High-risk operations

1. Description of the problem

The challenge of high-risk operations

In recent years significant efforts have been made to reduce perioperative harm. For example, surgical safety checklists and operating room briefings have been championed by Atul Gawande and the World Health Organization to help reduce the incidence of adverse outcomes such as wrong-site surgery, and to allow the team caring for the patient to express concerns and anticipate problems. High-risk surgical patients are an under-recognized group with a disproportionately high mortality. The methods used to identify high-risk surgical patients, and the techniques and equipment to manage high-risk operations, have also seen ongoing development and increased use. The use of such techniques has been associated with reduced postoperative complications and mortality.

High-risk operations can be defined as those that carry a mortality rate of 5% or more. This high mortality rate can be attributed to a number of factors related not just to the nature of the surgery, but also to the physiological status of the patient. These factors together are thought to leave the high-risk patient unable to meet the tissue oxygen demand caused by the inflammatory response to surgery, and therefore at risk of worsening inflammation, organ dysfunction and death.

The approach to patients undergoing high-risk operations, or with a medical history suggesting high perioperative risk, includes modifying their cardiovascular parameters to reach predetermined hemodynamic goals, in order to improve tissue oxygen flux. This is known as goal-directed therapy.

Improved survival, reduced complications and shorter length of hospital stay have been shown when goal-directed therapy is used to increase cardiac index (CI) and oxygen delivery index (DO₂i) to specifically targeted levels at any point in the perioperative period.

Current treatment strategies use fluid to optimize preload, then infusions of inotropic and vasodilator drugs such as dopexamine to increase cardiac output and tissue perfusion. The implementation of goal-directed therapy assumes that chronic illnesses have been properly managed and routine ICU parameters, including hemoglobin level and arterial oxygen tension, have been optimized.

It is important to select the correct patients to receive goal-directed therapy. Research has resulted in a number of validated scoring systems that can be used to help predict perioperative mortality and therefore aid in the selection of patients to receive goal-directed therapy. However, only a minority of high-risk patients currently receive goal-directed therapy. There remains controversy surrounding the methods used to select appropriate patients, the impact on critical care resources (as patients require admission to an intensive care unit), and the techniques used to monitor hemodynamic parameters.

Clinical features of the condition

Major surgery; poor cardiopulmonary reserve; inadequate tissue oxygen delivery secondary to the stress response following surgery; high mortality.

The following steps summarize the application of goal-directed therapy to the high-risk surgical patient.

1. Select the right patient

Use a validated clinical sieve, scoring system or physiological investigation to identify high-risk surgical patients. Ensure that the management of pre-existing illness is optimized.

2. Apply relevant monitoring

Select an appropriate technique to measure stroke volume and cardiac output, in order to calculate cardiac index and oxygen delivery index. Use flow monitoring, or another method of monitoring perfusion and/or oxygen delivery.

3. Ensure optimal circulating blood volume

With monitoring in place, give fluid boluses until there is no further significant increase in stroke volume, indicating that the patient is optimally filled.

4. Start an inodilator infusion, if appropriate

Start an infusion of an inodilator, such as dopexamine, to achieve supranormal cardiac index and oxygen delivery, at any point in the immediate perioperative period (pre-, intra- or post-operatively).

5. Critical Care Admission

Admit the patient to a critical care area postoperatively, where routine elements of ICU care may also be delivered alongside the monitoring, fluids and infusions required to deliver goal-directed therapy. Continue goal-directed therapy for a defined period postoperatively (e.g. 8 hours).

Pathophysiology of high-risk surgery and the rationale for goal-directed therapy

Major surgery causes a systemic inflammatory response, which leads to increased oxygen demand in the tissues. High-risk surgical patients are thought to be less able to increase cardiac output, and their ability to extract oxygen from the blood, in order to meet this increased demand. Tissue hypoxia results and leads to endothelial activation, increased vascular permeability, cytokine release, vasoconstriction, and activation of leukocytes and the complement cascade. If left untreated, these effects can lead to worsening inflammation, organ dysfunction and death.

Goal-directed therapy in the management of high-risk surgical patients aims to modify hemodynamic parameters so that higher-than-normal amounts of oxygen are delivered to the tissues. In this way increased oxygen demand caused by the postoperative inflammatory reaction is met, and the sequelae of tissue hypoxia, microcirculatory failure, organ failure and death may be avoided.

The relationship between global oxygen delivery (DO₂), cardiac output and arterial oxygen content is expressed in the following equation:

DO₂ (ml/minute) = Cardiac Output (CO) (L/minute) x Arterial oxygen content (ml/L) (CaO₂)

Oxygen delivery is the amount of oxygen delivered to tissues per minute. It is the product of cardiac output and the oxygen content of arterial blood. DO₂ can therefore be raised by both maximizing the oxygen content of arterial blood and by increasing cardiac output. Hemoglobin level and arterial oxygen tension, which determine arterial oxygen content, should be optimized in the course of the patient’s routine management. Cardiac output is left as the remaining factor to be modulated, using fluids and inotropes to increase and maintain preload, stroke volume, and afterload.

Another method of assessing if a patient is able to meet oxygen demand is by considering the oxygen extraction ratio. The oxygen extraction ratio (OER) is the ratio of oxygen consumption in a given organ (VO₂) to oxygen delivery (DO₂).In the context of goal-directed therapy and systemic hemodynamic targets, it is usual to consider global oxygen consumption in place of organ-specific oxygen consumption.

In healthy individuals at rest, oxygen delivery (DO₂) exceeds oxygen consumption (VO₂). As oxygen is not stored in the body, a continuous supply is required for aerobic metabolism to continue. In periods of physiological stress such as surgery, where DO
₂ falls, the OER increases as tissues extract more oxygen from the remaining blood flow. If DO₂ continues to fall there comes a critical point when DO₂ equals, then falls below, VO₂. After this point anaerobic metabolism occurs and oxygen consumption becomes supply-dependent. In severe illness tissues are less able to increase the OER, making it more likely that a critical level of DO₂ will be reached.

A raised OER can be used a surrogate marker of inadequate oxygen delivery. In practical terms this means measuring the central venous oxygen saturation (ScvO₂). A ScvO₂ <70% implies that oxygen extraction is increased, and that the OER is high. Reduced oxygen delivery (DO₂), oxygen consumption (VO₂), and reduced central venous oxygen saturations (ScvO₂) are all associated with postoperative complications and increased mortality in high-risk patients. Fundamental to the management of high-risk surgical patients, therefore, is the maintenance of oxygen delivery to the body’s tissues.

The high-risk surgical patient

High-risk operations have been defined as those with a mortality of >5%. This can be derived either from a procedure with an overall mortality of >5% or a patient with an individual mortality risk of >5%. Simple clinical criteria can be used to identify high-risk surgical patients.

However, a number of scoring systems and diagnostic tests have been used to help identify patients and operations with high risk and allow appropriate management to be started early in the perioperative period. The most commonly used systems are the POSSUM score and ASA grading. Cardiopulmonary exercise testing is the best-validated test to identify poor cardiorespiratory reserve and increased surgical risk.

There has been ongoing research into methods to accurately identify those patients who would most benefit from perioperative optimization of oxygen delivery. Factors that may influence a patient’s operative risk can be divided into two groups: patient-related and procedure-related.

Procedure-related factors increase the degree of surgical insult to the body and lead to a greater inflammatory response and oxygen demand. Patient-related factors limit the body’s ability to meet increased oxygen demand. In circumstances where oxygen demand is high and oxygen delivery low, complications and death are more common.

Procedure-related factors that increase risk include:

Major surgery: in terms of extent, invasiveness or complexity
Duration of operation (to a lesser degree)

Patient-related factors that suggest higher risk include:

Reduced physical/cardiopulmonary reserve
Significant comorbidities

In the U.K. the risk of death following surgery has changed little in recent years, and identifying high-risk patients with accuracy has proved a challenge. In 2006 Pearse and colleagues analyzed data from over 4.1 million episodes of general surgery in the UK that took place between January 1999 and October 2004.

Data were from two sources: the Intensive Care National Audit and Research Centre (ICNARC) database, and the CHKS Ltd. database of validated hospital episode data used to compare institutional performance. Procedures were placed into several hundred groups that were clinically similar. Groups of procedures were then identified where the risk of death was >5%. The groups of procedures with mortality >5% include:

Emergency aortic surgery
Major surgery on the large intestine in the presence of a complicating condition
Major abdominal surgery of all types in patients aged 70 or over
Complex hip or knee revision surgery
Neck of femur fracture in patients aged 70 or over in the presence of a complicating condition
Complex procedures involving the stomach, duodenum or esophagus
Elective abdominal vascular surgery

In the context of all surgical patients, a small cohort accounts for the vast majority of perioperative deaths. In the UK, where about 3 million operations take place each year, 30-day mortality for surgical patients is estimated at 0.7-1.7%. The same 2006 analysis that described high-risk operation types showed that over 80% of deaths occurred in a cohort of only 12.5% of procedures, where a 5% or greater risk of death was identified. Despite this group’s increased mortality, only 15% of cases were admitted to a critical care area postoperatively.

Identifying the high-risk surgical patient

A number of validated methods exist to identify patients at high operative risk. Some are scoring or grading systems based on comorbidities or the nature of the anticipated surgery, whereas others are tests of the patient’s physiological reserve. Lists of clinical criteria have also been used to identify high-risk patients likely to benefit from goal-directed therapy.

The example criteria given here include:

Clinical criteria: those used by Shoemaker and modified by Boyd and colleagues are given as an example.
P-POSSUM, which scores physiological and operative severity
ASA grading, an assessment of patient comorbidities
Cardiopulmonary exercise testing

Clinical criteria

The list of clinical criteria for the identification of high-risk surgical patients first used by Shoemaker, and modified by Boyd and colleagues in 1993, is reproduced in
Table I. The criteria have been used subsequently to select patients to receive goal-directed therapy in trials of the intervention.

Table I.

1 Severe cardiac or respiratory illness resulting in severe functional limitation

2 Extensive surgery planned for carcinoma involving bowel anastomosis

3 Acute massive blood loss (>2.5 liters)

4 Aged over 70 years with moderate functional limitation of one or more organ systems

5 Septicemia (positive blood cultures or septic focus)

6 Respiratory failure (PaO₂ <8kPa on FiO₂ >0.4, that is, PaO₂:FiO₂ ratio<20 kPa or ventilation >48 hours)

7 Acute abdominal catastrophe (for example, pancreatitis, perforated viscus, gastro-intestinal bleed)

8 Acute renal failure (urea >20 mmol/l, creatinine >260 μmol/l)

9 Surgery for abdominal aortic aneurysm

PaO₂ = arterial partial pressure of oxygen; FiO_{2 =} fractional inspired concentration of oxygen

Physiological and Operative Severity Score for the enumeration of mortality and morbidity (POSSUM) and P-POSSUM (Portsmouth-POSSUM)

The POSSUM score was developed within a general surgery population to facilitate audit and enable comparison of surgical performance between different institutions. Its use has since been extended to the preoperative estimation of surgical risk, which can be individualized to each patient. It uses physiological and biochemical patient variables, as well as factors concerning the type of surgery, to generate an estimate of perioperative morbidity and mortality.

P-POSSUM is a modified version of POSSUM that gives a more accurate estimation of morbidity and mortality particularly for low-risk patients, whose risk the original POSSUM overestimated. There also exist additional specialty or procedure-specific modifications of POSSUM.

A number of websites provide POSSUM and P-POSSUM calculators, including, among others:

http://www.vasgbi.com/riskpossum.htm
http://www.surgicalaudit.com/riskcalc.asp
http://www.riskprediction.org.uk/pp-index.php

Table II. Criteria used in the calculation of the P-POSSUM score

Table II.

Physiological severity	Operative severity
Age Cardiac signs Respiratory: the presence of dyspnea Systolic blood pressure Pulse Glasgow Coma Scale Hemoglobin (g/dl) White cell count Urea (mmol/l) Sodium (mmol/l) Potassium (mmol/l) ECG: presence of arrhythmias or ischemic changes	Multiple procedures Total blood loss (ml) Peritoneal soiling Malignancy Mode of surgery

Patient comorbidity and ASA Grading

The most widely used system for assessing patient comorbidity prior to surgery is the American Society of Anesthesiologists (ASA) grading. This uses a scale from I to V, with a suffix “E” to indicate emergency surgery. It originated in 1941 as primarily a statistical tool, but it remains recognizable and in common use today. Despite its simplicity, it has been shown to provide useful prognostic information with regard to both post-operative complications and mortality.

Table III. ASA physical status classification and mortality

Table III.

Class	Description	Mortality
I	Healthy	0.1%
II	Mild systemic disease – no functional limitation	0.7%
III	Severe systemic disease – definite functional limitation	3.5%
IV	Severe systemic disease – constant threat to life	18.3%
V	Moribund patient- unlikely to survive 24 hours with or without operation	93.3%
E	Emergency operation

Investigations to identify high-risk surgical patients

There are many tests of respiratory and cardiac function. As single screening tests, however, most fail to identify accurately those patients at increased surgical risk. Cardiopulmonary exercise testing, with calculation of anaerobic threshold, has been most extensively validated for identifying high-risk patients. Anaerobic threshold is the level of exercise above which a sustained increase in blood lactate concentration occurs.

It is expressed in ml/kg/min oxygen uptake. Mortality is most strongly associated with an anaerobic threshold of <11 ml/kg/min, accompanied by inducible myocardial ischemia. When surgical patients meeting these criteria have been preoperatively optimized on an ICU in study conditions, mortality fell from 18% to 8.9% compared with management on a ward.

The American College of Cardiology and American Heart Association in 2007 published guidelines for the investigation and management of cardiac risk in patients undergoing non-cardiac surgery. To be able to compare different protocols and regimens in the functional assessment of a patient, these guidelines use the concept of “metabolic equivalents” (METs) to stratify different levels of function. The resting oxygen consumption (VO₂) of a 70-kg, 40 year-old man is 3.5 ml/kg/min and is equal to 1 MET. Excellent functional capacity is defined by a score of >10 METs. Good function is 7-10 METs, moderate is 4-7 METs, and poor function is <4 METs. Poor functional capacity (i.e. reduced METs) puts the patient into a high-risk category.

Performing goal-directed therapy

The targets used in goal-directed therapy were originally derived from observation of the physiological parameters of survivors of high-risk surgery made by Shoemaker and colleagues in 1988. These included cardiac index >/= 4.5 l/min/m², oxygen delivery index >/= 600 ml/minute/m², and tissue oxygen consumption index (VO₂i)>170 ml/minute/m². These values, which were higher than those observed in the same patients at rest preoperatively, became known as “supranormal” values.

Using goal-directed therapy to reach these targets significantly reduced mortality compared to patients who were managed using conventional parameters such as heart rate, central venous pressure and arterial blood pressure. The effect of goal-directed therapy to significantly reduce mortality, postoperative complications and length of hospital stay has been demonstrated in a number of subsequent studies.

In these studies, goal-directed therapy has shown benefit when started preoperatively, intraoperatively and postoperatively. A number of meta-analyses have also supported the association between goal-directed therapy and improved patient outcome.

Routine patient management

Routine therapy includes optimization of hemoglobin level (generally >7 g/dl, >10 g/dl in patients with ischemic heart disease), and maintenance of oxygenation and coronary artery perfusion pressure. Once routine patient management is in place, goal-directed therapy can begin.

Ensure optimal circulating volume

The initial step in goal-directed therapy is to assess the patient’s fluid status. This is done by observing if his or her stroke volume and cardiac output increase in response to a fluid challenge (known as preload responsiveness). In instigating goal-directed therapy, some form of flow monitoring is used to enable accurate monitoring of hemodynamic variables. Classical methods of assessing fluid status, such as the central venous pressure, are less reliable.

Much of the initial work concerning goal-directed therapy in high-risk surgical patients used the pulmonary artery catheter to measure hemodynamic parameters. However, insertion of a pulmonary artery catheter can be associated with the complications of pneumothorax, bleeding, infection, thrombosis, arrhythmias and pulmonary artery rupture. Less invasive methods are now routinely used to measure hemodynamic variables, and a number of proprietary devices have been validated in various studies implementing goal-directed therapy.

Most devices use either Doppler ultrasound or analysis of the arterial pressure waveform to derive values of stroke volume and cardiac output. These sophisticated, minimally invasive techniques allow the fluid status, and fluid responsiveness, of high-risk surgical patients to be determined accurately.

Use drugs to increase cardiac output in an adequately filled patient

In some studies preload optimization with fluid boluses alone has led to cardiac output and oxygen delivery targets being met. However, some patients require further therapy to meet those goals, and in those patients the use of a drug with inotropic and vasodilator effects is suggested. Commonly used drugs include dobutamine and dopexamine.

Dobutamine has both positive inotropic and vasodilator effects and has been used in a number of goal-directed therapy studies demonstrating positive outcomes. However, there had been uncertainty whether the beneficial effects of goal-directed therapy were due to the use of fluids or dobutamine, or both. In 2006 a randomized controlled trial compared the use of dobutamine and fluid with the use of fluid alone to maintain DO₂i >600 ml/min/m² in high-risk surgical patients.

Patients given both dobutamine and fluid were more likely to achieve goal-directed targets and had a lower rate of cardiovascular complications (16% versus 52%) compared to patients in the fluid-only group.

Dopexamine is also a positive inotrope and peripheral vasodilator and has actions at both beta receptors and peripheral dopamine receptors. It is probably the best studied of all the drugs used in goal-directed therapy algorithms. A systematic review and meta-regression analysis of the data published in trials using dopexamine showed that when used in low doses, less than or equal to 1 mcg/kg/minute, it was associated with a shorter median length of hospital stay (13 days versus 15 days in the control group), and a 50% reduction in 28-day mortality (6.3% versus 12.3%).

Maintenance of hemodynamic parameters at supranormal levels

After target parameters have been achieved using fluid boluses and infusions of inodilator drugs, the high-risk patient’s oxygen delivery and cardiac index should be maintained at those levels. A number of strategies have been employed postoperatively. Pearse and colleagues in their 2005 study protocol maintained supranormal values for 8 hours, using further fluid boluses in response to a falling stroke volume, and infusion of low-dose dopexamine to a maximum rate of 1 mcg/kg/min.

Side effects of dopexamine

Dopexamine infusions can cause tachycardia and induce myocardial ischemia. If the patient becomes tachycardic or complains of chest pain or anginal symptoms, or electrocardiographic changes consistent with myocardial ischemia are seen, the infusion should be stopped and the patient monitored for resolution of those changes.

The application of goal-directed therapy is summarized in Figure 1.

Summary flowchart of the use of goal-directed therapy.

Goal-directed therapy in regional anesthesia

A recent study showed a statistically significant reduction in minor postoperative complications in patients undergoing total hip replacement, under spinal anesthesia, managed with goal-directed therapy. There was also a non-significant reduction in major complications and postoperative nausea and vomiting compared to patients managed with conventional monitoring. However, the sample sizes used in the study were small, and the authors conclude that further research is required. This is, however, the first formal assessment of goal-directed therapy in regional, rather than general, anesthesia.

Commercially available flow monitors used in study of goal-directed therapy

The CardioQ (Deltex Medical, Chichester, UK) is a flow monitoring system that uses an esophageal Doppler probe to measure blood flow in the aorta. Its use in the perioperative period to guide fluid management is associated with reduced postoperative complications, shorter length of hospital stay, and faster return of gastrointestinal function.

It calculates stroke volume, corrected flow time (FTc) and cardiac index, and has high validity for monitoring changes in cardiac output compared to use of pulmonary artery catheter thermodilution. FTc is inversely proportional to systemic vascular resistance and is sensitive to changes in cardiac filling and left heart preload.

A number of studies have shown fluid optimization alone to reduce postoperative mortality and length of hospital stay. In these studies the esophageal Doppler was used to guide fluid therapy to maintain maximal stroke volume and cardiac index.

A meta-analysis of 420 patients in five studies undergoing major abdominal surgery, whose hemodynamic management was based on esophageal Doppler flow monitoring, showed a reduced length of hospital stay, fewer complications, a shorter period of gut dysfunction following surgery, fewer admissions to critical care areas and a reduced need for inotropes. Doppler-guided intraoperative fluid management is now recommended by the NHS (National Health Service) Technology Assessment Centre in the UK.

The LiDCOplus haemodynamic monitor (LiDCO Ltd, Cambridge, UK) uses an algorithm to convert arterial pressure waveform to a stroke volume measurement, and is calibrated using lithium dilution techniques. It is also well validated against the widely accepted standard of thermodilution using the pulmonary artery catheter.

A randomized controlled trial by Pearse and colleagues in 2005 using the LiDCO plus to guide postoperative goal-directed therapy led to fewer patients suffering complications (44% versus 68% in the control group) and shorter length of hospital stay (median 11 days versus 14 days in the control group). The LiDCO rapid hemodynamic monitor (LiDCO Ltd, Cambridge, UK) is an uncalibrated monitor that uses the same pulse pressure waveform algorithm as the LiDCOplus.

The PiCCO (Pulsion Medical Systems AG, Munich, Germany) is a system that uses another proprietary pulse pressure waveform algorithm. It is sensitive to changes in preload and has been used successfully in trials of goal-directed therapy in high-risk cardiac surgery patients. In a 2007 study, use of the PiCCO system to direct fluid administration intra- and post-operatively led to more rapid discharge from the ICU, along with reduced use of vasopressors and catecholamines, and shorter time spent on a ventilator.

Other methods to measure cardiac output include arterial pressure waveform analysis without calibration, using devices such as the Flowtrac sensor/Vigileo monitor (Edwards, Irvine, CA). In a randomized controlled trial of 60 high-risk patients undergoing abdominal surgery, there was a significant reduction in length of hospital stay (15 days versus 19 days in the control group), number of patients suffering complications (20% versus 50% in the control group), and total number of complications in each group (17 versus 49 complications).

Another study used the Flowtrac/Vigileo to guide fluid management targeted against stroke volume variation, and led to a reduced incidence of complications, fever episodes of hypotension, and reduced serum lactate postoperatively.

Drugs used in goal-directed therapy

The drugs used in goal-directed therapy vary based on institutional or study protocols, local availability, and user preference. In general, boluses of a starch, gelatine or dextran-based fluid are used to optimize the preload. A common protocol is of 250-ml boluses given stat, repeated until the measured rise in stroke volume is <10%. Fluids used include:

Succinated gelatin 4% solution (Volplex®, IS Pharmaceuticals, Chester, UK)
Hydroxyethyl starch 6% 130/0.4 solution (Voluven®, Fresenius Kabi, Bad Homburg, Germany)

Inodilator drugs used include Dopexamine (Dopacard®, Cephalon Pharmaceuticals, Frazer, PA, USA). Dopexamine is given as a low-dose infusion of 0.25-1 microgram/kg/min.

What's the evidence?

General and review articles concerning goal-directed therapy

Lees, N, Hamilton, M, Rhodes, A. “Clinical review: Goal-directed therapy in high risk surgical patients”. Critical Care. vol. 13. 2009. pp. 231(A review summarizing the pathophysiology of high-risk surgery, identification and management of high risk operations.)

Pathophysiology of High-Risk Surgery and the Rationale for Goal-Directed Therapy

Karimova, AK, Pinsky, DJ. “The endothelial response to oxygen deprivation: biology and clinical implications”. Intensive Care Med. vol. 27. 2001. pp. 19-31. (Review of the physiological response to hypoxia at the tissue and cellular level.)

Jhanji, S, Vivian-Smith, A, Lucena-Amaro, S, Watson, D, Hinds, CJ, Pearse, RM. “Haemodynamic optimisation improves tissue microvascular flow and oxygenation after major surgery: a randomised controlled trial”. Critical Care. vol. 14. 2010. pp. R151(A study demonstrating the effects of fluid optimization with the addition of dopexamine infusion on sublingual and cutaneous microvascular flow, compared to patients receiving conventional postoperative management.)

Identifying the High-Risk Surgical Patient

Pearse, RM, Harrison, DA, James, P, Watson, D, Hinds, C, Rhodes, A, Grounds, RM, Bennett, ED. “Identification of the high-risk surgical population in the United Kingdom”. Critical Care. vol. 10. 2006. pp. R81(An analysis of outcome data from two large databases of surgical activity in the United Kingdom. This paper helped define the groups of patients and procedures that fall into the high-risk category of >/= 5% mortality. It also showed that only 15% of these high-risk patients were admitted to critical care areas postoperatively.)

Older, P, Hall, A. “Clinical review: how to identify high-risk surgical patients”. Crit Care. vol. 8. 2004. pp. 369-372. (A review of the investigations used to identify high-risk surgical patients.)

Boyd, O, Jackson, N. “Clinical review: How is risk defined in high-risk surgical patient management?”. Critical Care. vol. 9. 2005. pp. 390-396. (A review discussing the concepts and assessment of risk in high-risk surgical patients.)

Prytherch, DR, Whiteley, MS, Higgins, B, Weaver, PC, Prout, WG, Powell, SJ. “POSSUM and Portsmouth POSSUM for predicting mortality. Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity”. Br J Surg. vol. 85. 1998. pp. 1217-20. (Describes the development of the P-POSSUM score for prediction of mortality in surgical patients.

Wolters, U, Wolf, T, Stutzer, H, Schroder, T. “ASA classification and perioperative variables as predictors of postoperative outcome”. Br J Anaesth. vol. 77. 1996. pp. 217-22. (A study examining the association between ASA physiological status classification and postoperative outcome.)

Fleisher, LA. “ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery) Developed in Collaboration With the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery”. J Am Coll Cardiol. vol. 50. 2007. pp. e159-241. (The ACC/AHA guidelines for preoperative cardiovascular evaluation.)

Performing Goal-Directed Therapy

Shoemaker, WC, Appel, PL, Kram, HB, Waxman, K, Lee, TS. “Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients”. Chest. vol. 94. 1988. pp. 1176-86. (This early study helped establish the concept of using supranormal physiological values as targets for goal-directed therapy. The targets used were derived from observing those parameters in patients who had survived high-risk surgery. The group of patients for whom supranormal targets of CI, DO2i and VO2i were used had a significantly reduced mortality.)

Boyd, O, Grounds, RM, Bennett, ED. “A randomized clinical trial of the effect of deliberate perioperative increase of oxygen delivery on mortality in high-risk surgical patients”. JAMA. vol. 270. 1993. pp. 2699-707. (A randomized controlled trial applying goal-directed therapy to a cohort of high-risk surgical patients led to a 75% reduction in mortality in the intervention group.)

Pearse, R, Dawson, D, Fawcett, J, Rhodes, A, Grounds, RM, Bennett, ED. “Changes in central venous saturation after major surgery, and association with outcome”. Critical Care. vol. 9. 2005. pp. R694-9. (Demonstrated the relationship between low central venous oxygen saturations and increased morbidity and mortality.)

Pearse, R, Dawson, D, Fawcett, J, Rhodes, A, Grounds, RM, Bennett, ED. “Early goal-directed therapy after major surgery reduces complications and duration of hospital stay. A randomised, controlled trial [ISRCTN38797445]”. Critical Care. vol. 9. 2005. pp. R687-93. (A randomized controlled trial of goal-directed therapy, using a minimally invasive hemodynamic monitor, reduced the proportion of patients developing complications from 68% in the control group to 44%, and the median length of hospital stay from 14 days to 11 days.)

Commercially available flow monitors used in studies of goal-directed therapy

Jhanji, S, Dawson, J, Pearse, RM. “Cardiac output monitoring: basic science and clinical application”. Anaesthesia. vol. 63. 2008 Feb. pp. 172-81. (A review of the basic science of cardiac output monitoring.)

Alhashemi, JA, Cecconi, M, Hofer, CK. “Cardiac output monitoring: an integrative perspective”. Critical Care. vol. 15. 2011. pp. 214(A review of the techniques and devices used in monitoring cardiac output and other hemodynamic variables.)

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