Managing the perioperative patient on direct oral anticoagulants

Purpose

Patients are increasingly treated with direct oral anticoagulants (DOACs) for the prevention of stroke due to non-valvular atrial fibrillation and for the treatment of venous thromboembolism. When these patients present for urgent or emergent surgical procedures, they present a challenge to the anesthesiologist who must manage perioperative risk due to anticoagulation. The purpose of this module is to review the literature surrounding the perioperative management of DOACs. Timing, laboratory monitoring, and availability of reversal agents are important considerations to optimize patients being treated with DOACs who require emergent surgery.

Principal findings

Laboratory tests are not recommended for routine monitoring of DOACs since they do not correlate well with anticoagulant activity. Most widely available laboratory tests lack the sensitivity to detect anticoagulant effects at low plasma concentrations. However, a normal thrombin time for dabigatran excludes clinically significant drug levels. If the risk of bleeding is judged to be high because of a recent dose of DOAC, various options are available to mitigate bleeding. When possible, surgery should be delayed for at least 12 hr after the last dose of DOAC. Activated charcoal may mitigate the anticoagulant effect caused by DOACs if administered less than two hours after the drug was ingested. Four-factor prothrombin complex concentrates (PCCs) may be useful to reduce life-threatening bleeding associated with factor Xa inhibitors. Activated PCCs have been shown to reverse abnormal coagulation tests associated with all DOACs, but there is a lack of reported evidence of clinical benefit. Idarucizumab is a specific antidote that is effective for reversal of anticoagulation due to dabigatran. An antidote for rivaroxaban and apixaban (andexanet alfa) as well as a universal antidote for all DOACs and heparin (PER977) are in clinical development.

Conclusion

Perioperative management of anticoagulation due to DOACs is a growing concern as the number of patients prescribed these medications increases each year. These patients can be safely optimized for urgent or emergent surgery by giving appropriate consideration to timing, monitoring, and reversal agents.

     

Perioperatives Gerinnungsmanagement bei Ersatz der Aorta ascendens unter Apixaban

The direct oral anticoagulants (DOACs) present a valid therapeutic alternative to vitamin K antagonists in patients with non-valvular atrial fibrillation, for the prevention of venous thromboembolism, and for the treatment and prevention of the recurrence of pulmonary embolisms and deep vein thrombosis. Despite Idarucizumab as an antagonist of Dabigatran there are no other specific antidotes available yet. Therefore, perioperative coagulation management by DOACs is challenging in patients undergoing emergency surgical procedures with a high risk of bleeding complications. This case study describes the perioperative procedure during ascending aorta replacement after aortic dissection with apixaban administration.     

New oral anticoagulants: clinical indications,monitoring and treatment of acute bleeding complications

New oral anticoagulants like the direct thrombin inhibitor, dabigatran (Pradaxa®), and factor Xa‐inhibitors, rivaroxaban (Xarelto®) and apixaban (Eliquis®) are available for prophylaxis and treatment of thromboembolic disease. They are emerging alternatives to warfarin and provide equal or better clinical outcome together with reduced need for routine monitoring. Methods for measuring drug concentrations are available, although a correlation between plasma drug concentrations and the risk of bleeding has not been firmly established. Standard laboratory measures like prothrombin time and activated partial thromboplastin time are not sensitive enough to detect thrombin or factor Xa inhibition provided by new oral anticoagulants. Thus, these standard tests may only be used as a crude estimation of the actual anticoagulation status. Further challenges regarding patients receiving new oral anticoagulants who presents with major bleeding or need for emergency surgery pose a unique problem. No established agents are clinically available to reverse the anticoagulant effect, although preclinical data report prothrombin complex concentrate as more efficient than fresh frozen plasma or other prohaemostatic agents. This review summaries current knowledge on approved new oral anticoagulants and discusses clinical aspects of monitoring, with particular focus on the management of the bleeding patient.     

Equivalence of DOACS and LMWH for thromboprophylaxis after hip fracture surgery: Systematic review and meta-analysis

BackgroundPatients with hip fractures (HF) have an increased risk of venous thromboembolism (VTE). In elective orthopedic surgery direct oral anticoagulants (DOACs) have proven to be similarly or more effective compared to low molecular weight heparin (LMWH), but DOACs are not yet approved for thromboprophylaxis in trauma patients with HF. The aim of this study was to systematically review the literature comparing the effectiveness of DOACs and LMWH for thromboprophylaxis in trauma patients with surgically treated HF.Materials and MethodsWe searched PubMed, the Cochrane Library, Web of Science, and Embase. The primary outcome was the incidence of VTE (symptomatic and asymptomatic combined). Secondary outcomes were symptomatic VTE; a symptomatic VTE, symptomatic deep venous thrombosis (DVT); symptomatic pulmonary embolism (PE); major, clinically relevant non-major (CRNM), and minor bleeding. Meta-analysis was performed to compare the odds of VTE and secondary outcomes between DOACs and LMWH.ResultsThe search resulted in 738 titles. Five studies matched inclusion criteria. In total, 4748 hip fracture patients were analyzed (DOACs: 2276 patients, LMWH: 2472 patients). The pooled odds ratio for the risk of VTE for DOAC use was 0.52 (95% confidence interval 0.25–1.11, p = 0.09) compared to LMWH. No statistically significant differences between DOAC and LMWH were found for asymptomatic VTE, symptomatic DVT, PE, major or CRNM bleeding, and minor bleeding.ConclusionsMeta-analysis of the literature suggests that DOACs are associated with equivalent effectiveness and safety compared to LMWH.     

Direct oral anticoagulants (DOACs) and neck of femur fractures: Standardising the perioperative management and time to surgery

Demographic projections for hip fragility fractures indicate a rising annual incidence by virtue of a multimorbid, ageing population with more noncommunicable diseases (NCDs). NCDs are characterised by slow progression and long duration ranging from ischaemic cardiovascular disease, cerebrovascular disease, diabetes, chronic obstructive pulmonary disease to various cancers. Management of this disease burden often involves commencing patients on oral anticoagulants to reduce the risk of thromboembolic events. The use of direct oral anticoagulants (DOACs) in clinical practice has increased due to their rapid onset of action, short half-life and predictable anticoagulant effects, without the need for routine monitoring. Safe and timely surgical intervention relies on reversal of anticoagulants. However, the lack of specific evidence-based guidelines for the perioperative management of patients on DOACs with hip fractures has proved challenging; in particular, the accessibility of DOAC-specific assays, justification of the cost-benefit ratio of targeted reversal agents and indications for neuraxial anaesthesia. This has led to potentially avoidable delays in surgical intervention. Following a literature review of the pharmacokinetic and pharmacodynamics of commonly used DOACs in our region including the role of surrogate markers, we propose a systematic, evidence-based guideline to the perioperative management of hip fractures DOACs. We believe this standardised protocol can be easily replicated between hospitals. We recommend that if patients are deemed suitable for a general anaesthesia, with satisfactory renal function, optimal surgical time should be 24 h following the last ingested dose of DOAC.     

Rivaroxaban and dabigatran etexilate: two new oral anticoagulants for extended postoperative prevention of venous thromboembolism after elective total hip arthroplasty

Extended thromboprophylaxis is vital in patients undergoing total hip arthroplasty (THA) because of the prolonged risk of venous thromboembolism (VTE). Despite evidence that extended prophylaxis can reduce the incidence of symptomatic VTE in this high-risk patient population and the evidence-based guideline recommendations, a large proportion of patients still do not receive an adequate duration of thromboprophylaxis. This is partly due to the limitations of conventional anticoagulants, such as the subcutaneous route of administration or the requirement for routine coagulation monitoring and dose adjustment. New oral anticoagulants (such as the direct thrombin inhibitor dabigatran etexilate and the Factor Xa inhibitor rivaroxaban) could address the current unmet need. Phase III clinical studies in VTE prevention in patients undergoing THA and total knee arthroplasty (TKA) showed that dabigatran etexilate was non-inferior to the EU regimen of enoxaparin, but did not achieve non-inferiority to the US regimen of enoxaparin. In contrast, rivaroxaban demonstrated superiority to both enoxaparin regimens for the prevention of VTE after THA and TKA, without a significant increase in major bleeding rates. Their convenient, once-daily, fixed dosing, with no need for routine coagulation monitoring, could facilitate adherence to evidence-based guideline recommendations of extended thromboprophylaxis after THA.     

Direct oral anticoagulant considerations in solid organ transplantation: A review

For more than 60 years, warfarin was the only oral anticoagulation agent available for use in the United States. In many recent clinical trials, several direct oral anticoagulants (DOACs) demonstrated similar efficacy with an equal or superior safety profile, with some other notable benefits. The DOACs have lower inter‐ and intrapatient variability, much shorter half‐lives, and less known drug‐drug and drug‐food interactions as compared to warfarin. Despite these demonstrated benefits, the use of DOACs has not gained uniform acceptance because of lack of supportive data in special patient populations, including recipients of solid organ transplants maintained on immunosuppression. This review describes the properties of several novel DOACs including their pharmacology and mechanisms of action as they relate to use among solid organ transplant recipients. We have particularly focused on (i) dosing in patients with impaired renal and hepatic function; (ii) considerations for drug‐drug interactions with immunosuppressive medications; and (iii) management of the anticoagulated patients at the time of unplanned surgery. The risks and benefits of the use of DOACs in solid organ transplant recipients should be carefully evaluated prior to the introduction of these agents in this highly distinct patient population.     

Outcomes with direct-acting oral anticoagulants in patients with a history of bariatric surgery: a retrospective cohort study

BackgroundPatients who undergo bariatric surgery have major physiologic changes in their gastrointestinal tract, which can theoretically alter drug absorption and pharmacokinetics. This is especially concerning for drugs with a narrow therapeutic index, as small changes in absorption can have significant effects on safety and efficacy. One class of interest is direct-acting oral anticoagulants (DOACs), for which there is a paucity of data in this population.ObjectiveTo characterize the use of DOACs (apixaban, dabigatran, rivaroxaban) in patients with a history of bariatric surgery and incidence of clotting and bleeding events.SettingPublic healthcare system/university hospital, United States.MethodsThis retrospective cohort study included adult patients who were prescribed a DOAC for the prophylaxis or treatment of venous thromboembolism or for stroke and systemic embolism prevention in atrial fibrillation between January 2011 and December 2018.ResultsA total of 191 patients with a history of bariatric surgery were included. Clotting events occurred in 11 of 191 patients (5.8%) receiving DOAC therapy, with a calculated clotting rate of 3.9 clots per 100 person-years. Bleeding events occurred in 42 of 191 patients (22%) receiving a DOAC, with a calculated bleeding rate of 17.1 bleeds per 100 person-years. The use of rivaroxaban versus apixaban was associated with a statistically significant increased risk of bleeding in patients with a history of bariatric surgery.ConclusionIn this retrospective cohort of bariatric surgery patients receiving DOACs, we found clotting rates consistent with expected rates and bleeding rates above expected rates based on historical data. We also found an increased risk of bleeding in rivaroxaban users compared with apixaban users. Careful evaluation of bleeding risks in bariatric surgery patients is encouraged.     

Enoxaparin Versus Direct Oral Anticoagulants for Venous Thromboembolism in Asians Undergoing Total Knee Arthroplasty: A Meta-Analysis and Systematic Review

BackgroundThe introduction of direct oral anticoagulants (DOACs) shows promise for their role as a chemoprophylaxis agent after total knee arthroplasty (TKA) for the prevention of venous thromboembolism (VTE). However, existing studies are largely based on Western populations that do not account for the different risk profiles and lower rates of VTE in Asians. This systematic review and meta-analysis aimed to evaluate the efficacy of DOACs compared with enoxaparin in an Asian-based population study.MethodsThe review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. All studies that compared outcomes between enoxaparin and DOACs as VTE prophylaxis after TKA in the Asian population were included.ResultsFive studies with 121,153 patients were included. DOACs demonstrated a convincing benefit over enoxaparin in overall VTE prevention (odds ratio [OR] = 0.42, 95% confidence interval [CI]: 0.24-0.74). However, although the OR trended in favor of DOACs for the reduction of deep vein thrombosis events (OR = 0.54, 95% CI: 0.20-1.48) and pulmonary embolism (OR = 0.75, 95% CI: 0.07-8.20), statistical significance was not reached. In terms of bleeding complications, both arms had similar rates of major (0.91% vs 0.20%), clinically relevant nonmajor (3.28% vs 2.94%), and minor bleeding complications (12.8 vs 13.3%). A nonsignificance advantage of enoxaparin over DOACs was revealed in the OR for major bleeding (OR = 3.17; 95% CI: 0.81-12.43), whereas DOACs were favored to reduce risk of clinically relevant nonmajor (OR = 0.82; 95% CI: 0.01-91.51) and minor bleeding (OR = 0.76; 95% CI: 0.11-5.33).ConclusionDOACs confer a significantly reduced rate of overall VTE compared with enoxaparin in Asians after TKA. No significant differences in deep vein thrombosis, pulmonary embolism, and rates of bleeding complications exist.     

围手术期新型口服抗凝药的调整策略

背景抗凝治疗对于血管内栓塞或血栓形成疾病的防治十分重要。新型口服抗凝药neworal anticoagulants,NOACs）具有起效快、代谢迅速、药代动力学预测性好、药物相互作用少及无需常规监测凝血指标等优点。目的综述围手术期应用NOACs调整策略的研究进展。内容论述NOACs的药理学特点、围手术期出血风险、管理策略及某些特殊情况下的麻醉处理。趋向应根据具体情况积极评估和调整NOACs的用量,关注围手术期NOACs可能导致的出血风险。     

Überbrückung, Pausieren und Wechsel von Antikoagulanzien in der Unfallchirurgie

Patients under long-term administration of vitamin K antagonists may require temporary interruption of anticoagulation therapy for invasive procedures or trauma surgery. Due to the long half-life of these substances bridging therapy with anticoagulants having a shorter half-life may become necessary. In this situation the risk of bleeding due to the intervention and the risk of thromboembolism due the underlying disease must be assessed. Low molecular weight heparins (LMWHs) are considered to be the medication of choice for bridging anticoagulation, mainly due to practical reasons and as they do not require coagulation monitoring and dose adjustment out of hospital treatment is feasible. Low molecular weight heparins are not authorized for the indication of bridging anticoagulation, however, on the basis of recent studies on large patient cohorts, the evidence of efficacy and safety is significantly better for LMWHs than for unfractionated heparin. New oral anticoagulants will soon become available for stroke prevention in patients with atrial fibrillation and for treatment of venous thromboembolism. Due to the shorter half-lives these compounds will no longer require bridging anticoagulation. However, the trauma surgeon should be familiar with the dosing regimens for different indications in order to adequately decide about the preoperative cessation and the perioperative pause of these anticoagulants.     

Management of direct action oral anticoagulants in the peri-operative period and invasive techniques

The new direct-acting oral anticoagulants (ACOD) in patients on prolonged treatment require the need to balance the risk of haemorrhage by administering them against the risk of thrombosis on withdrawing them. Recommendations for their management are proposed in the present article: A) Thromboprophylaxis and general anaesthesia: the performing of regional anaesthesia if administered with an ACOD as thromboprophylaxis requires some safety intervals based on their pharmacokinetic parameters; B) Management of ACOD in elective surgery: in patients with normal renal function and a low haemorrhage/thrombosis risk, stop the ACOD two days before the surgery; it the haemorrhage/thrombosis risk is high and/or renal function is impaired, therapy with a low molecular weight heparin is proposed from 5 days prior to the surgery, and C) Management of ACOD in urgent surgery and associated haemorrhage: the systematic prophylactic administration of haemostatics is recommended. In the event of acute bleeding that may place the life of the patient at risk (due to volume or location), the administration of concentrated prothrombin complex, fresh plasma, or factor VIIa, must be assessed, together with general control measures of acute haemorrhage. These recommendations should be considered in the context of the use drugs that do have a specific antidote, where their monitoring by the usual coagulation tests is not routine, and with those in which there is limited experience. We believe they need to be reviewed in the future, depending on further studies and clinical experience obtained.     

New oral pharmacotherapeutic agents for venous thromboprophylaxis after total hip arthroplasty

Patients undergoing total hip arthroplasty(THA)are at high risk for developing venous thromboembolism and,therefore,require short term prophylaxis with antithrombotic agents.Recently,target specific oral anticoagulants(TSOA)including the direct thrombin inhibitor,dabigatran,and the factorⅩa inhibitors rivaroxaban,apixaban,and edoxaban have been approved for THA thrombopropylaxis in various countries.The TSOAs provide a rapid acting,oral alternative to parenteral agents including low-molecular weight heparins(LMWH)and fondaparinux;and compared to warfarin,they do not require routine laboratory monitoring and possess much fewer drug-drug interactions.Based on phaseⅢclinical studies,TSOAs have established themselvesas an effective and safe option for thromboprophylaxis after THA compared to LMWH,particularly enoxaparin,but require additional evaluation in specific populations such as the renally impaired or elderly.The ability to monitor and reverse these TSOAs in the case of bleeding complications or suspected sub-or supra-therapeutic anticoagulation is of importance,but remains investigational.This review will focus on the drug-specific characteristics,efficacy,safety,and economic impact of the TSOAs for thromboprophylaxis following THA,as well as the aspects of therapeutic monitoring and anticoagulation reversal in the event of bleeding complications or a need for urgent reversal.     

Safety and efficacy of direct oral anticoagulants under long-term immunosuppressive therapy after liver,kidney and pancreas transplantation

The safety of direct oral anticoagulants (DOACs) in patients after solid organ transplantation (SOT) is not well defined. This study aimed at describing the safety and efficacy of DOACs in patients after SOT. Patients after kidney and/or liver transplantation under maintenance immunosuppression treated with rivaroxaban (n = 26), apixaban (n = 20) and edoxaban (n = 1) were included. Clinical data were collected retrospectively and using a questionnaire. DOAC plasma levels and thrombin generation (TG) were measured in patients after SOT and compared with nontransplanted controls receiving DOACs. DOACs were administered for 84.6 patient-years. Mean immunosuppressive trough levels after DOAC initiation increased from baseline by 18.8 ± 29.6% compared to 3.0 ± 16.5% in matched controls (P = 0.004), without significant differences in dose adjustments. No transplant rejection or significant change in liver or renal function was observed. There was one major bleeding after the observation period but no thromboembolic complication. DOAC plasma levels reached the expected range in all patients. The intrinsic hemostatic activity in transplanted patients was higher compared to nontransplant controls. Treatment with DOACs after SOT is safe and effective. Immunosuppressive trough levels should be monitored after DOAC initiation, particularly in the early phase after SOT. These data should be confirmed in a prospective study.     

Impact of venous thromboembolism on clinical management and therapy after hip and knee arthroplasty

Postoperative deep vein thrombosis (DVT) occurs most often in the large veins of the legs in patients undergoing major joint arthroplasty and major surgical procedures. These patients remain at high risk for venous thromboembolic events. In patients undergoing total hip or total knee arthroplasty (THA or TKA, respectively), different patterns of altered venous hemodynamics and hypercoagulability have been found, thus the rate of distal DVT is higher than that of proximal DVT after TKA. In addition, symptomatic venous thromboembolism (VTE) occurs earlier after TKA than THA; however, most of those events occur after hospital discharge. Consequently, extended thromboprophylaxis after discharge should be considered and is particularly important after THA owing to the prolonged risk period for VTE. Evidence-based guideline recommendations for the prevention of VTE in these patients have not been fully implemented. This is partly owing to the limitations of traditional anticoagulants, such as the parenteral route of administration or frequent coagulation monitoring and dose adjustment, as well as concerns about bleeding risks. The introduction of new oral agents (e.g., dabigatran etexilate and rivaroxaban) may facilitate guideline adherence, particularly in the outpatient setting, owing to their oral administration without the need for routine coagulation monitoring. Furthermore, the direct Factor Xa inhibitor rivaroxaban has been shown to be more effective than enoxaparin in preventing VTE.     

A European consensus statement on the use of four-factor prothrombin complex concentrate for cardiac and non-cardiac surgical patients

Modern four-factor prothrombin complex concentrate was designed originally for rapid targeted replacement of the coagulation factors II, VII, IX and X. Dosing strategies for the approved indication of vitamin K antagonist-related bleeding vary greatly. They include INR and bodyweight-related protocols as well as fixed dose regimens. Particularly in the massively bleeding trauma and cardiac surgery patient, four-factor prothrombin complex concentrate is used increasingly for haemostatic resuscitation. Members of the Transfusion and Haemostasis Subcommittee of the European Association of Cardiothoracic Anaesthesiology performed a systematic literature review on four-factor prothrombin complex concentrate. The available evidence has been summarised for dosing, efficacy, drug safety and monitoring strategies in different scenarios. Whereas there is evidence for the efficacy of four-factor prothrombin concentrate for a variety of bleeding scenarios, convincing safety data are clearly missing. In the massively bleeding patient with coagulopathy, our group recommends the administration of an initial bolus of 25 IU.kg^-1. This applies for: the acute reversal of vitamin K antagonist therapy; haemostatic resuscitation, particularly in trauma; and the reversal of direct oral anticoagulants when no specific antidote is available. In patients with a high risk for thromboembolic complications, e.g. cardiac surgery, the administration of an initial half-dose bolus (12.5 IU.kg^-1) should be considered. A second bolus may be indicated if coagulopathy and microvascular bleeding persists and other reasons for bleeding are largely ruled out. Tissue-factor-activated, factor VII-dependent and heparin insensitive point-of-care tests may be used for peri-operative monitoring and guiding of prothrombin complex concentrate therapy.     

Emergency care of patients receiving non-vitamin K antagonist oral anticoagulants

Non-vitamin K antagonist oral anticoagulants (NOACs), which inhibit thrombin (dabigatran) and factor Xa (rivaroxaban, apixaban, edoxaban) have been introduced in several clinical indications. Although NOACs have a favourable benefit-risk profile and can be used without routine laboratory monitoring, they are associated–as any anticoagulant–with a risk of bleeding. In addition, treatment may need to be interrupted in patients who need surgery or other procedures. The objective of this article, developed by a multidisciplinary panel of experts in thrombosis and haemostasis, is to provide an update on the management of NOAC-treated patients who experience a bleeding episode or require an urgent procedure. Recent advances in the development of targeted reversal agents are expected to help streamline the management of NOAC-treated patients in whom rapid reversal of anticoagulation is required.     

Coagulation and anticoagulation in extracorporeal membrane oxygenation

The hemostatic system poses a major problem in extracorporeal membrane oxygenation (ECMO). The foreign surface in the extracorporeal circuit activates platelets and the clotting system. To avoid loss of platelets and activation of the clotting system, anticoagulation is necessary. In addition, in many patients on ECMO, preexisting clotting disorders are present. Therefore, bleeding and/or thrombosis are frequent complications in ECMO patients that require specific treatment and may even necessitate termination of ECMO. Most ECMO centers use heparin for anticoagulation and the activated clotting time (ACT) for monitoring. Reduction of problems with hemostasis may be obtained with less thrombogenic surfaces, new anticoagulants with a short half-life, platelet inhibitors, protease inhibitors, or selective anticoagulation in the extracorporeal circuit. While there will probably never be a complete nonthrombogenic surface available and all anticoagulants will have some risk of bleeding, improvement can be obtained by a combination of measures including better surfaces, more sophisticated anticoagulation regimens, and close laboratory monitoring.     

Management of massive operative blood loss

Coagulopathy associated with massive operative blood loss is an intricate, multicellular and multifactorial event. Massive bleeding can either be anticipated (during major surgery with high risk of bleeding) or unexpected. Management requires preoperative risk evaluation and preoperative optimization (discontinuation or modification of anticoagulant drugs, prophylactic coagulation therapy). Intraoperatively, the causal diagnosis of the complex pathophysiology of massive bleeding requiring rapid and specific coagulation management is critical for the patient's outcome. Treatment and transfusion algorithms, based on repeated and timely point-of-care coagulation testing and on the clinical judgment, are to be encouraged. The time lapse for reporting results and insufficient identification of the hemostatic defect are obstacles for conventional laboratory coagulation tests. The evidence is growing that rotational thrombelastometry or modified thrombelastography are superior to routine laboratory tests in guiding intraoperative coagulation management. Specific platelet function tests may be of value in platelet-dependent bleeding associated e.g. with extracorporeal circulation, antiplatelet therapy, inherited or acquired platelet defects. Therapeutic approaches include the use of blood products (red cell concentrates, platelets, plasma), coagulation factor concentrates (fibrinogen, prothrombin complex, von Willebrand factor), pharmacological agents (antifibrinolytic drugs, desmopressin), and local factors (fibrin glue). The importance of normothermia, normovolemia, and homeostasis for hemostasis must not be overlooked. The present article reviews pathomechanisms of coagulopathy in massive bleeding, as well as routine laboratory tests and viscoelastic point-of-care hemostasis monitoring as the diagnostic basis for therapeutic interventions.