Their intervention consisted of educating nursing staff to recognize delirium, systematic cognitive screening of patients, a scheduled pain protocol, and the availability of a consulting geriatric nurse or physician. Although they did not find a significant decrease in the prevalence of delirium, they did observe a significant decrease in the duration (p = 0.03) and severity (p = 0.015) of delirium. Marcantonio et al.8 performed a prospective, randomized, blinded study to investigate the effect of a structured geriatrics consultation on the development of delirium after hip fracture surgery. The intervention group received a proactive geriatrics consult either preoperatively or within twenty-four hours after surgery. The geriatrician made daily visits for the duration of the hospital stay and gave targeted recommendations based on a structured protocol. The prevalence of delirium was 32% in the intervention group compared with 50% in the usual-care group (p = 0.04), and the prevalence of severe delirium was decreased as well (12% compared with 29%). This study emphasized that delirium can be prevented or lessened in many patients but that there is no single intervention that consistently prevents delirium. Efforts to prevent delirium need to focus on minimizing the number of metabolic or other potential central nervous system insults that the patient experiences once admitted to the hospital. A patient's age, cognitive status, fracture, or need for surgery cannot be prevented. In some patients, these four factors alone will be sufficient to induce delirium. However, some patients have enough brain reserve to withstand these insults, and it is other insults, such as a decrease in blood pressure, hypoxia, urinary tract infection, or uncontrolled pain, that eventually trigger delirium. Reducing or eliminating these insults can prevent delirium in many patients or can decrease its severity. If delirium does develop, treatment then focuses on supportive care, identification of likely precipitants, and treatment of any underlying causes that can be corrected (Table IV)8,33,41. This generally involves a dedicated team including the orthopaedic surgeon, nursing staff, and consulting specialist(s) with experience and expertise in diagnosing and treating delirium. Medical management must be reviewed and optimized, and the team must systematically rule out potential causes of new-onset delirium. Table V provides an organized approach for prevention and treatment of delirium in patients with a hip fracture.
Physical examination should include measurement of vital signs with pulse oximetry, assessment of signs suggestive of alcohol withdrawal, and an investigation for evidence of fat emboli syndrome. It is also important to look for any localizing signs of wound or other infections and to assess hydration. Thyroid, heart, lung, abdominal (including the lower abdomen because a distended bladder can be evidence of anticholinergic excess), and neurological examinations are important as well. A rectal examination is recommended if there is concern about severe constipation or impaction15,16,36,41. Important laboratory and radiographic studies are listed in Table IV. Any pertinent abnormalities identified through a review of the history, a review of systems, or physical and laboratory examinations should be corrected, with a focus on adequate oxygenation, restoring fluid and electrolyte balance, treating pain, eliminating or weaning the patient off of unnecessary medications, regulating bowel and bladder function, providing adequate nutritional intake, mobilizing the patient if possible, addressing any vision or hearing impairments, normalizing the sleep-wake cycle, and providing appropriate environmental stimuli, reassurance, orientation, and support8,15,16,37,41. Regarding pain control, the natural response when a patient has delirium is to withdraw narcotic medication. However, as Morrison et al.3 demonstrated, inadequate pain control may also contribute to delirium. If the underlying cause or causes of delirium are corrected, the course of the delirium is often self-limited and the patient recovers completely. If the cause or causes persist, delirium can persist and progress to dementia. Although dementia is a risk factor for delirium, delirium is also a risk factor for dementia9,43. Thus, the prognosis for an episode of delirium appears to improve when the duration is shorter8. If a patient with delirium is agitated, delusional, or hallucinating or is too inattentive or confused to cooperate with treatment, adjunctive medication may be needed15,36,41. Treating these symptoms can diminish the patient's distress, decrease the risk of patient injury, and reduce excessive energy expenditure. The most frequently used and studied medication in this situation is Haldol (haloperidol), a first-generation antipsychotic medication, although there are few studies to guide treatment15,35,36,41. Haldol; the second-generation antipsychotic medications Zyprexa (olanzapine), Risperdal (risperidone), Seroquel (quetiapine fumarate), and Geodon (ziprasidone); or the third-generation antipsychotic agent Abilify (aripiprazole) can help to reduce confusion, agitation, or hallucinations by decreasing dopamine levels, thereby improving the acetylcholine-todopamine ratio. Because there is a small risk of potentially fatal torsade de pointes (ventricular tachycardia characterized by polymorphic QRS complexes) with intravenous Haldol, baseline and follow-up electrocardiograms (to look for prolongation of the QTc interval) and serum potassium and magnesium monitoring are needed41. Safety is further increased by utilizing continuous cardiac telemetry monitoring19. The newer antipsychotic agents can be more difficult to regulate than Haldol, which has minimal anticholinergic side effects and no active metabolites44. The newer antipsychotic agents also have pharmacologic effects beyond reducing dopamine levels44 that can make it difficult to determine whether they are diminishing or exacerbating delirium. They are sometimes utilized on a scheduled basis with use of Haldol as an as-needed agent for breakthrough symptoms45. In addition to extrapyramidal side effects (muscle tightening or Parkinson symptoms), antipsychotic medication can cause akathisia (a subjective sense of restlessness and an inability to sit still) or, rarely, neuroleptic malignant syndrome (which consists of a high fever, muscle rigidity, and autonomic instability). Tardive dyskinesia (abnormal movements of the tongue, mouth, arms, legs, and trunk) primarily occurs with long-term use but can occur with short-term use. Elderly women constitute a group at high risk for tardive dyskinesia44. Also, the United States Food and Drug Administration (FDA) recently determined that second and third-generation antipsychotic medications are associated with a 1.6 to 1.7-fold increase in death (from cardiac-related events such as heart failure or sudden death, or infections, especially pneumonia) of elderly patients with dementia when used to treat behavioral disorders46. The FDA is considering adding a similar warning to Haldol and other first-generation antipsychotics46. Zyprexa and Risperdal are also associated with a small risk of stroke and other adverse cerebrovascular events in elderly patients with dementia47,48. Because of these possible adverse effects, antipsychotic medication should be carefully titrated to the most effective dose and used only as long as it is needed to control the above-noted deleterious behaviors associated with delirium. Other medications, such as benzodiazepines or physostigmine, are used less frequently41. Benzodiazepines are useful for managing alcohol or sedative-hypnotic withdrawal and delirium tremens39. They can also be used to augment antipsychotic medication in the treatment of delirium when larger doses appear to be needed41. Benzodiazepines are usually not effective as monotherapy for general cases of delirium and can cause behavioral disinhibition, especially in the elderly41. Physostigmine, which is a cholinergic medication, is useful only if the delirium is known to be caused by an anticholinergic medication41. Physostigmine is associated with a higher risk of side effects, including seizures, bradycardia, asystole, bronchospasm, and pulmonary edema, than are antipsychotic medications49. Aricept (donepezil) has been occasionally used as a safer alternative to physostigmine in these situations50.
Delirium is a serious medical condition that consists of a disturbance of consciousness with a reduced ability to focus, sustain, or shift attention. There are also cognitive and/or perceptual changes. Delirium generally develops over a period of hours to days and tends to fluctuate over the course of the day. It is a frequent and dangerous complication of hip fracture in the elderly that has received little attention in the orthopaedic literature. However, multiple studies1,5,6 have shown that postoperative delirium following hip fracture is associated with prolonged hospital stays, higher costs, and poor outcomes. Patients who experience delirium are less likely to return to their prefracture level of walking or activities of daily living. They are also substantially more likely to be placed in a nursing home for the first time and to die. Although the pathophysiology of delirium is not fully understood, it appears that multiple metabolic and neurochemical insults disrupt neuronal functioning in susceptible areas, especially in the corticothalamic networks. These insults commonly lead to an imbalance in the dopamine-to-acetylcholine ratio in these important brain regions. Prevention and optimal treatment consist of minimizing or correcting these metabolic and other insults. Maintaining oxygen saturation at >90%, systolic blood pressure at >90 mm Hg, and the hematocrit at >30% is important, as is attention to the fluid and electrolyte status. Pain control, careful review of the patient's medications, regulation of bowel and bladder function, adequate nutritional intake, early mobilization and rehabilitation, appropriate environmental stimulation, and normalization of the patient's sleep-wake cycle are also key. Early detection of coexisting or postoperative medical problems, infections, or other complications is crucial. Antipsychotic medication can be used to reduce agitation that interferes with the patient's ability to cooperate with treatment, places the patient in danger of harm, or excessively increases metabolic demands. There is no single intervention that can eliminate delirium. Treatment and, when possible, prevention require awareness of the diagnosis, reduction or elimination of modifiable risk factors, early diagnosis and treatment, and excellent teamwork among the orthopaedist, anesthesiologist, nursing staff, and other consulting medical specialists.
NOTE: The authors thank Dr. Marc Swiontkowski and Dr. Terence Gioe.
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Introduction
Definition
A hip fracture is
sustained by 250,000 Americans every year. The most common complication
associated with hip fracture is delirium. 
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