Significant alterations in pharmacokinetics accompany aging and must be considered when selecting and optimizing medication therapy in the elderly patient. Enteral absorption is minimally affected by the process of aging alone, but subcutaneous and intramuscular absorption may be affected by decreases in total body water and muscle mass in the aged. Decreases in total body water and alterations in plasma protein concentrations change the volume of distribution for many commonly used medications. Elderly patients may require lower doses of hydrophilic agents such as heparin, insulin, and warfarin to account for this change in drug disposition. Hepatic drug metabolism by the cytochrome P450 system is variably affected due to age-related decreases in some isozymes’ activity. Drug elimination is the pharmacokinetic process most affected by aging, as glomerular filtration and renal drug elimination are inversely correlated with age. Many commonly prescribed medications require dosage adjustment in patients with renal dysfunction, including most antibiotics, antihypertensives, cardiac glycosides, histamine receptor antagonists, hypoglycemic agents, and analgesics.

Early studies on the effects of pre-injury warfarin were derived retrospectively from large databases and were unable to detect differences in outcomes between patients receiving warfarin and control groups. However, when elderly patients with head trauma are considered, most subsequent studies have shown that pre-injury warfarin treatment is associated with injury severity, risk for an intracranial hemorrhage (ICH) after a fall, mortality after ICH, and overall mortality. However, warfarin therapy alone is not necessarily a predictor of adverse outcome. Patients who are more intensively anticoagulated are more likely to present with a Glasgow Coma Scale score (GCS) of less than 13 and have an increased risk of both overall mortality and mortality after ICH. Warfarin does not seem to impose a higher risk of morbidity or mortality on patients without head injury.

Pre-injury anticoagulant therapy often complicates the management of the elderly trauma patient. Warfarin is an inhibitor of the vitamin K epoxide reductase complex (VKORC) which results in decreased activation of clotting factors II, VII, IX, and X, in addition to proteins C and S. Warfarin, used commonly for the treatment and prevention of thromboembolic diseases, was the only oral anticoagulant available in the United States for many years. Dabigatran is an orally administered direct thrombin inhibitor approved for the reduction of stroke risk and systemic embolism in patients with non-valvular atrial fibrillation. In clinical trials, bleeding complications with dabigatran therapy were similar to rates for warfarin. Potential advantages of dabigatran therapy compared to warfarin include the lack of required therapeutic drug monitoring and fewer drug-drug and dietary interactions. However, dose adjustments are necessary for dabigatran when prescribed for patients with renal failure (creatinine clearance (CrCl) less than 30 mL/min).

Rivaroxaban is an oral factor Xa inhibitor approved for reduction of risk of stroke and systemic embolism in non-valvular atrial fibrillation and prevention of venous thromboembolism (VTE) after knee or hip replacement surgery. Like dabigatran, it requires dose adjustments for renal insufficiency (CrCl less than 50 mL/min). One small pharmacokinetic study showed only a moderate effect of severe renal impairment on elimination half-life. This finding may be due in part to alternate clearance pathways, including hepatic metabolism. Apixaban is another oral factor Xa inhibitor currently marketed in the European Union. There are currently no data that describe the outcomes of injured patients who are receiving either of these anticoagulants.

Aspirin, clopidogrel, and prasugrel are all drugs which decrease platelet activation and aggregation via glycoprotein IIb/IIIa but by different mechanisms. Pre-injury antiplatelet therapy does not seem to impact outcomes of the non-head-injured trauma patient. However, the impact of pre-injury therapy on outcomes in head injury remains controversial and optimal management is unclear. Much of the data describing these patients is retrospective, and few studies have analyzed the offending agents separately.

Several studies have attempted to address the impact of pre-injury antiplatelet therapy on the elderly patient with a head injury. The majority of patients in these studies were only on antiplatelet therapy, but some patients were also using warfarin. This confounder makes it difficult to interpret the data and conclusions. Pre-injury therapy was associated with 18.5–38 % mortality compared to a rate of 8–9.5 % in matched controls. A study from 2002 was the first to report that ASA and warfarin therapy prior to injury were equivalent risk factors for increased morbidity and mortality. Other studies have shown pre-injury clopidogrel, but not ASA, to increase the risk of both being discharged to a long-term care facility and mortality compared to matched controls. In studies that excluded patients using warfarin, pre-injury clopidogrel was associated with an increased necessity for transfusion of blood and also repeat intracranial surgery. Antiplatelet therapy was associated with a higher-grade hemorrhage.

It is logical to conclude that pre-injury anticoagulation or antiplatelet therapy would be risk factors for increased morbidity and mortality. However, coagulopathy is also a known complication of injury, and some authors have suggested that the pre-injury use of anticoagulants or antiplatelet therapy may have a paradoxically protective effect in patients older than 70 years. Data from the only prospective study addressing the effects of pre-injury anticoagulation implies that low-dose ASA (100 mg/day) does not increase the risk of ICH in elderly patients with mild to moderate head injury. There are no data describing outcomes in injured patients treated with the newer agents prasugrel or ticagrelor.

Vitamin K is the antidote for warfarin toxicity, and when administered intravenously, its effects can be seen within 12–24 h. However, rapid reversal of the anticoagulant effects of warfarin has been shown to decrease progression of ICH and mortality. Administration of fresh frozen plasma (FFP) can begin to normalize coagulation by supplying clotting factors II, VII, IX, and X while awaiting the full effects of reversal with vitamin K. While a targeted therapy, FFP use is fraught with limitations: optimal dosing is unknown, clotting factor concentrations are variable in each unit, the required volumes of FFP to be infused may be problematic for patients with known cardiovascular comorbidities, additional time is required for thawing prior to administration, and time to correction of INR is highly variable.

Prothrombin complex concentrates (PCCs) and recombinant activated factor VIIa (rFVIIa) may be beneficial for emergent reversal. “Three-factor” PCCs available in the United States contain little to no factor VII. “Four-factor” PCCs available in the European Union contain high concentrations of factors II, VII, IX, and X. Although there is little data on the use of PCC, it represents a potentially valuable therapy for patients who require rapid warfarin reversal. Multiple small, nonrandomized studies have shown that four-factor PCC is associated with more rapid reversal of anticoagulation and decreased hematoma expansion compared to FFP in patients with an ICH on warfarin. However, optimal dosing is unknown. Fixed doses of 500–1,040 international units (IU) of factor IX activity are sufficient for reversal, while an open-label study showed that a weight- and INR-adjusted dose was associated with 89 % of patients reaching a target INR within 15 min of administration compared to 43 % (p < 0.001) in the group that received the fixed 500 IU dose. Three-factor PCC has been described as insufficient for reversal. Retrospective data suggests that the combination of three-factor PCC with low-dose rFVIIa may be effective. It should be noted though that the half-lives of PCC and rFVIIa are much shorter than that of warfarin, so phytonadione should also be administered for optimal reversal. Because PCC is a pooled plasma product, there remains a remote risk of infection.

There are even fewer studies evaluating the efficacy of rFVIIa in warfarin-associated ICH compared to the data for PCC. In a retrospective study, rFVIIa was effective at reversing anticoagulation in neurosurgical patients who failed phytonadione and FFP, although less than half of the patients had warfarin as the cause of the abnormal coagulation. In another retrospective study of mostly elderly patients with a traumatic ICH who were also therapeutically anticoagulated, rFVIIa was effective at restoring coagulation and was associated with decreased use of FFP. However, there was no difference in mortality rates. There was a trend towards an increased risk of VTE in the group receiving rFVIIa. One small retrospective study concluded that rFVIIa was superior to three-factor PCC for correcting the INR in warfarin-related ICH. Recent guidelines for anticoagulant reversal from the American College of Chest Physicians recommend use of four-factor PCC for restoring coagulation with warfarin-associated bleeding rather than plasma infusion. Prospective studies are needed to describe the optimal dosing, therapeutic agent, and the impact of these therapies on clinical outcomes.

The introduction of dabigatran, rivaroxaban, and likely apixaban presents the trauma surgeon and acute care surgeon with new challenges. Data from prospective trials has suggested that there may be a lower risk of bleeding with these newer agents compared to warfarin. There are no known or recommended reversal agents, however. Data suggests that four-factor PCC reduces hematoma expansion and mortality in mice injected with dabigatran; however, a small study of 12 healthy human volunteers showed that four-factor PCC was unable to reverse the effects of dabigatran. Emergent hemodialysis can remove up to 62 % of circulating dabigatran in 2 h due to its large unbound fraction and should be considered in life-threatening situations. The same study concluded that the effects of rivaroxaban were completely reversed by administration of PCC. However, in a rabbit model of bleeding, both rFVIIa and PCC were able to improve bleeding times, but did not have an impact on the amount of hemorrhage itself. In a small ex vivo study of ten healthy patients, rFVIIa, PCC, and factor eight inhibitor bypassing activity (FEIBA) were variably effective at reversing dabigatran and rivaroxaban. An in vitro study showed that clotting assays altered by apixaban were inconsistently reversed by rFVIIa and PCC.

The antithrombin effects of low-molecular-weight heparins may be reversed by protamine, but it has little to no effect on their anti-Xa activity. Protamine doses have been used up to 100 mg (1 mg protamine for each mg enoxaparin given in the preceding 8 h). However, protamine administration is associated with serious complications, including life-threatening hypersensitivity reactions and counterintuitively hemorrhage. Recombinant FVIIa has been used in a number of case reports and laboratory investigations and has been at least partially effective at doses of 20–120 mcg/kg. Several case reports have described clinical success in reversing the anticoagulant effects of fondaparinux with rFVIIa, but results were inconsistent in the largest case series currently published.

Platelet transfusion is commonly employed in the management of traumatic intracranial hemorrhage in all injured patients, but particularly the elderly, receiving antiplatelet therapy, despite a lack of data to support its efficacy. Both aspirin and clopidogrel bind irreversibly to platelets causing dysfunction for the life of the platelet. Transfusion is only beneficial by providing functional platelets. Two retrospective studies have shown no benefit with transfusion of platelets on either morbidity or mortality. Platelet transfusion can lead to a number of complications including transfusion-related acute lung injury (TRALI) and infection. In one study, patients receiving platelet transfusion had a subsequent medical decline when compared to the group not transfused. Given the available evidence, platelet transfusion cannot be currently recommended in this setting.

Extrapolating data from other patient populations, several studies have suggested using intravenous desmopressin (DDAVP) to reverse platelet dysfunction although it has not been studied in trauma patients. Desmopressin is known to increase concentrations of von Willebrand factor and factor VIII. It has been used in doses of 0.3–0.4 mcg/kg.

There are numerous assays currently marketed that assess the therapeutic response to antiplatelet agents. Current cardiology literature does not support antiplatelet testing to individualize therapy given the variability between assays and lack of established reference ranges. One study in trauma patients examined point-of-care testing for patients with a reported history of taking clopidogrel. The results confirmed the findings from studies conducted in uninjured patients in that many patients are either noncompliant or nonresponders to antiplatelet therapy. To date, antiplatelet testing cannot be used to guide therapy in the management of traumatic hemorrhage but may have a role for assessing the therapeutic effect of clopidogrel on platelet function at the time of admission and thus select specific patients who may need platelet transfusion.

Beta-blockers are commonly prescribed in elderly patients as antihypertensives and antiarrhythmics. Studies have concluded there is a survival benefit for patients receiving beta-blocker therapy for cardiac and high-risk vascular procedures. For nonvascular operations, the data for beta-blocker use is less conclusive, where the cardiac events are less, but the mortality rates are not improved compared to those treated perioperatively for cardiac or vascular procedures.

Nonrandomized, cohort-controlled studies in both adult burn and trauma patients have suggested reduced morbidity and mortality. The effects of beta-receptor blockade include decreased cardiac oxygen consumption and hypermetabolism. Additional benefit from antisympathomimetics includes a decrease in systemic and cerebral perfusion pressure. Theorized mechanisms for these effects include suppression of IL-6 production which has been associated with increased mortality for trauma and sepsis patients. A small, randomized trial of patients treated with beta-blockers found lower IL-6 levels. In a study comparing older patients who were case matched for age, Injury Severity Score, Glasgow Coma Scale score, and mechanism of injury concluded that beta-blocker use decreased mortality. A similar study in adult burn patients showed faster rates of healing and reduced hospital length of stay in the group receiving beta-blockers. Patients in these studies who arrived to the hospital on beta-blockers were older and more severely injured.

A subsequent retrospective study that did not use a cohort group or case matching in the study design found that patients admitted on beta-blockers without head injury had higher mortality than those admitted without beta-blocker therapy. There was no difference in the mortality rate for the group admitted on a beta-blocker; however, this group was also more frequently treated with Coumadin and had a higher incidence of vascular diseases. However, in a subset analysis of head injuries, the data suggest a benefit with beta-blocker therapy.

The last study posed the question that beta-blockers may have caused injured patients to appear less ill due to less tachycardia at presentation and that this may have affected their subsequent resuscitation. Alternatively, beta-blocker use in the elderly may have been a surrogate for pre-injury comorbidities.

Potential side effects of beta-blocker therapy may be vasoconstriction and bradycardia due to antagonism of beta-mediated vasodilation and increased risk of vasovagal reaction. The effects of beta-blockers may mask normal tachycardia in response to hemorrhage, an early clinical sign of hypovolemia, so the clinician should seek other signs of hypoperfusion such as acidosis, decreased urine output, and altered mentation since hypotension is a later manifestation of shock.

Unlike dementia, which is a chronic confusional state, delirium is an acute confusional state which occurs most commonly in older, hospitalized patients. Acute brain dysfunction, or delirium, occurs in up to 70 % of mechanically ventilated patients in the surgical ICU and recently has been reported in a similar proportion of trauma ICU patients. Delirium has been identified in 15–53 % of older patients undergoing elective surgical procedures and is associated with mortality rates of 22–76 %, equivalent to mortality rates for sepsis and acute myocardial infarction.

Evidence suggests that delirium may be secondary to altered neurotransmission, inflammation, and even chronic stress. Administration of anticholinergic drugs has been shown to cause delirium in both animals and humans. Excess dopaminergic activity may also contribute to delirium as a regulator of acetylcholine, which supports the use of antipsychotic agents for treatment of delirium symptoms.

Multiple studies have concluded that the use of sedatives and analgesics is associated with delirium in the ICU population. In addition, continuous sedative infusions are also associated with increased mechanical ventilator days and intensive care unit lengths of stay. In a study of elderly (mean age 81 years) patients with hip fractures, the group managed with spinal anesthesia and light sedation had 50 % less postoperative delirium than the group managed with a general anesthetic.