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- 1. TERAPIA DIRIGIDA POR METAS EN CIRUGÍA MAYOR NO CARDIACA SERGIO OCHOA CASTRILLÓN RESIDENTE DE ANESTESIOLOGÍA TERCER AÑO TUTOR DR JAVIER BENÍTEZ
- 2. Anesthetic considerations for the patient with liver disease. Curr opin anesth 2012
- 3. CONTENIDO DEFINICIÓN CAMBIOS FISIOPATOLÓGICOS EN CIRUGÍA MAYOR CONCEPTOS, BENEFICIOS Y RIESGOS DE LA TERAPIA DIRIGIDA POR METAS MONITORIA IDEAL INTERVENCIONES Y ALGORITMO CONCLUSIONES
- 4. Anesthetic considerations for the patient with liver disease. Curr opin anesth 2012
- 5. GENERALIDADES • Cirugía mayor: 230 millones/año • 18% complicaciones POP – Compromiso funcionalidad – Mayor mortalidad a mediano plazo • 3 – 5% mortalidad antes del egreso • Papel terapia dirigida por metas • ¿Por qué no la usamos? Marik P. Perioperative hemodynamic optimization: a revised approach. Journal of Clinical Anesthesia (2014)
- 6. DEFINICIÓN • Uso apropiado fluidos, inotrópicos y vasoactivos Intervenciones terapéuticas para lograr una meta determinada • Evitar disoxia tisular – Relación DO₂/VO₂ • Garantizar perfusión orgánica durante cirugía Satisfacer aumento en la demanda de oxígeno • Subutilización Reducción morbimortalidad POP Independientemente del monitor hemodinámico utilizado Clinical review: Goal-directed therapy - what is the evidence in surgical patients? The eff ect on diff erent risk groups. Critical Care 2013
- 7. CAMBIOS FISIOPATOLÓGICOS EN CIRUGÍA MAYOR • Directa: acceso quirúrgico y remoción de órgano • Indirecta: pérdidas hemáticas, perfusión, técnica anestésica Lesión primaria • Consecuencia • Mediada directamente: citoquinas, hormonal, neural Lesión secundaria RESPUESTA AL ESTRÉS Scott M. Pathophysiology of Major Surgery and the Role of Enhanced Recovery Pathways and the Anesthesiologist to Improve Outcomes. Anesthesiology Clin. 2015
- 8. Scott M. Pathophysiology of Major Surgery and the Role of Enhanced Recovery Pathways and the Anesthesiologist to Improve Outcomes. 2015
- 9. LESIÓN PRIMARIA INDIRECTA • Pérdidas hemáticas – Reducción DO₂ – Causa SIRS • Hipoperfusión local – Disfunción celular secundaria – Riesgo infecciones – Compromiso anastomosis • Papel del anestesiólogo – Tono vasomotor – Fluidoterapia Scott M. Pathophysiology of Major Surgery and the Role of Enhanced Recovery Pathways and the Anesthesiologist to Improve Outcomes. Anesthesiology Clin. 2015
- 10. Joosten A. Defining Goals of Resuscitation in the critically I ll Patient. Crit Care Clin. 2015
- 11. Joosten A. Defining Goals of Resuscitation in the critically I ll Patient. Crit Care Clin. 2015
- 12. HIPOVOLEMIA “Sacrificio órganos no vitales” Activación SNS y eje RAA Aumento respuesta inflamatoria Conlleva a mayor dosis de vasopresores Joosten A. Defining Goals of Resuscitation in the critically I ll Patient. Crit Care Clin. 2015
- 13. HIPERVOLEMIA Extravasación fluidos (edema secundario) Mayor demanda miocárdica Disminución oxigenación tisular Hemodilución (coagulopatía) Mayor mortalidad (balance positivo) Joosten A. Defining Goals of Resuscitation in the critically I ll Patient. Crit Care Clin. 2015
- 14. ORIGEN DEUDA DE OXÍGENO Marik P. Perioperative hemodynamic optimization: a revised approach. Journal of Clinical Anesthesia (2014)
- 15. Anesthetic considerations for the patient with liver disease. Curr opin anesth 2012
- 16. HISTORIA TERAPIA DIRIGIDA POR METAS (GDT) • Shoemaker (1988) • CAP: metas suprafisiológicas (IC ≥ 4.5 L/min/m², DO₂ ≥ 600 ml/min) • Disminución mortalidad en pacientes de alto riesgo • Relación < IC e hipoperfusión mucosa intestinal • Optimización volumen y uso inotrópicos Waldron N. Perioperative Goal-DirectedTherapy. Journal of Cardiothoracic and Vascular Anesthesia. 2014
- 17. Cirugía mayor Complicaciones POP prevenibles Morbimortalidad a largo plazo Clinical review: Goal-directed therapy - what is the evidence in surgical patients? The eff ect on diff erent risk groups. Critical Care 2013
- 19. BENEFICIOS TERAPIA DIRIGIDA POR METAS Menor estancia hospitalaria Menor estancia en UCI Menores complicaciones gastrointestinales • Balance perfusión y edema intersticial Disminución incidencia injuria renal aguda Mayor sobrevida a largo plazo (15 años) Menor íleo y PONV ¿Riesgo sobrecarga hídrica y descompensación cardiaca? Waldron N. Perioperative Goal-DirectedTherapy. Journal of Cardiothoracic and Vascular Anesthesia. 2014
- 20. • Revisión sistemática • MEDLINE – EMBASE – COCHRANE • 32 ensayos clínicos controlados • 2.808 pacientes (1.438 GDT – 1.370 controles) • 1988 – 2011 Clinical review: Goal-directed therapy - what is the evidence in surgical patients? The eff ect on diff erent risk groups. Critical Care 2013
- 21. MORTALIDAD Grupo riesgo intermedio (mortalidad 0 – 4.9%) Grupo riesgo alto (mortalidad 5 – 19.9%) Grupo riesgo extremadamente alto (mortalidad ≥ 20%)
- 22. MORBILIDAD Grupo riesgo intermedio (mortalidad 0 – 4.9%) Grupo riesgo alto (mortalidad 5 – 19.9%) Grupo riesgo extremadamente alto (mortalidad ≥ 20%)
- 23. RESULTADOS Optimización de metas demostró mejores desenlaces Uso combinado de fluidos e inotrópicos fue superior No hay duda del beneficio de la terapia dirigida por metas Se requiere un protocolo claramente definido ¿POR QUÉ NO LA UTILIZAMOS? Clinical review: Goal-directed therapy - what is the evidence in surgical patients? The eff ect on diff erent risk groups. Critical Care 2013
- 24. Anesthetic considerations for the patient with liver disease. Curr opin anesth 2012
- 25. ¿CUÁL ES LA MONITORIA IDEAL EN GDT? • Monitor ideal • Representativo de perfusión tisular • Disponible • Continua • Reproducible • No invasivo • Bajo costo Waldron N. Perioperative Goal-DirectedTherapy. Journal of Cardiothoracic and Vascular Anesthesia. 2014
- 26. Frecuencia cardiaca Tensión arterial Gasto urinario Waldron N. Perioperative Goal-DirectedTherapy. Journal of Cardiothoracic and Vascular Anesthesia. 2014 • Medidas insensibles del estado de volemia • Monitoria indiscutible PVC PCCP • Utilidad limitada demostrada como medida de precarga
- 27. CATÉTER ARTERIA PULMONAR • Gran papel histórico • Controversial • Errores en interpretación • No se ha demostrado mejoría en desenlaces en GDT • Papel importante en poblaciones especiales: – Estado hemodinámico complejo – Pacientes ancianos Isbell J. Impact of hemodynamic monitoring on clinical Outcomes. Best Practice & Research Clinical Anaesthesiology 2014
- 28. DOPPLER ESOFÁGICO • Medición flujo aorta descendente • Valoración volumen sistólico y gasto cardiaco • Disminución morbilidad y estancia hospitalaria en GDT • Recomendado por Instituto Nacional de Excelencia Clínica y Salud (NICE) Waldron N. Perioperative Goal- DirectedTherapy. Journal of Cardiothoracic and Vascular Anesthesia. 2014
- 29. TÉCNICAS BASADAS EN ANÁLISIS DEL CONTORNO DE PULSO Waldron N. Perioperative Goal- DirectedTherapy. Journal of Cardiothoracic and Vascular Anesthesia. 2014
- 30. UTILIDAD MEDIDAS DINÁMICAS Variación de ondas de presión arterial depende de la volemia Predice respuesta a fluidos No son marcadores de volemia ni precarga Mejores predictores que medidas de presión de llenado % utilización: • Año 1998: 1% • Año 2012: 45% ¿Mejora desenlaces? The effects of goal-directed fluid therapy based on dynamic parameters on post-surgical outcome: a meta-analysis of randomized controlled trials. Critical Care 2014
- 31. UTILIDAD MEDIDAS DINÁMICAS Meta-análisis Desenlace primario: morbilidad POP 14 artículos: 961 pacientes 2007 – 2013 Europa – China – USA – India – Brasil • Variabilidad volumen sistólico (SVV) • Variabilidad presión de pulso (PPV) • Variabilidad presión sistólica (SPV) • Índice de variabilidad pletismográfica (PVI) The effects of goal-directed fluid therapy based on dynamic parameters on post-surgical outcome: a meta-analysis of randomized controlled trials. Critical Care 2014
- 32. Anesthetic considerations for the patient with liver disease. Curr opin anesth 2012
- 33. Reducción significativa en morbilidad global The effects of goal-directed fluid therapy based on dynamic parameters on post-surgical outcome: a meta-analysis of randomized controlled trials. Critical Care 2014 Reducción significativa en estancia en UCI, morbilidad infecciosa, cardiovascular y abdominal Tendencia a la reducción de complicaciones respiratorias No diferencias en complicaciones renales
- 34. UTILIDAD MEDIDAS DINÁMICAS Beneficios de parámetros dinámicos similar a parámetros de flujo Método más simple, no requiere cálculos Costo-eficiente • Requiere Vt ≥ 8 ml/kg • No útil en presencia de arritmias, hipertensión abdominal o tórax abierto • Heterogeneidad en protocolos de tratamiento Sin embargo tiene limitaciones: The effects of goal-directed fluid therapy based on dynamic parameters on post-surgical outcome: a meta-analysis of randomized controlled trials. Critical Care 2014
- 35. MARCADORES DE BIENESTAR TISULAR Complemento a dispositivos de monitoria continua Indicadores de aporte/consumo O₂ Medida intermitente Beneficio en desenlaces clínicos No hay clara superioridad de alguna en GDT (lactato – BE - SVO₂ - ERO₂ - P(v a)CO₂) Isbell J. Impact of hemodynamic monitoring on clinical Outcomes. Best Practice & Research Clinical Anaesthesiology 2014
- 36. MICROCIRCULACIÓN • Objetivo fundamental de todo manejo • Estudios clínicos iniciales Isbell J. Impact of hemodynamic monitoring on clinical Outcomes. Best Practice & Research Clinical Anaesthesiology 2014
- 37. Anesthetic considerations for the patient with liver disease. Curr opin anesth 2012
- 38. PRESIÓN CONT MANEJO ÁCIDO BASE MANEJO VENT OXIGEN MEDIDA DESEMPEÑO CARDIACO VALORACIÓN DEPENDENCIA VOLUMEN PVC O SVCO₂ PCCP O SVMO₂ CVC SI LÍNEA ARTERIAL SI SI SI SI CONTORNO PULSO SI SI SI SI SI CAP SI SI SI SI DOPPLER ESOFAGICO SI SI BIOIMPED SI SI
- 39. FLUIDO IDEAL Coloides no reducen riesgo de complicaciones ni muerte Hidroxietil starch aumenta riesgo de muerte (RR 1 IC95% 1.02 – 1.09) Coloides costo mucho mayor a cristaloides Perel P. Colloids versus crystalloids for fluid resuscitation in critically ill patients (Review) The Cochrane Collaboration. 2013 No hay gran evidencia en cuanto al inotrópico o vasoactivo ideal en GDT
- 40. FLUIDO IDEAL • ¿Cristaloides balanceados o no? • Revisión sistemática 706 pacientes • No diferencias en morbimortalidad entre grupos • Cristaloides no balanceados: – Mayor hipercloremia y acidosis metabólica – Mayor necesidad de trasfundir plaquetas Burdett E. Perioperative buffered versus non-buffered fluid administration for surgery in adults (Review) The Cochrane Collaboration. 2013
- 41. FLUIDO IDEAL Rusell L. The ideal fluid. Curr Opin Crit Care 2014, 20.
- 42. Anesthetic considerations for the patient with liver disease. Curr opin anesth 2012
- 43. ¿Existe riesgo de complicaciones cardiacas en pacientes de alto riesgo?
- 44. RIESGOS TERAPIA DIRIGIDA POR METAS • Metaanálisis • 22 RCT • 2129 pacientes • Reducción complicaciones cardiovasculares (OR: 0.54 (0.38 – 0.76) y arritmias (OR: 0.54 (0.35 – 0.85) • No diferencias en desarrollo de edema pulmonar agudo ni isquemia miocárdica • Mayor beneficio con monitoria mínimamente invasiva Arulkumaran N. Cardiac complications associated with goal directed therapy in high-risk surgical patients: a meta analysis. British Journal of Anaesthesia. 2014
- 45. TERAPIA DIRIGIDA POR METAS Elegir monitoria según contexto del paciente Control periódico medidas de bienestar tisular VVS < 12% IC ≥ 2.5 l/min/m² TAM en metas Revalorar cada 15 minutos Cristaloide balanceado (si ↓ IC considerar dobutamina) Dobutamina Norepinefrina NO NO NO
- 46. CONCLUSIONES • Es fundamental lograr una adecuada perfusión tisular en el paciente llevado a cirugía mayor • La terapia dirigida por metas basada en fluidos, inotrópicos y vasoactivos ha demostrado claramente un beneficio a corto, mediano y largo plazo • La elección del monitoreo depende del contexto de cada paciente
- 47. CONCLUSIONES La pregunta que queda por resolver es…. ¿POR QUÉ NO LA USAMOS?
- 48. Joosten A. Defining Goals of Resuscitation in the critically I ll Patient. Crit Care Clin. 2015
- 49. Anesthetic considerations for the patient with liver disease. Curr opin anesth 2012
- 50. Anesthetic considerations for the patient with liver disease. Curr opin anesth 2012 MUCHAS GRACIAS
- 51. Anesthetic considerations for the patient with liver disease. Curr opin anesth 2012
- 52. Anesthetic considerations for the patient with liver disease. Curr opin anesth 2012
- 53. Anesthetic considerations for the patient with liver disease. Curr opin anesth 2012
- 54. Anesthetic considerations for the patient with liver disease. Curr opin anesth 2012
- 55. Anesthetic considerations for the patient with liver disease. Curr opin anesth 2012
- 57. • Un hermano puede no ser un amigo, pero un amigo será siempre un hermano Demetrio de Falero Anesthetic considerations for the patient with liver disease. Curr opin anesth 2012
Notas del editor
- La que hace referencia a los procedimientos quirúrgicos más complejos, con más riesgo, frecuentemente realizados bajo anestesia general o regional (anestesia epidural, lumbar o espinal) y asistencia respiratoria, comportando habitualmente cierto grado de riesgo para la vida del paciente o de grave discapacidad y en la que tanto la preparación para la misma, excepto en la cirugía de emergencia, como su recuperación puede tomar varios días o semanas. Cualquier penetración de la cavidad corporal (cráneo, tórax, abdomen o extensas cirugías de extremidades.) es considerada una Cirugía Mayor. Respecto al riesgo cardiaco, las intervenciones quirúrgicas pueden clasificarse en intervenciones de bajo riesgo, riesgo intermedio y riesgo alto, con tasas estimadas de eventos cardiacos (muerte cardiaca e IM) a los 30 días < 1, 1-5 y > 5%, respectivamente (tabla 4). Pese a tratarse de una clasificación muy amplia, esta estratificación de riesgo es un instrumento útil para establecer la necesidad de una valoración cardiaca, el tratamiento farmacológico y el cálculo de riesgo de eventos cardiacos. En el grupo con alto riesgo se incluye la cirugía vascular mayor. En la categoría de riesgo intermedio, éste depende de la magnitud, la duración, la localización, la pérdida de sangre y la alteración de fluidos relacionados con el procedimiento específico. En el grupo con riesgo bajo, el riesgo cardiaco es insignificante, excepto en presencia de otros factores de alto riesgo específicos del paciente.
- More than 230 million major surgical procedures are undertaken worldwide each year [1]. Data from the United States and Europe suggest that approximately 18% of patients undergoing surgery will develop a major postoperative complication, and 3% to 5% will die before hospital discharge [1–4]. Those patients who develop a postoperative complication and survive to hospital discharge have diminished functional independence and reduced long-term survival. In a landmark study, Khuri and coworkers demonstrated that survival up to 8 years after major surgery was strongly related to the development of a major postoperative complication within 30 days of surgery [4]. Interventions that reduce the risks of postoperative death and complications, particularly in high-risk patients, have become a priority in perioperative medicine [5]. Preemptive goal-directed hemodynamic therapy (GDT) appears to be a promising approach to reducing postoperative complications and deaths. In general, GDT is based on the titration of fluids and inotropic drugs to physiological, flowrelated endpoints. Randomized controlled trials (RCTs) performed over the last two decades have shown that GDT improves patient outcomes [6–9]. Furthermore, the U.K. National Health Service’s National Institute for Health and Clinical Excellence (NICE) has recommended GDT (using esophageal Doppler) for patients undergoing major or highrisk surgery [10,11].However, these recommendations and the encouraging results from clinical trials have not led to the widespread adoption of perioperative hemodynamic optimization [12]. Over 30 RCTs have been performed to explore the benefits ofGDT.Anumber of different technologies (pulmonary artery catheter, esophageal Doppler, and pulse contour analysis) and treatment algorithms have been used to optimize perioperative hemodynamics. Most of these studies have used both fluids and inotropic agents to optimize cardiac output (CO). Furthermore, GDT has been initiated preoperatively, intraoperatively, and postoperatively. Meta-analyses of these studies have demonstrated that this approach reduces complications in patients undergoing elective noncardiac surgery [6–9], and reduces mortality in high-risk patients [6]. However, the most recent Cochrane review on this topic reported no overall mortality benefit. It concluded that “the balance of current evidence does not support widespread implementation of this approach reducing mortality but does suggest that complications and duration of hospital stay are reduced” [13]. This recommendation was based on the overall treatment effect, which included studies performed in cardiac surgery patients and patients undergoing emergency surgery, the two groups of patients least likely to benefit fromperioperative hemodynamic optimization. In the Cochrane analysis, there was a significant reduction in mortality in patients undergoing elective surgery [RR of 0.68 (95% CI: 0.48 - 0.94); P = 0.02]. Few studies have been performed comparing different GDT strategies; therefore, the optimal approach remains unclear [14–16]. Recent data suggest that major surgery is associated with a significant mortality risk.1 An even higher numberof patients develop postoperative complications.2 3 The associated health and financial impact associated with postoperative complications is important, as these patients are at greater risk of longterm morbidity and mortality.4 Identifying patients who are at greatest risk of perioperative complications enable appropriate preventive measures to be taken.5 A limited cardiopulmonary reserve is a major risk factor for perioperative morbidity and mortality; as such, patients are less likely to meet the increased oxygen demand incurred during major surgery.6 Perioperative goal-directed therapy (GDT) utilizesflow-basedhaemodynamic monitoring and therapeutic interventions as a means to augment the patients’ global oxygen delivery to achieve a predetermined haemodynamic endpoint. This is with the aim of ensuring that those with poor perioperative cardiovascular (CVS) performance achieve the DO2I seen in survivors without postoperative complications. When carried out early, in the right patient cohort, and with a clearly defined protocol, GDT has been shown to reduce postoperative mortality and morbidity.7 Despite this, postoperativeGDT is not carried out widely. This may relate to lack of resources or doubts about its benefits. It is estimated that about 240 million anesthesia procedures are performed each year around the world.50 Among them, 24 million (w10%) are conducted in “high-risk” patients. Although it can be considered a small percentage of the whole population, one must remember that this sample accounts for more than 80% of the overall mortality related to surgery.51 Moderate-risk surgery is much more common and represents approximately 40% of the whole population (96 million patients a year). Thankfully, most of these patients present with uncomplicated postoperative course. However, it is estimated that approximately 30% of them (w29 million patients a year) present with a “minor” postoperative complication, most commonly a gut injury inducing delayed enteral feeding, abdominal distension, nausea, vomiting, or wound complications, such as wound dehiscence or pus from the operation wound.52 Even if these complications are said to be “minor,” they still induce increased postoperative medication, increased length of stay (LOS) in the hospital, and an increase in the cost of the medico-surgical management. In most of these patients, postoperative complications are related to tissue hypoperfusion and inadequate perioperative resuscitation.52,53 Upgrading surgical patients from moderate risk to high risk depends on surgical and patient-related factors. High-risk surgical patients are those with an individual mortality risk greater than 5% or undergoing a surgery carrying a mortality of 5%. These patients commonly have a limited cardiopulmonary reserve and an inability to meet the increased oxygen demand imposed by the perioperative surgical stress during major surgery, which is associated with a significant mortality risk.
- Perioperative goal-directed therapy (GDT) aims to match the increased oxygen demand incurred during major surgery, by fl ow-based haemodynamic monitoring and therapeutic interventions to achieve a predetermined haemodynamic endpoint. When carried out early, in the right patient cohort, and with a clearly defi ned protocol, GDT has been shown to reduce postoperative mortality and morbidity [5]. Despite this, postoperative GDT is not carried out widely, perhaps due to the lack of evidence for its benefi t from large multicenter randomized clinical trials. Scepticism about GDT may exist for a number of reasons: many of the studies performed may be considered outdated; the high mortality rates in some of the studies performed are not representative of current clinical practice; and pulmonary artery catheters (PACs) are used in many of the clinical trials but have been largely superseded by less invasive haemodynamic monitors. A recent meta-analysis has demonstrated that although studies prior to 2000 demonstrate a benefi t in mortality, studies con ducted after 2000 demonstrate a signifi cant reduction in complication rates [5]. Furthermore, the reduction in complication rates is signifi cant regardless of the type of haemodynamic monitor used. The primary role of anesthesiologists is to mitigate risk and improve outcomesthroughouttheperioperativeperiod.While shepherding patientsthroughthepre-,intra-,andpostoperative periods, thereareseeminglyendlesshazardstoavoidand details tobecheckedtoprovideoptimalcare.However,despite the uniquedetailsofeachandeverysurgicalprocedure,the final commonpathwayinmanyperioperativeorganinsultsis tissue dysoxiaoranimbalancebetweenoxygensupplyand demand.1 As such,animportantwayinwhichtheauthorsare able toreduceperioperativeriskandimproveoutcomesis through ensuringoptimalend-organperfusionduringsurgery. Adverse outcomeshavebeenassociatedwithbothunder- and over-resuscitation.2 Inadequate intraoperativeresuscitation can leadtoinadequateend-organperfusion,3 which may worsen perioperativeoutcomes.2 Conversely, excessiveintra- operative fluid volumesorover-resuscitationcanresultin increased intra-aswellasextravascularvolumes,whichmay precipitate peripheraland/orpulmonaryedema.Certainsurgical types, suchasgastrointestinalandthoracicsurgery,necessitate diligent attentiontopreventingperioperative fluid overload,as this mayimpairgastrointestinal2 and pulmonary4 function. To trytoaddressthisneedforoptimaltissueoxygendelivery, the conceptofgoal-directedtherapywasintroduced,whereby hemodynamic parametersand/oroxygendeliveryaremoni- tored closely(typicallyusing flow-based monitors)andopti- mized with fluids and/orinotropes. Recentmeta-analysis found thatthereductioninmortalitywithperioperativeGDT was significant onlyinpatientswithanextremelyhigh (420%) mortalityrate,andthatmortalityratehasdeclined significantly overtime.24,70 It islikelythatpatientswiththe highest riskofmortalitybenefit mostfromaggressiveGDT(ie, PAC placement,useofvasoactivesubstancestotargetsupra- normal hemodynamicparameters),whereasmostpatients derive amorbiditybenefit fromperioperativeGDT.Unfortu- nately, surveydatashowthatthereisstillanunderutilizationof perioperative GDT,partiallyowingtoaperceivedlackof benefit aswellasinadequateavailabilityofortrainingwith various monitors.71
- PRIMARY INJURY Direct Cellular Injury Surgical access, tissue dissection, mobilization, and extraction The stress response to surgery is proportional to the type of injury and duration of insult. This results in localized tissue trauma, and cytokine and inflammatory mediator release, which drive a complex bundle of metabolic, hormonal, and immunologic processes in the body, the so-called stress response. Minimizing this process can have a profound effect on how the body responds to surgery. However, some surgical procedures have more impact than others, even through similar surgical access sites, because the organ being removed or operated on can trigger a large systemic inflammatory response or impair gut function, which can impair the restoration of normal homeostasis (eg, open two-stage esophagectomy). Secondary injury from surgery is classically described as the stress response. This process releases local cytokine and inflammatory mediators driving a complex process of metabolic, hormonal, and immunologic processes in the whole body. The peak cytokine response and duration is proportional to primary surgical injury and blood loss. These can be minimized by surgical technique. The hormonal and metabolic effects in response to surgery are one of the key factors that an ERP attempts to modify, principally by achieving early gut function (to reverse the catabolic response to surgery) and restoring the patient to independent mobility. Neural effects can also be minimized by appropriate analgesic techniques to reduce the central effects of pain and improve mobility, function, and sleep postoperatively. Cytokine Cellular injury causes the release of cytokines and inflammatory mediators, such as interleukin IL-6, IL-1, IL-8, tumor necrosis factor-a, and C-reactive protein. This causes local inflammation and stimulation of afferent neurons, which carry impulses through the spinal cord up to the brain. There is release of corticotrophin from the hypothalamus and activation of the locus-coeruleus-noradrenergic systems. Both systems have a positive feedback on each other. The coeruleus-noradrenergic system stimulates the sympathetic nervous system and catecholamine release from the adrenal medulla. Circulating catecholamines have a varied effect on organs and tissue throughout the body. The effect on b cells of the pancreas is to inhibit the secretion of insulin, which is an anabolic hormone. Hormonal Hormonal effects after surgery are complex and variable. The key issue for surgical outcome is that the body develops a state of insulin resistance. Insulin is needed for the passage of glucose and amino acids into cells, so this has a direct effect on cellular function and crucially, healing of damaged tissue. Several studies have shown that the degree of insulin resistance is proportional to the magnitude of surgery. Insulin resistance can usually be overcome with administration of more endogenous insulin.19 Glycemic control has been shown to be an important predictor of complications.20 Glycemic control within the range of 8 to 10 mmol/L with the use of exogenous insulin is normal practice on intensive care units with the Leuven study showing improved outcomes21; however, overaggressive management of blood sugar levels was shown to increase mortality.22 Early feeding (hormonal effects) and mobility (muscle effect) help to reverse the state of insulin resistance. Neural The neural mechanism of the stress response is mediated by receptors activated by tissue injury and subsequent inflammation. Surgical access causes damage to skin and muscle injury, and injury to intra-abdominal organs and the peritoneum cause visceral fiber activation. The ascending pathways cause release of corticotrophin fromthe hypothalamus and activation of the locus-coeruleus-noradrenergic systems as outlined previously. The key issue for the anesthesiologist is that the use of local, truncal, and regional anesthetic techniques can alter this part of the stress response. Consequential Effects The result of the stress response, pain and gut dysfunction after surgery, leads to a state of fasting and immobility that can further exacerbate an altered metabolic state of insulin resistance, which reduces the availability of glucose and amino acids for cellular function and repair. Unfortunately, this process is often exacerbated by medical intervention. For instance, the normal treatment of ileus can be insertion of a nasogastric tube and intravenous fluids (often with high sodium), which can lead to further bowel edema and prolong the period of ileus. The abdominal distention leads to pressure on the diaphragm and pulmonary basal hypoventilation, which leads to hypoxia and increased risk of pulmonary infection and a SIRS response. Therefore, a multimodal strategy to prevent ileus is extremely important. The key factors to reduce ileus are reducing surgical manipulation and handling of the gut; maintaining gut perfusion during the perioperative period; avoiding fluid excess, particularly above 30 mL/ kg total fluid gain; avoiding salt overload; and reducing opioids to a minimum.
- Indirect Cellular Injury Indirect cellular injury during surgery is caused by changes in blood supply or oxygen and nutrient delivery. Blood loss Blood loss reduces global oxygen delivery, which can lead to reduction in localized tissue oxygen delivery. Total oxygen delivery is determined by the combination of cardiac output, hemoglobin concentration, and oxygen saturation. Local oxygen delivery can be further complicated by changes in local perfusion, the causes of which are discussed next. Blood loss also triggers a systemic inflammatory response syndrome (SIRS), particularly if intravascular volume is compromised to cause organ dysfunction. 13,14 It is likely this effect is proportional to the total volume of blood loss. Thus, blood loss of up to 5 mL/kg is well tolerated, but increasing losses after this have a greater physiological impact. Local perfusion and microvascular changes Local perfusion to organs can be affected by a multitude of factors. Retraction of tissue, clamping or coagulation of blood vessels, and mobilization of the gut can alter local perfusion and delivery of oxygen and nutrients to the cells causing cellular dysfunction. Local perfusion may also be affected during pneumoperitoneum because of direct pressure effects and changes in oxygen delivery15 and effects on vital organs. 16 Even after surgery there is evidence that microcirculatory blood flow around surgical sites, such as anastomosis, can be impaired for a significant period postoperatively even in the face of normal global oxygen delivery. Most anesthetic drugs reduce vasomotor tone and interfere with autoregulatory mechanisms to maintain local pressure and flow. Remifentanil, which is popular as a continuous opioid infusion for rapid awakening, can reduce venous tone and pulse pressure. TEA and spinal anesthesia effect arteriolar and venous tone because of a sympathetic block, which leads to vasodilatation and hypotension unless corrected by the anesthetist. Vasopressors can restore these physiologic effects but if used inappropriately they can also cause problems particularly if vasoconstriction is maintained in the face of hypovolemia. Boluses can lead to erratic changes in blood pressure and venous tone because there is variation in arteriolar and venous effect of vasopressors depending on the patient and their intravascular volume status. Fluid therapy is an important component of Enhanced Recovery under the control of the anesthesiologist. Fluid therapy has a direct effect on intravascular volume and cardiac output with a resultant effect on oxygen and nutrient delivery to the tissues. There are also complex effects downstream on the microcirculation and vascular beds.
- Decrease in CO or CaCO2, VO2 is maintained by a compensatory increase in the oxygen extraction. If DO2 continues to decrease, a threshold is reached wherein the OER is maximal and cannot increase further (critical DO2). Any further reduction in DO2 will lead to tissue hypoxia, anaerobic metabolism, and lactate production (VO2 becomes DO2-dependent). The understanding and appreciation of this relationship (Fig. 3) during critical illness are capital and have led to the proposition that therapies designed to induce a “supra-physiologic” state could be beneficial for tissue perfusion. Specifically, this idea came from Shoemaker and colleagues,6 who observed that survivors of critical illness had supranormal levels of DO2 compared with nonsurvivors. Unfortunately, studies comparing supranormal to conventional resuscitation in critically ill patients have been deleterious: Hayes and colleagues7 found that achieving supranormal values (cardiac index [CI] >4.5 L/min/m2, DO2 >600 mL/min/m2, VO2 >170 mL/ min/m2) increased mortality compared with normal goal levels. Gattinoni and colleagues8 similarly targeted critically ill patients by using 3 optimization goals: normal CI (2.5–3.5 L/min/m2), supranormal CI (>4.5), or normal SvO2 (>70%) and found no benefit in achieving supranormal values for cardiac index. A meta-analysis showed that interventions designed to achieve supraphysiologic goals of cardiac index, DO2, and VO2 did not significantly reduce rates of mortality in all critically ill patients.9 The current conclusion is that DO2 must be optimized, not maximized. Using that mindset, different therapeutic targets (using the determinants of DO2) have been proposed to manage patients. In fact, the main question the anesthesiologist has to answer before performing volume expansion is, “will my patient increase cardiac output in response?” or, more correctly, “is my patient preload dependent?”. Preload dependence is defined as the ability of the heart to increase SV in response to an increase in preload. To understand this concept, the Frank-Starling relationship has to be revisited. This relationship links preload to SV and presents 2 distinct parts: a steep portion and a plateau. If the patient is on the steep portion of the Frank-Starling relationship, then an increase in preload (induced by volume expansion) is going to induce an important increase in SV. Alternatively, if the patient is on the plateau of this relationship, then increasing preload will have no effect on SV. Moreover, the Frank-Starling relationship does not only depend on preload and SV but also depends on cardiac function. When cardiac function is impaired, the Frank-Starling relationship is flattened and for the same level of preload the effects of volume expansion on SV are going to be less significant. This concept further explains why preload parameters such as CVP or PCWP are not accurate predictors of fluid responsiveness.
- One of the most important questions for a clinician at the bedside of a critically ill patient must be: “Is oxygen delivery sufficient to meet the patient’s cellular oxygen demand?” If the answer to this question is not confidently affirmative, a clinician risks exposing his patient to cellular ischemia, organ dysfunction, and death. Knowing the adequacy of the patient’s oxygen transport balance is essential to the understanding of the pathophysiology and management of critically ill patients. Therefore, one should always keep in mind the determinants of DO2 and consumption (Fig. 2). Oxygen delivery (DO2) is the total amount of oxygen delivered to body tissues by the heart per minute and is expressed using the following equation (HR, heart rate; SaO2, arterial hemoglobin oxygen saturation; Hb, hemoglobin concentration; PaO2, arterial oxygen partial pressure): DO2 (mL/min)5Cardiacoutput (CO, L/min)Arterialoxygen content (CaO2,mLO2/dL) DO2 (mL/min) 5 HR SV [(SaO2 Hb 1.34) 1 (0.003 PaO2)] Increasing DO2 is achieved through 2 different approaches: increasing CO and CaO2. Generally, CO is more frequently manipulated by using fluids and/or inotrope agents. Conversely, CaO2 is most commonly increased by augmenting SaO2 and/or Hb concentration because the quantity of dissolved O2 is low. Oxygen consumption (VO2) is the volume of oxygen consumed by the tissues per minute (CaO2; CvO2, venous oxygen content). VO2 (mL/min) 5 CO (L/min) [CaO2 CvO2 (mL O2/dL)] Oxygen demand is the amount of oxygen required by the tissues to function aerobically. Extraction oxygen ratio (EOR) in the tissues is defined as follows: EOR 5 VO2/DO2 EOR 5 [CO (CaO2 CvO2)]/[CO (SaO2 Hb 1.34)] Venous oxygen saturation (SvO2) can then be calculated and reduced to the following formula: SvO2 5 SaO2 (VO2/(CO Hb 1.34)) Any decrease in SvO2 may therefore result from a decrease in SaO2, a decrease in CO, a decrease in hemoglobin level, or an increase in VO2. Providing that SaO2, VO2, and hemoglobin level are in normal ranges, SvO2 can then be used as a surrogate for CO. Also, if VO25CO(CaO2CvO2), DO2 (mL/min)5CO[(SaO2Hb1.34)1(0.003 PaO2)], and EOR 5 VO2/DO2, then after simplification: EOR 5 (SaO2 SvO2)/SaO2. Consequently, when SaO2 5 100%, then EOR 5 1 SvO2 and SvO2 5 1 EOR. Thus, SvO2 can also be a good surrogate for EOR. Clinically, SvO2 is one of the most used parameters to assess the balance between tissue O2 supply and O2 demand and therefore the hemodynamic status of the patient. SvO2 and central venous O2 saturation (ScvO2) have commonly been used for both GDT protocols in severe sepsis and in the operative room (OR). When ScvO2 is low, it reflects that something is wrong and should lead clinicians to understand the reasons for it and to propose an appropriate optimization strategy.
- the major concern of the anesthetist in the perioperative period is to (1) optimize the patient’s volemic status by maximizing DO2 through “well-defined” goals using flow-related hemodynamic parameters and (2) avoid any impairment in DO2 or cardiac output (CO). Regardless of setting, critically ill patients often present with hypovolemia, and volume expansion is one of the most frequent clinical interventions performed in daily practice. It is commonly the first treatment for hemodynamic resuscitation because it can increase DO2 to the tissues, through increasing left ventricular stroke volume (SV) and CO. This concept of targeting predefined goals of resuscitation in critically ill patient is not novel. Goal-directed therapy (GDT) has come to encompass the concept of using established targets of continuous blood flow and/or tissue oxygenation to guide therapy (intravenous fluid and/or inotropes). This strategy is becoming the standard of care in the ICU and in the operating rooms. However, despite studies suggesting that this approach is beneficial, GDT is still poorly adopted in clinical practice3,4 and, in many cases, fluids are still administered without adequate goals and monitoring to guide volume therapy. This can lead to adverse clinical outcomes related to hypovolemia or hypervolemia (Table 1). Both risks can potentially lead to a decrease in DO2 to the tissues and to an increase in postoperative morbidity (Fig. 1).5 Therefore, the optimization of the patient’s hemodynamics through targets of resuscitation is one of the most important goals to improving patient morbidity and mortality.
- Current literature suggests that an oxygen debt occurs intraoperatively and that the degree of oxygen debt is related to the risk of postoperative infectious complications, wound breakdown, myocardial ischemia, acute kidney injury, and death [6–9,13]. Goal-directed hemodynamic therapy with the optimization of intraoperative CO is believed to prevent this intraoperative oxygen debt [6–9,13]. However, hemodynamic optimization appears to improve outcome whether this intervention is initiated preoperatively, intraoperatively, or postoperatively (Figs. 1, 2). This observation casts doubt on the intraoperative oxygen debt theory. Furthermore, critical analysis of these studies suggests that tissue dysoxia occurs postoperatively rather than intraoperatively. These observations have important implications for the management of surgical patients, and suggest that the immediate postoperative management of high-risk surgical patients may play a pivotal role in reducing postoperative complications and death. This is an important issue as the vast majority of patients who die are not admitted to an intensive care unit (ICU) after surgery. In the European Surgical Outcomes Study (EuSOS), 73% of patients who died were not admitted to an ICU at any stage after surgery [2]. In a study of 26,051 patients undergoing noncardiac surgical procedures performed in a large National Health System Trust, only 35.3% of high-risk patients were admitted to a critical care unit after surgery [17]. A landmark paper published by Shoemaker et al in 1982 demonstrated that postoperative patients with an oxygen delivery (DO2) b 550 mL/min/m2 and cardiac index (CI) b 4.5 L/min/m2 were at a significantly greater risk of dying than patients whose DO2 and CI were above these thresholds [18]. These authors hypothesized that optimizing postoperative DO2 using the cardiorespiratory pattern of those who survived (DO2 N 550 mL/min/m2 and CI N 4.5 L/min/m2) would improve the outcome of patients undergoing high-risk surgery [19]. At face value, it would appear to be counterintuitive that anesthesia would result in an oxygen debt. General anesthesia and neuromuscular blockade (NMB) reduce metabolic rate and oxygen consumption while DO2 remains largely unchanged [23,24]. Hypothermia occurs frequently during anesthesia, which further reduces metabolic oxygen requirements [25,26]. Indeed, in the study by Shoemaker and colleagues, VO2 decreased during the intraoperative period, reaching a nadir at the end of surgery [20]. In this study, VO2 increased sharply after surgery, reaching the preoperative VO2 value at one hour and peaking at 4 hours. Thus, it is difficult to understand how anesthesia induces an oxygen debt. This apparent contradiction is best resolved by an analysis of the time course of the mixed venous oxygen saturation (SmvO2) or central venous oxygen saturation (ScvO2) during the perioperative period. Mixed venous oxygen saturation (or ScvO2) is a reflection of the balance between DO2 and VO2; in patients who incur an oxygen debt, SmvO2 should decrease. A number of studies have monitored SmvO2/ScvO2 in the perioperative period. [16,27–31]. These studies reproducibly demonstrate that the SmvO2/ScvO2 remains stable or increases slightly during anesthesia and surgery, but decreases sharply in the immediate postanesthesia period. Furthermore, the lowest postoperative SmvO2/ScvO2 was independently predictive of postoperative complications [16,27–30]. These data suggest that the oxygen debt is incurred postoperatively with the withdrawal of anesthesia (and NMB) and with the development of postoperative pain, agitation, shivering, and increased sympathetic tone. Furthermore, those patients with limited cardiac reserve and those with inadequate intraoperative hemodynamic optimization are most likely to have the largest postoperative decrease in SmvO2/ScvO2 and incur the largest oxygen debt (Fig. 3). Indeed, it is these patients who are at greatest risk of death and postoperative morbidity [16,28]. These observations suggest that optimization of CO should begin intraoperatively and continue into the postoperative period for at least 8 to 12 hours. Both fluids and inotropic agents should be used to optimize stroke volume/CO using noninvasive or minimally invasive hemodynamicmonitors [31,32]. Furthermore, all efforts should be made to prevent intraoperative hypotension, as even short episodes of hypotension (1 to 5 min) increase the risk of acute kidney injury and myocardial complications [33]. Central venous oxygen saturation should be monitored both intraoperatively and postoperatively in high-risk patients with the goal of maintaining ScvO2 above 70% [28]. This approach would require high-risk patients to be admitted to an ICU or intermediate care unit for the first postoperative day, which is in keeping with current recommendations to improve surgical outcomes [2,17]. In addition to these patient-specific risk factors, perioperative risk factors include multiple interventions that can negatively influence the balance between oxygen demand and consumption. Nociceptive surgical stimulations, volume variations due to acute blood losses or transfusions, and administration of anesthetic agent can significantly influence this VO2-DO2 relationship. Some studies evaluated the VO2-DO2 relationship in major surgery54–56 and showed a decreased capacity for tissue O2 extraction, which may have led to tissue hypoxia.57 These observations demonstrate the importance of adequately evaluating theDO2-VO2 relationship in conjunction with the patient’s metabolic demand, which is once again strongly affected by surgical conditions.
- Theconceptofgoal-directedhemodynamicoptimi- zation beganinearnest,however,withtheworkofShoemaker et al,7 who in1988showedthatplacementofaPACand attainment ofsupraphysiologichemodynamicparameters(ie, CI Z 4.5 L/min/m2, DO2Z 600 mL/min)wereassociated with agreaterchanceofsurvivalinhigh-risksurgicalpatients. In addition,Shoemakeretal8 conducted aprospectivecohort study of300surgicalpatientswithsepticshockanddiscovered that survivorshadahighercardiacindexaswellashigher oxygen consumptionanddelivery.Drawingonthiswork,other investigators testedearlyGDTprotocolsandfounddecreased mortality inpatientswhoreceivedpreoperativePACand hemodynamic optimization.9 From thesediscoveriescamethe concept ofsuperoptimizationorusingvasopressorsandino- tropes totargetsupranormalindicesofcardiacperformanceand oxygen delivery.Superoptimizationhasbeenassociatedwith mixed outcomes.Usinginotropestoincreaseoxygendelivery (DO2) duringsurgerydecreasedperioperativemorbidityand mortality inhigh-risksurgicalpatients9 as wellaspatients undergoing majorelectivesurgicalprocedures.10 In addition, patients undergoingcardiothoracicsurgery,11 as wellasmajor general surgery,12 whose oxygendeliverywassuperoptimized upon arrivalintheintensivecareunit(ICU)haddecreased hospital length-of-stay(LOS).However,studiesutilizingsuper- optimization inseptic13 as wellamixedgroupofcriticallyill ICU patients14 have notdemonstratedaneffectonmortality. However, thesestudieshavebeencritiquedforstarting resuscitation 412 hoursafterarrivaltotheICU,afterpatients perhaps hadirreversibletissuedysoxiaandorgandamage. Not longaftertheworkofShoemakeretal,Mythenetal15 demonstrated asignificant relationshipbetweengutmucosal hypoperfusion duringhigh-risksurgeryandpostoperative complications, includingmortality.Interestingly,itwasnoted that patientswhodidnotexperiencegutmucosalhypoperfu- sion hadanincreaseincardiacindexduringsurgery,whereas patients whodidexperiencehypoperfusiondidnothavean intraoperative increaseinCI.Mythenetalfollowedthiswith the initialintraoperativegoal-directed fluid therapystudy,in which patientsundergoingcardiacsurgeryreceivingintra- venous colloidboluseswiththegoalofoptimizingstroke volume andcentralvenouspressure(CVP)werefoundtohave a lowerincidenceofgastrointestinal(GI)mucosalhypoperfu- sion, majorcomplications,aswellasshorterhospitalandICU LOS.3 Following thiswork,Sinclairetal16 utilized esophageal Doppler-guided GDTin40patientsundergoingrepairof femoral neckfracturesandfoundthatpatientsreceivingcolloid boluses tooptimizestrokevolume(SV)andcorrected flow time hadshorterhospitalstaysthancontrolpatients.Witha growing literaturebase,thestudyandpracticeofGDTbeganto increase.
- A signifi cant number of patients who undergo major surgery suff er postoperative complications, many of which may be avoidable [1,2]. Th e associated health and fi nancial loss is signifi cant, especially considering patients who suff er from postoperative complications suff er long-term morbidity [3]. A signifi cant proportion of patients undergoing surgery suff er from postoperative complications, and identifi cation of this cohort of patients may enable appropriate preventative measures to be taken
- Perioperative GDTrepeatedlyhasbeenassociatedwith improved outcomesfollowingmoderate-to-majorsurgery, including shorterhospitalLOS,fewerICUadmissions,fewer GI complications,anddecreasedratesofacutekidney injury.2,3,16–21 Excitingly, thereareemergingdatathatsuggest a long-termsurvivalbenefit (upto15yearspostoperatively)in ICU patientswhounderwentperioperativeGDTassociated with high-risksurgery.22 In addition,thereare2recentmeta- analyses thatshowmortalityandmorbiditybenefits inpatients undergoing perioperativeGDT.23,24 However, arecentlarge multicenter prospectivetrialofhemodynamicoptimization versus usualcareinhigh-riskpatientsundergoingmajor gastrointestinal surgeryshowednodifferenceinpostoperative morbidity ormortality,althoughanup-to-datemeta-analysis including thesedatastillshowsareductioninmorbiditywith perioperative GDT. By optimizingoxygendelivery,GDTmayimproveperfu- sion ofmicrovascularbedsinthesplanchniccirculation,thus improving postoperativebowelfunction.Tworecentmeta- analyses haveshownreductionsinpostoperativenauseaand vomiting (PONV)andileus,26 as wellasafasterreturnof normal GIfunction,18 in patientsreceivingperioperativeGDT. Of note,thesereviewsandothers27 have foundsignificantly fewer postoperativecomplicationsandshorterhospitalLOSin GDT patients. A 2009 meta-analysis showed a reduction in both minor(eg,PONV)andmajor(eg,anastomoticleak)GI complications inpatientsreceivingGDT.19 These differences may resultfromimprovedvisceralperfusionaswellasan avoidance ofinterstitialedema,asthereareanimaldatathat increased volumesofcrystalloidareassociatedwithweaker intestinal anastomoses. Though GDToptimizesintravascularvolumeandoxygen delivery, concernshavebeenraised30 that volumeexpansion during GDTcouldresultinoverloadand/orcardiacdecom- pensation. Furthermore,routineexposuretovasoactiveinfu- sions tooptimizeoxygendeliveryisnotwithoutrisk.Assuch, Arulkumaran etal31 performed ameta-analysisof22trialsthat did notrevealanyincreaseincardiovascularriskinpatients treated withGDT.Infact,theydemonstratedareductioninthe risk ofcardiovascularcomplicationsinpatientsreceivingGDT that wasmostnotableinstudiesusing fluids andinotropes, supranormal oxygendeliverygoals,andminimallyinvasive cardiac outputmonitors(ie,notaPAC).32 Ultimately, itwouldbeidealifthereductioninmorbidity associated withGDTledtoareductioninperioperative mortality. Infact,3recentreviewsdemonstratedthatGDT reduced perioperativemortality,potentiallybyreducingthe number ofpostoperativecomplications.Inameta-analysisof 32 trialsofperioperativeGDTfocusingonmaintainingtissue perfusion (ie,optimizingcardiacindexand/orDO2oroxygen consumption), GurgelanddoNascimento23 found that although GDTreducedtheincidenceoforgandysfunctionin all patients,itreducedmortalityonlyincohortsinwhichthe baseline perioperativemortalityexceeded20%.Inaddition,a meta-analysis of29trialsofperioperativeGDTwithvarious goals andmonitoringtechniquesbyHamiltonetal24 found reductions inmorbidityandmortalityinGDTpatients,butdid note thatsubgroupanalysesshowedamortalitybenefit predominantly inoldertrials,trialsusingaPAC,trialsutilizing vasoactive infusions,andthosetargetingsupranormalvalues. Similarly, Poezeetal33 found decreasedoddsofmortalityin perioperative GDTpatientswhilenotinginsubgroupanalyses that thisbenefit wasfoundonlyinpatientsinwhomsupra- normal valuesweretargeted.Together,thesedatamaysuggest that perioperativeGDTreducesavastarrayofcomplications, and mayreducemortalityinhigh-riskpatientgroupswho receive aggressiveGDT. The concept of deliberate perioperative supranormal DO2 was tested in a RCT by Boyd and colleagues, published in 1993 [21]. In this study, 107 high-risk surgical patients were randomized to a control group or a protocol group in which DO2 was increased to greater than 600 mL/min/m2 by the use of a dopexamine hydrochloride infusion. Mortality was 5.7% in the protocol group compared with 22.2% (P = 0.01) in the control group, with half the number of complications noted in the protocol group as in the control group (P = 0.008). Patients enrolled in this RCT were followed for 15 years after randomization to ascertain their length of survival after surgery [22]. Remarkably, 20.7% of the goal-directed therapy patients versus 7.5% of the control group were alive at 15 years. The study of Boyd and colleagues was followed by over 30 GDT RCTs [6–9,13]. The initial preemptive hemodynamic studies used the pulmonary artery catheter and targeted the Shoemaker et al “supranormal” goals, while more recent studies have “optimized” CO using esophageal Doppler or dynamic indices of fluid responsiveness.
- We hypothesized that the benefi ts of GDT are greater in patients who are at higher risk of mortality. We defi ned risk by the mortality rate of the study population undergoing major surgery. We conducted this metaanalysis to determine if GDT in high-risk surgical patients undergoing major non-cardiac surgery improves postoperative mortality and morbidity, and if this was aff ected by the mortality risk among the population studied. We reported only randomized controlled trials, that reported morbidity (complications) and mortality as primary or secondary outcomes. GDT was defi ned as the term encompassing the use of haemodynamic monitoring and therapies aimed at manipulating haemodynamics during the perioperative period to achieve a predetermined haemodynamic endpoint(s). Studies with GDT started pre-emptively in the perioperative period (24 hours before, intraoperative or immediately after surgery) were included. Th e GDT must have an explicit protocol, defi ned as detailed step-by-step instructions for the clinician based on patient-specifi c haemodynamic data obtained from a haemodynamic monitor or surrogates (for example, lactate, oxygen extraction ratio), and predefi ned interventions carried out by the clinician in an attempt to achieve the goal(s). Interventions included fl uid administration alone or fl uids and inotropes together. As the use of inotropic agents was aimed at a specifi c haemodynamic goal(s) and titrated accordingly, fi xed dose studies of inotropes were excluded. Only studies involving adult general surgical populations were included, and studies involving cardiac, trauma and paediatric surgery were excluded. Information sources A systematic literature search of MEDLINE (via Ovid), EMBASE (via Ovid) and the Cochrane Controlled Clinical trials register (CENTRAL, issue 4 of 2012) was conducted to identify suitable studies. Only articles written in English were considered. Date restrictions were not applied to the CENTRAL and MEDLINE searches. EMBASE was restricted to the years 2009 to 2012 [6]. Th e last search update was in April 2012. Hospital mortality was reported in all the included articles and was the primary outcome of our study. Morbidity, expressed as number of patients with complications, was the secondary outcome. Mortality risk groups were based on the defi nition of the high-risk surgical patient by Boyd and Jackson, such that patients whose risk of mortality was 5 to 19% and ≥20% were classifi ed as high-risk and extremely high-risk, respectively [9]. We therefore performed subgroup analyses based on the control group mortality in each study. We created three subgroups based on the mortality rate of the control group. Mortality rates of 0 to 4.9%, 5 to 19.9%, and ≥20% were considered intermediate, high risk, and extremely high risk, respectively. Mortality and complications were analyzed according to the above subgroups. Studies were also analyzed according to the type of monitor used, type of interventions, the therapeutic goals, and the use of ‘supranormal’ physiological goals. Description of studies A total of 32 studies were included in the meta-analysis (Table 1) [64-95]. Th ese 32 studies included a total of 2,808 patients, 1,438 in the GDT arm and 1,370 in the control treatment arm. Five studies included patients who were considered extremely high risk, 12 included patients who were high risk, and 15 included patients who were intermediate risk. Th e intermediate-risk, highrisk, and extremely high-risk mortality subgroups included 1,569, 924, and 315 patients, respectively. Th ere were similar numbers of patients in the GDT and control arms. Twenty studies initiated GDT at start of surgery, whilst the other studies initiated GDT before or immediately after surgery.
- All 32 studies included mortality rates (Figure 2). Although there was an overall benefi t on mortality (OR 0.52, 95% CI 0.36 to 0.74; P = 0.003), subgroup analyses revealed that mortality benefi t was seen only in studies that included extremely high risk patients (OR 0.20, 95% CI 0.09 to 0.41; P < 0.0001) but not for the intermediate-risk patients (OR 0.83, 95% CI 0.41 to 1.69; P = 0.62). Th ere was a trend towards a reduction in mortality in the high risk group (OR 0.65, 95% CI 0.39 to 1.07; P = 0.09; Figure 2). Further subgroup analyses of mortality as an endpoint revealed that mortality was reduced in the studies using a pulmonary artery catheter (OR 0.3, 95% CI 0.15 to 0.60; P = 0.0007), fl uids and inotropes as opposed to fl uids alone (OR 0.41, 95% CI 0.23 to 0.73; P = 0.002), cardiac index or oxygen delivery index as a goal (OR 0.36, 95% CI 0.21 to 0.36; P = 0.0003), and a supranormal resuscitation target (OR 0.27, 95% CI 0.15 to 0.47; P < 0.00001) (Table 2).
- Morbidity Twenty-seven studies (including 2,477 patients) reported the number of patients with postoperative complications. Meta-analysis of these studies revealed an overall signifi cant reduction in complication rates (OR 0.45, 95% CI 0.34 to 0.60; P < 0.00001; Figure 3). Consistent with the mortality benefi ts, the reduction in morbidity was greatest in the extremely high-risk group (OR 0.27, 95% CI 0.15 to 0.51; P < 0.0001). However, there was also a signifi cant morbidity benefi t in the intermediate risk group (OR 0.43, 95% CI 0.27 to 0.67; P = 0.0002) and the high-risk groups (OR 0.56, 95% CI 0.36 to 0.89; P = 0.01) (Figure 3). Th e reduction in the number of patients suff ering postoperative complications was seen across all subgroups, apart from studies that did not use the oxygen delivery index (DO2I; ml/minute/m2), the cardiac index (CI; ml/minute/m2), stroke volume (SV; ml), or corrected fl ow time (FTc) as a goal (OR 0.48, 95% CI 0.22 to 1.04; P = 0.06), although this approached statistical signifi cance (Table 3).
- We believe that GDT in high-risk surgical patients is likely to have the greatest benefi t if carried out early, in the right patient cohort and with a clearly defi ned protocol. We performed this meta-analysis to test the hypothesis that patients with the highest perioperative risk gain the greatest benefi ts from GDT. A reduction in mortality associated with GDT was seen only in the extremely high-risk group of patients (baseline mortality rate of >20%). A baseline mortality rate of >20% is unusual in current practice [4,96]; in this sense it is interesting to note that two of fi ve studies with a baseline mortality rate of >20% were carried out within the past decade. Neither of these studies demonstrated a survival benefi t with GDT [80,97]. One of these studies demonstrated a reduction in complication rates [97], whilst the other demonstrated a trend towards a reduction in complication rates [80]. Supranormal physiological targets, targeting DO2I or CI, the use of inotropes in addition to fl uids, and the use of a PAC were also associated with an improvement in survival. As fi rst demonstrated by Shoemaker and colleagues [19], a supra normal physiological target of global oxygen delivery to ameliorate the oxygen defi cit incurred during major surgery is associated with a survival benefi t. Th is is likely to explain the other associations with an improve ment in morbidity across all risk groups. Th e combination of fl uids and inotropes is more likely to achieve a supranormal physiological target, as opposed to fl uids alone. Th e survival benefi t associated with the use of PACs is unlikely to be due to the use of the PACs per se. Th e survival benefi t associated with PAC use may be explained by a number of factors. Th ese include the ability to measure and there fore achieve supranormal DO2I, and the use of inotropes in addition to fl uids in all studies using a PAC. Consistent with the trends seen with mortality, the reduction in complication rates was most profound in the extremely high-risk group of patients, protocols with supranormal physiological targets, targeting DO2I or CI, and the use of inotropes in addition to fl uids. In contrast to the benefi ts seen in mortality, however, the subgroup using the ‘other cardiac output monitors’ had a greater reduction in complication rate than the subgroup using the PAC. Th is may relate to the complexity and invasive nature of the PAC in comparison to less invasive cardiac output monitors [98-100]. Th ere remains signifi cant heterogeneity in complication rates among postoperative patients in diff erent centres [4,96]. Although diff erences in patient demographics are not modifi able, optimal management of the high-risk surgical patient during the perioperative phase may improve overall outcomes. Despite a requirement for an increase in healthcare resources to off er early GDT to high-risk surgical patients, reductions in immediate postoperative complications translate to overall benefi ts in healthcare costs. Any perceived increase in resource allocation results in a lower patient mortality and morbidity, and therefore a fi nancial saving [101]. Furthermore, reduc tion in immediate postoperative complications has far-reaching eff ects, with a potential benefi cial eff ect on long-term survival [102]. This meta-analysis includes trials from 1988 to 2011. Th ere was an approximate halving of mortality rates in the control group every decade (29.5%, 13.5%, 7%). Despite a reduction in mortality rate, the morbidity rate remained constant, with approximately a third of patients experiencing post operative complications. Perioperative GDT should there fore off er a reduction in complication rates in current practice. One of the main limitations of this study is the lack of data on the volume and type of fl uids given, and the dose of inotropes used due to variation and inconsistencies in reporting. However, it must be emphasised that the absolute volume of fl uids used per se is not as important as the way in which fl uid is given. Fluid therapy must be titrated against a patient’s response to a fl uid challenge, with the use of haemodynamic monitoring [103]. Such ‘goal-directed’ fl uid therapy must also be given at the right time, as GDT is not benefi cial after complications have already developed [104,105].
- Unfortunately, there is no one best endpoint for perioper- ative GDT. The ideal endpoint would be representative of end- organ perfusion, readily available in the perioperative period, continuous, and reproducible. In general,monitoringforperioperativeGDTismoving toward increasinglyless-invasivetechniques,57 in partbecause of perceivedcomplicationsofcentralvenouscannulation.At this point,mostallofthemodernmonitors,includingthe esophageal Dopplermonitor,58,59 the pulse-contourtechni- ques,60,61 and thetransthoracicbioreactancetechniques62,63 have beenvalidatedagainstthePAC,despitethisbeingan imperfect “gold standard”.64,65 Recently, investigatorshave been comparingvariousminimallyinvasivemonitorsto ascertain theconvenienceandaccuracyofeachmethod. Unfortunately, thesestudiesoften find widevariabilityand questionable agreementbetween2noninvasivetechniques, including pulse-contourtechniquesandtheEDM,31,66 as well as bioreactanceandEDM.32 However, highlevelsofvariability also havebeenfoundbetweenmostallminimallyinvasive techniques andthermodilutionviaPAC.67 This mayhavetodo with imprecisionofthereferencetechnique,though,asmany studies showacceptableaccuracybutunacceptablelimitsof agreement (precision).68 Arguably moreimportantthanabso- lute agreementaretheabilityofvariousmonitorstonetsimilar clinical outcomes.Tothatend,arecentprospectivetrialof colorectal surgerypatientsdemonstratedsimilaroutcomes between patientswhoseperioperativeGDTweretitratedusing a bioreactancetechnique(NICOM)andtheEDMdespitewide limits ofagreement.42 Similarly, ameta-analysisofmorethan 2,000 patientssuggestedthatperioperativeGDTreduced morbidity regardlessofthemonitoringtechniqueused,24 which has ledsomeinvestigatorstopostulatethatthebenefit of GDT arisesfromasystematicapproachtohemodynamic optimization.69
- Traditionalpressure-based parameters suchasbloodpressure(BP),heartrate(HR), CVP, andpulmonaryarteryocclusionpressure(PAOPor wedge pressure)areappealingastheyarereadilyavailable. Unfortunately, thesemeasuresallfallshortasaccurateend- points forperioperativeGDT.BothHRandBPhavebeen demonstrated tobeinsensitiveindicatorsofvolumestatus,26 and ithasbeenproposedthatanintraoperativegoalof normotension isinferiortoGDT.34 The utilityofCVPand PAOP asmeasuresofpreloadhavebeenquestionedinboth healthy volunteers35 and criticallyillpatients,36 and some investigators haveshownnobenefit andincreasedcomplica- tions inhigh-risksurgicalpatientsreceivingaPAC.37 However, arecentmeta-analysisofperioperativeGDTdemon- strated amorbidityreductionregardlessofthemonitoring technique, butamortalityreductiononlyinpatientsmonitored with PAC.24 The importance of maintaining adequate blood pressure is awell-accepted axiom. Fluid boluses and vasoactive agents are used routinely during surgery and postoperatively to maintain blood pressure and ensure that perfusion is adequate in the context of the physiologic stress of surgery. Conversely, maintaining blood pressure below specified thresholds is also sometimes important, such as to minimize myocardial oxygen demand or the risk of stroke. There is little published data describing ideal blood pressure parameters, and this is likely related to the heavy influence of anesthesiologist and surgeon experience and preference guiding intraoperative and postoperative blood pressure management. There have been recent efforts by Gawande et al. to delineate a scoring system for patients undergoing surgery to clarify a patient's condition and likelihood of major complications upon completion of a surgical procedure. This scoring system utilizes blood pressure as one of just three metrics. The surgical outcome score (referred to as the surgical Apgar score) uses lowest mean arterial pressure (MAP), estimated blood loss, and lowest heart rate during the procedure, with a clear increase in mortality for those receiving lower scores. Some clinicians administer an initial fluid bolus (fluid challenge) and assess the effect (increase SV) by measuring static parameters such as central venous pressure (CVP) and/or pulmonary artery occlusion pressure (PAOP). Unfortunately, they think that CVP reflects intravascular volume and that patients with a low CVP are fluid depleted and vice versa. It is well recognized that neither the PAOP nor the CVP can predict ventricular preload and fluid responsiveness.11 Volume expansion is important for the initial resuscitation of severe hypotension. Subsequent fluid administration should be given cautiously and only when there is evidence of fluid responsiveness to avoid fluid overload.12 Indeed, several studies correlate excessive amounts of fluid (positive fluid balance) with increased mortality in acute respiratory distress syndrome or septic patients and failure of weaning from mechanical ventilation.13–16 Moreover, only 50% of hemodynamically unstable patients are fluid responsive.17,18 BP is not a good indicator of low CO, low DO2, or hypovolemia: shocked patients may appear adequately resuscitated based on BP even with significant hypoperfusion! That is why other markers of tissue well-being should also be assessed, such as SvO2, ScvO2, DPCO2, and lactate. They may be also very useful goals of resuscitation when vasopressors are required for persistent hypotension once adequate intravascular volume expansion has been achieved and to evaluate the efficacy of treatment. However, recent survey studies suggest that goal-directed fluid management is poorly adopted in clinical practice.3 Most anesthetists use the combination of formulas and fixed-volume calculations with vital sign optimization (BP, HR, CVP, urine output) to guide their perioperative fluid therapy. Le Manach and colleagues64 showed that changes in BP cannot be used to track changes in SV induced by volume expansion. Consequently, optimization of DO2 to the tissues during surgery cannot be conducted by monitoring arterial pressure alone. Because arterial pressure and CO both depend on systemic vascular resistance, a normal or even supranormal arterial pressure does not guarantee an adequate CO.
- Since the introduction of pulmonary artery catheterization by Swan et al., in 1970, this device has been used in a wide variety of clinical contexts. Pulmonary artery catheters (PACs) are utilized in critically ill patients with shock as well as in the preoperative, intraoperative, and postoperative settings. The device has beenwell studied with respect to clinical outcomes, both in retrospective analyses and in randomized controlled trials [4]. While some studies have shown benefit to pulmonary artery catheterization, several groups have found limited benefit with respect to the risk of complications from the device as well as misinterpretation of PAC data. The group found that physicians correctly predicted hemodynamic profiles in just 56% of the patients who received a PAC. They compared the group of patients who experienced a change in therapy based on PAC measurements and those who did not, and found a mortality benefit in those patients who did experience a change in therapy after pulmonary artery catheterization. Friese et al. performed a retrospective database analysis of patients in a national trauma database, adjusting for age, injury severity, and other factors. Of 53,312 patients in the database, 1933 were managed with a PAC. These patients were more likely to have more severe injuries and were older in age. Even after adjusting for a number of factors, the mortality rate was higher in the PAC group. However, the authors found improved outcomes with PAC use in patients who were older, had an arrival base deficit worse than 11, and an injury severity score between 25 and 75. They suggest that in the most severely injured patients or elderly patients with moderate shock, the PAC can provide useful guidance in resuscitation. Sandham et al. performed a randomized, controlled trial using the PAC to guide goal-directed therapy (GDT) in high-risk surgical patients. A total of 1994 patients considered high-risk due to age (60 or older) and American Society of Anesthesiologists (ASA) class (III or IV) were randomized to management with or without a PAC. The standard-care group was managed using typical ICU parameters and CVP measurementwas allowed. The PAC groupwas managed with parameters for oxygen delivery, cardiac index, pulmonary capillary wedge pressure, heart rate, MAP, and hematocrit. The researchers found no benefit with PAC management in overall mortality, morbidity, or length of stay, and they also found no evidence of increased mortality in those randomized to PAC use [12]. While some benefit may be seen for patients with an unclear hemodynamic status, elderly trauma patients, and some select groups, most agree that routine use of PACs does not produce meaningful outcome benefit in mortality, morbidity, length of stay, or cost. Flow-based parameterssuchasSVandcardiacoutput(CO) increasingly arebeingusedforperioperativeGDT.Although the “gold standard” for COmeasurementisthePAC,therare complications associatedwithPACinsertionpromptedthe development ofalternative,oftenless-invasive,monitors.
- The esophageal Doppler(EDM)isathinprobeplacedinapatient’s esophagus thatmeasuresdescendingaorticblood flow and using anomogramtocalculateaorticcross-sectionalarea, transforms thisintoCOandSV.38 The EDMisaccurateforuse in GDT,17,39 where itsusehasbeenshowntobesuperiorto usual careintermsofLOSandpostoperativecomplica- tions.16,17,20 Given thebroadevidencebasesupportingthe use oftheEDMforGDT,itisrecommendedforusebythe National InstituteofHealthandClinicalExcellence.40 Esophageal Doppler monitoring (EDM) provides an assessment of stroke volume and cardiac output by measuring the Doppler signal of moving blood cells in the descending thoracic aorta. This is primarily used intraoperatively as it requires an intra-esophageal probe. To date, the device is used mainly in conjunction with goal-directed protocols to administer fluid and maximize stroke volume. In summary, EDM with fluid administration protocol designed to maximize stroke volume intraoperatively has shown shorter length of stay in several studies, as well as improvements in diet tolerance in those undergoing abdominal surgery. This is made possible both in the setting of patients receiving more fluid than controls (as in femoral fracture fixation) and when the EDM patients receive a similar amount of fluid compared to controls. Echocardiography is widely viewed as a useful diagnostic modality in patients in the operating room or the ICU. There is a significant body of work examining the feasibility and usefulness of echocardiography performed by intensivists, but only a few researchers have specifically studied the impact of echocardiography in the operative or critical care settings with respect to patient outcomes or cost-effectiveness. Both transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) can be useful modalities when used in the appropriate setting. Shillcutt et al. used echocardiography-derived parameters to guide hemodynamic management during noncardiac surgical procedures on patients with known left ventricular diastolic dysfunction. A variety of echocardiographic parameters were used to guide management of fluids and vasoactive agents, while the standard hemodynamic management group received therapies to maintain systolic blood pressure within 10e15% of the patient's baseline. Due to a limited number of patients, the feasibility of TEE examination and safety were the primary endpoints; secondary outcomes included fluids administered and 30-day postoperative complications (atrial fibrillation, congestive heart failure (CHF), myocardial infarction (MI), stroke, etc.). Patients monitored with TEE received less fluid intraoperatively. Measures of 30-day outcomes were not statistically significant but trended toward shorter hospital stay, lower incidence of CHF, and less atrial fibrillation in the patients managed with TEE parameters [15]. One difficulty in using TTE in critically ill patients is the lack of adequate acoustic windows in mechanically ventilated patients who may have dressings, lines, or other devices limiting access to the appropriate surface anatomy for echocardiographic exam. Cook et al. evaluated the failure rate of TTE in the surgical ICU setting and found that routine use of TTE with TEE as a secondary modality is not costeffective. The failure rate of TTE rises with patients receiving >15 cm H2O of positive end-expiratory pressure (PEEP), patients who have gained >10% body weight compared to admission weight, and those with chest tubes. The group found the lowest overall costs with TEE alone, and some cost-savings when TEE is used as the primary modality for patients at high-risk of TTE failure and TTE used for those at low risk of failure [16].
- Pulse contour techniques(eg,LiDCO,FloTrac/Vigileo)usethe arterial waveformtocalculateCOandSV,andalsooftenwill calculate dynamicmeasuressuchasstroke-volumevariation (SVV) and/orpulse-pressurevariation(PPV).Perioperative GDT usingtheFloTrac/Vigileohasbeenshowntodecrease postoperative woundinfection,41 whereas LiDCO-guidedGDT was associatedwithdecreasedpostoperativecomplicationsand shorter hospitalLOS.12 Dynamic parameterssuchasSVV,PPV,andplethvaria- bility index(PVI)aregainingpopularityasendpointsfor perioperative GDT.IntraoperativeSVV-guidedGDTdecreased GI complicationsinpatientsundergoingmajorabdominal surgery,43 decreased woundinfectioninhigh-risksurgical patients,41 and reduced fluid volumesandnausea/vomitingin thoracic surgerypatients.4 The useofPPVforintraoperative GDT hasbeenshowntodecreaselengthofmechanical ventilation, postoperativecomplications,andICUandhospital LOS inpatientsundergoinghigh-risksurgery.44 Both SVVand PPV takeadvantageofcardiorespiratoryinteractionovera mechanically ventilatedrespiratorycycleandarelimitedby their requirementforsomewhathigh(Z8 mL/kgidealbody weight) tidalvolumes,normalsinusrhythm,andanormal interaction betweentherightheartandthelungs.45
- It has been known for a while that mechanical ventilation may induce cyclic changes in left ventricular stroke volume and arterial pressure [1]. Many experimental and clinical studies have demonstrated that the magnitude of the arterial pressure waveform variation is highly dependent on blood volume [2]. The idea to use the systolic pressure variation (SPV) or the pulse pressure variation (PPV) not only to track changes in blood volume, but also to predict fluid responsiveness (defined as the hemodynamic response to a fluid load), emerged 15 years ago [3-5]. Tavernier et al. [5] demonstrated that SPV is a better predictor of fluid responsiveness than left ventricular end-diastolic area, an echocardiographic marker of cardiac preload. Michard et al. [3] demonstrated that PPV is an accurate predictor of fluid responsiveness, dramatically better than cardiac filling pressures, and slightly but significantly better than SPV. Since then, many clinical studies have confirmed the value of SPV and PPV to predict fluid responsiveness [2]. Others dynamic parameters, mainly the stroke volume variation (SVV) measured by pulse contour methods [6] and the pleth variability index (PVI) derived from pulse oximetry [7], have also been proposed and used with success to predict fluid responsiveness. Today, most hemodynamic monitors calculate automatically and display these dynamic parameters. According to published peer-reviewed surveys, their clinical use to guide fluid therapy increased from 1% in 1998 [8] to 45% in 2012 [9]. If the ability of dynamic parameters to predict fluid responsiveness is now hardly disputable (pending the limitations to their use being respected), whether their use is associated with improved quality of care and outcome remains an open question. In 2007, Lopes et al. [10] were the first to demonstrate that intra-operative goaldirected fluid therapy (GDFT) based on PPV monitoring is able to decrease post-operative complications and hospital length of stay in patients undergoing major abdominal surgery. However, the following year, Buettner et al. [11] failed to reproduce these results, although their study design was very similar. Since then, several other randomized controlled trials (RCTs) have been performed where fluid therapy was driven by the use of dynamic parameters. These studies have yielded conflicting results. Therefore, we performed the present meta-analysis in order to clarify if GDFT based on dynamic parameters (GDFTdyn) may decrease post-surgical morbidity when compared to standard fluid management. Many post-surgical complications are related, at least in part, to insufficient or excessive fluid administration during the peri-operative period [41]. A U-shaped relationship is classically described between the amount of fluid administered peri-operatively and the morbidity rate [41]. It has been suggested that giving fluid until patients’ heart has reached the plateau of the Frank-Starling relationship may be the most efficient way to prevent both hypovolemia and fluid overload. In clinical practice, this approach consists of giving fluid until flow parameters (stroke volume or cardiac output) reach a plateau value (to prevent hypovolemia), then to stop giving any additional fluid volume (to prevent fluid overload). Dynamic predictors of fluid responsiveness are not markers of blood volume, nor markers of cardiac preload, but markers of the position on the Frank-Starling curve [2]. In this regard, they have been proposed to identify when the plateau of the Frank-Starling relationship is reached without the need to give fluid and to monitor flow parameters [42]. Several devices using analysis of arterial waveform to provide hemodynamic information are commercially available. PiCCO and LiDCO use thermodilution and lithium indicator dilution, respectively, to provide cardiac output measurements. These devices also use specific algorithms to estimate cardiac output from the arterial pressure waveform. The Vigileo FloTrac system uses the arterial waveform to calculate cardiac output, without requiring calibration. These devices have been studied with respect to outcomes mainly in conjunction with GDT protocols with promising results. Instead of monitoring a given parameter, functional hemodynamic monitoring assesses the effects of a stressor on commonly recorded variables.49 For the assessment of preload dependence, the stress is a “fluid challenge” and the parameter is SV. In mechanically ventilated patients under general anesthesia, the effects of positive pressure ventilation on preload and SV are used to detect fluid responsiveness. If mechanical ventilation induces important respiratory variations in stroke volume (SVV) or in arterial pulse pressure (PPV), it is more likely that the patient is preload-dependent.5 These dynamic parameters (SVV, PPV) have consistently been shown to be superior to static parameters (CVP, PCWP) for the prediction of fluid responsiveness. Our best clinical evidence currently demonstrates that CVP and PCWP, as well as oliguria, hypotension, and tachycardia, should not be used for predicting the effects of volume expansion on CO.17,69
- Different search strategies were performed to retrieve relevant studies by using MEDLINE, The Cochrane Library and EMBASE databases (last update September 2013). No date restriction was applied for MEDLINE and The Cochrane Library databases, while the search was limited to 2006 to 2013 for EMBASE database The primary outcome measure was post-surgical morbidity. Morbidity was defined as the proportion of patients with one or more post-surgical complication. The specific post-surgical infectious, cardiac, respiratory, renal and abdominal complications, as well as ICU and hospital length of stay were assessed as secondary outcome variables. Abdominal complications included both gastrointestinal and liver complications. The search strategies identified 3,297 (MEDLINE), 9,852 (Cochrane Library) and 2,205 (EMBASE) articles. Thirteen articles were identified through other sources (reference lists). After initial screening and subsequent selection, a pool of 105 potentially relevant RCTs was identified. The subsequent eligibility process (Figure 1) excluded 91 articles. Overall, 14 articles [10,11,29-40] with a total sample of 961 patients, were considered for the analysis. Study characteristics All selected articles were RCTs evaluating the effects of GDFTdyn on post-operative complications or length of stay. All studies were published between 2007 and 2013. All RCTs but two [30,33] were single-center trials. Eleven studies included major abdominal procedures, two cardiac surgeries and one a thoracic procedure. Eight studies were performed in Europe, three in China nd one in each of the following countries: the United States, India and Brazil (Table 1). Missing or uncertain information was gathered by direct communication with the authors (see Acknowledgements section). Characteristics concerning the 14 RCTs analyzed are summarized in Table 1. Dynamic parameters used to guide fluid therapy were SVV in eight studies, PPV in four studies, SPV in one study and PVI in one study. SVV was measured by the FloTrac/Vigileo system (Edwards Lifesciences, Irvine, CA, USA) in seven studies and by the PiCCO system (Pulsion Medical Systems SE, Munich, Germany) in one study, PPV was measured by the bedside monitor in three studies and the ProAQT/Pulsioflex system (Pulsion Medical Systems SE) in one study, SPV was measured by the bedside monitor and PVI by the Radical 7 pulse oximeter (Masimo Corp, Irvine, CA, USA).
- Outcome measures The overall morbidity rate was obtained from 10 studies [10,30,32,33,35-40] and a significant reduction was observed in favor of GDFTdyn (OR 0.51; CI 0.34 to 0.75; P <0.001; I2 = 28%) (Figure 2). A significant reduction in infectious (OR 0.45; CI 0.27 to 0.74; P = 0.002; I2 = 30%), cardiovascular (OR 0.55; CI 0.36 to 0.82; P = 0.004; I2 = 0%) and abdominal complications (OR 0.56; CI 0.37 to 0.86; P = 0.008; I2 = 3%) was observed in favor of GDFTdyn (Figures 3, 4 and 5). A non-significant trend towards a reduction in respiratory complications was observed (0.60; CI 0.33 to 1.09; P = 0.09; I2 = 0%). Renal complications were not significantly reduced by GDFTdyn (0.57; CI 0.24 to 1.35; P = 0.20; I2 = 40%). A significant reduction in ICU length of stay was also observed (WMD −0.75 days; CI −1.37 to −0.12; P = 0.02; I2 = 52%) (Figure 6), whereas hospital length of stay did not significantly decrease (WMD −1.33 days; CI −2.90 to 0.23; P = 0.10; I2 = 78%).
- From a physiological standpoint, maximizing stroke volume or minimizing dynamic parameters with fluid are equivalent [42]. Therefore, one can expect similar benefits when using dynamic parameters than when using flow parameters to guide fluid therapy. This is what our meta-analysis does confirm: clinical benefits of GDFTdyn are comparable to those reported with GDFT based on flow parameters [46,51]. For GDFT, the use of dynamic parameters has several potential advantages over the use of flow parameters. First, it has the advantage of being simple, whereas the use of flow parameters requires interventions and calculations. For instance, the stroke volume fluid optimization strategy, currently recommended both in the UK and in France [54,55], requires the assessment and quantification of the percentage change in stroke volume during a standardized fluid challenge. Oxygen delivery optimization strategies require intermittent calculations of the oxygen delivery index based on the simultaneous measurement of cardiac output, hemoglobin and arterial oxygen saturation by different devices. As a result, fluid strategies based on flow parameters are often perceived as complex and timeconsuming by caregivers. In contrast, using dynamic parameters does not require any intervention to know if the patient is a fluid responder or not (a high SPV, PPV, SVV or PVI value suggests that the patient is fluid responsive), nor any calculations (delta change in stroke volume, oxygen delivery). Caregivers simply have to monitor dynamic parameters and ensure the value remains below a predefined target value (usually around 10 to 12%). Simplicity may be a key element to expand the clinical adoption of GDFT. Second, using dynamic parameters may be considered as a cost-saving approach. Indeed, although SVV measurement requires the use of a cardiac output monitor, the estimation of PPV is possible from any bedside monitor displaying an arterial pressure curve. The use of dynamic parameters has also disadvantages. The main disadvantage is the fact that they cannot be used in many patients because of limitations, which have been described in detail elsewhere [2], and do include small tidal volume (<8 ml/kg), open chest, sustained cardiac arrhythmia and abdominal hypertension (for example laparoscopy) [56]. A study [57] looking at more than 12,000 non-cardiac surgical patients concluded that, given their limitations, dynamic parameters could have been used to guide fluid therapy in only 39% of the cases, the most frequent limitation being the use of a small tidal volume for mechanical ventilation (one-third of the cases in this specific study). If fluid management was always based on the monitoring of dynamic parameters, different trigger values, ranging from 9 to 13% (Table 1), were used to give fluid. In addition, some hemodynamic protocols included additional static parameters such as blood pressure and cardiac output (Table 1). The heterogeneity among treatment protocols and definition of complications is a common feature of previous GDFT meta-analyses [43-50], but it is important to bear in mind that it may have influenced our findings. Dynamic parameters of fluid responsiveness based on cardiopulmonary interactions have several limitations that need to be clearly stated before they can be adequately used in the clinical setting. First, these parameters have to be used inmechanically ventilated patients under general anesthesia. Up to now, studies conducted in spontaneously breathing patients failed to demonstrate that PPV can predict fluid responsiveness.70 Moreover, tidal volume has an impact on the predictive value of PPV and a tidal volume of 8 mL/kg of body weight is required.71 In addition, patients have to be in sinus rhythm; chest must be closed (open chest aswell as open pericardiumstronglymodify the cardiopulmonary interactions), and intra-abdominal pressure has to be within normal ranges.72 Unfortunately, only 39%of the patients undergoing surgical procedures in theORmet the criteria for the monitoring of fluid responsiveness using noninvasively measured PPV.73 Also, despite a strong predictive value, PPV may be in the inconclusive “gray zone” (between 9%and 13%) in approximately 25%of patients during general anesthesia.74
- Use of serum markers of perfusion provides an adjunct to continuous monitoring devices; the measurement of central venous or mixed-venous oxygen saturation is one example. Gattinoni et al. published one of the initial studies of GDT using mixed-venous oxygen saturation as a parameter for intervention. They compared three groups: controls receiving resuscitation to achieve normal cardiac index, intervention group with the goal of achieving supranormal cardiac index, and oxygen saturation group with the goal of achieving normal mixed-venous oxygen saturation level. They found no difference in mortality, end-organ dysfunction, or ICU length of stay [37]. A subsequent publication by Rivers et al. studied patients with suspected sepsis starting in the emergency room, with a randomized trial and 263 participants. They compared conventional management based on MAP, CVP, and urine output parameters to a GDT group with the treatment goals used in the control group aswell as the goal of maintaining central venous oxygen saturation >70%. They found a decline in absolutemortality aswell as lower base deficit and lactate levels in the intervention group. The authors posit that their results may derive fromthe timing of the intervention, with treatment beginning in the emergency department as early as possible in the course of the patients' illnesses [38]. Several years later, Donati et al. published their results using GDT to maintain an oxygen extraction ratio (calculated from arterial and mixed-venous oxygen saturations) of <27%. The population examined included 135 high-risk patients undergoing major abdominal surgery. The authors found a lower incidence of organ failure in the intervention group, as well as reduction in length of hospital stay [39]. The authors felt that the early and aggressive resuscitation of their postoperative patient population was critical to success, just as the Rivers group found success in very early resuscitation of septic patients. These studies demonstrate that the use of an intermittent measure of a serum marker can be used in a manner similar to other hemodynamic devices to provide feedback for GDT. When applied to early resuscitation in sepsis or postoperative patients, improvement in clinical outcomes is observed; additional ongoing studies may elucidate the additive benefit of this technology over standard vital parameters. Markers oftissuewell-being(lactate,SvO2,SCvO2,gastric tonometry) bridgethegapbetweenhemodynamicmonitoring and monitoringtissuedysoxia.Althoughlactateisestablished as amarkerinsepticshock,50,51 lactate hasnotbeenwell- studied asanendpointforGDT.Similarly,SvO2isnotwell- studied inperioperativeGDToutsideofcardiacsurgery,52 but perioperativeGDTwithSCvO2,acloselycorrelated surrogate,53,54 has beenshowntoreducepostoperativecom- plications andhospitalLOSinpatientsundergoingabdominal surgery.55 This variable gives an estimation of O2 saturation of blood returning to the right heart. It is correlated with tissue O2 extraction and the balance between O2 delivery and demand. However, it needs a pulmonary artery catheter (PAC), which is very invasive. In this context, ScvO2 may represent an interesting alternative because it can be easily measured by obtaining a blood sample from the central venous catheter. Reinhart and colleagues19 have shown a good correlation between SvO2 and ScvO2. Despite this, there is still debate regarding the equivalence between them,20–23 especially when 118 Joosten et al comparing lower values.24 However, the surviving Sepsis Campaign recognized the clinical utility of ScvO2 by recommending a SvO2 of 65% and ScvO2 of 70% in the resuscitation of severe sepsis and septic shock patients. This variable is directly proportional to oxygen debt and is commonly taken as an indicator of impaired tissue perfusion because of inadequate O2 delivery resulting in anaerobic metabolism. It has been shown that during circulatory shock, repeated lactate determinations represent a more reliable prognostic index than an initial value taken alone. Changes in lactate concentration can provide an early and objective evaluation of the patient’s response to an intervention.25 Furthermore, elevation or nonnormalization of serum lactate concentration is predictive of adverse outcome in the critically ill patient in shock.26 Altered levels of serum lactate must also be examined alongside the larger clinical picture because multiple nonhypoxic causes can also result in lactic acidosis, including renal or metabolic disturbances. The difference between venous-arterial carbon dioxide partial pressure (DPCO2) has also been used to guide the treatment of shock. In the absence of a shunt, CO2 from the venous blood must be higher than from the arterial blood. The DPCO2 may be a marker of the global hemodynamic status. For example, DPCO2 has been shown to be an indirect marker of the adequacy of systemic flow, which allows for more directed resuscitation.27 The Fick equation applied to CO2 indicates that combing DPCO2 5 CvCO2 CaCO2 with VCO2 5 CO (CvCO2 CaCO2) leads to DPCO2 5 VCO2 k/CO (k is constant) and further indicates that DPCO2 is proportionally related to CO2 production and inversely proportional to CO.28 Therefore, with all other variables constant, if CO is low, DPCO2 is high (>6 mm Hg).29 Vallee and colleagues30 found that patients with a DPCO2 higher than 6 mm Hg had worse prognosis when compared with those with lower than 6 mm Hg, despite a ScvO2 greater than 70% in both groups. Fig. 4 gives example of the algorithm used in the critically ill patient to guide therapy based on ScvO2 and DPCO2. Donati and colleagues87 demonstrated improved outcome in patients treated with GDT using fluids and dobutamine titrated to optimize oxygen extraction (ERO2) at less than 27% (ScvO2 >73%). Reductions in ScvO2 in the perioperative setting are independently associated with a higher risk of postoperative complications.88 The central venous to arterial carbon dioxide difference P(v a)CO2 has been proposed by some authors for assessment of tissue perfusion. 30,89 Values of P(v a)CO2 larger than 6 mm Hg were found to be associated with poor outcome and organ dysfunctions.27,30 Other markers, such as as lactate serum,90,91 base deficit, and tissue hypercarbia, require further investigation as GDT end points before conclusions can be drawn in high-risk surgery.
- While macrocirculation is the focus of many hemodynamic monitoring devices, attention to microcirculation has increased with findings of alterations in microcirculatory flow in various states of shock and critical illness. There are several techniques available to monitor microcirculation, capable of detecting changes in capillary density, changes in perfusion to the microcirculation, and microvascular reactivity. Sakr et al. found that persistent microcirculatory changes in patients with septic shock are correlated with poor survival, as opposed to microcirculatory changes which rapidly improve in those who eventually survive [47]. To date, microcirculatory monitoring has not been used as a therapeutic endpoint and outcomes specifically related to microcirculatory monitoring have not been studied. Trzeciak et al. made strides in this direction by measuring microcirculatory changes in patients undergoing early GDT. The group found that increases in microcirculatory flow were associated with decrease in organ failure at 24 h, despite similar global (macro) hemodynamics [48]. This study implied that monitoring the microcirculation and directly treating microcirculatory alterations along with GDT for macrocirculatory hemodynamics might have an additive effect in outcome improvement in sepsis.
- GDT algorithms typicallyincludeabaselineinfusionofbalanced crystalloid aswellasintermittentbolusesofcolloidtooptimize CO, sometimesinadditiontovasoactivemedications.Theuse of nonbufferedcrystalloidshasbeenassociatedwithmore metabolic derangements(hyperchloremia,metabolicacidosis) than buffered fluids,76 perhaps explainingthedominanceof buffered versusnonbuffered fluids inanesthesiology.Colloids were thoughttooptimizethemicrocirculationbetterthan crystalloids77 and arealsowidelythoughttohavesuperior volume-expansion properties,allowingsmallervolumesof fluid tobeusedwithimprovedperioperativeoutcomes.78 Studiescomparingcrystalloid-versus colloid-basedGDTinbothcolorectal82 and neurosurgical83 procedureshavedemonstratedlowerIV fluid volumesin colloid-basedGDTpatientswithoutanymeaningfulclinical differencesbetweenthe2groups.Astudycomparingbal- anced crystalloid-versuscolloid-basedGDTalgorithmsin patients undergoingcytoreductivesurgeryforprimaryovarian cancer demonstratedlowervolumesofintravenous fluids, higher CO,andhigherSVincolloidpatients,thoughthey found nodifferencesinpostoperativecomplicationsofLOS.84 It appearsthatcolloidsdoallowforbettervolumeexpansion, but thatthisisassociatedwithlittletonoclinicalbenefit in perioperativeGDT,especiallywhentheadministeredvolumes are modest.Itmaybethatperioperativepatientsarelessprone to diffusecapillaryleakthansepticpatients,and,thus,atless riskofharmfromsyntheticcolloids.However,thisidea deservesfurtherconsiderationandstudybeforeconclusions arereached. Before theadventofGDT,therewasdebateastothe relative meritsof “wet”85 and “dry”86 intraoperative fluid strategies.2 After GDTwaspopularized,therehavebeen studies showingimprovedoutcomesprimarilywithincreased fluid volumeswithGDT.17,20,87,88 However, perioperative fluid overload hasbeenassociatedwithadverseoutcomes,89,90 which hasledinvestigatorstocompareGDTwithrestrictive volume regimens.Interestingly,recentstudies91,92 comparing perioperative GDTtorestrictive fluid protocolsincolorectal surgery foundnodifferencesinpostoperativeoutcomes. Randomised controlled trials (RCTs) of colloids compared to crystalloids, in patients requiring volume replacement.We excluded crossover trials and trials involving pregnant women and neonates. We identified 78 eligible trials; 70 of these presented mortality data. Colloids compared to crystalloids Albumin or plasma protein fraction - 24 trials reported data on mortality, including a total of 9920 patients. The pooled risk ratio (RR) from these trials was 1.01 (95% confidence interval (CI) 0.93 to 1.10). When we excluded the trial with poor-quality allocation concealment, pooled RR was 1.00 (95% CI 0.92 to 1.09). Hydroxyethyl starch - 25 trials compared hydroxyethyl starch with crystalloids and included 9147 patients. The pooled RR was 1.10 (95% CI 1.02 to 1.19). Modified gelatin - 11 trials compared modified gelatin with crystalloid and included 506 patients. The pooled RR was 0.91 (95% CI 0.49 to 1.72). (When the trials by Boldt et al were removed from the three preceding analyses, the results were unchanged.) Dextran - nine trials compared dextran with a crystalloid and included 834 patients. The pooled RR was 1.24 (95% CI 0.94 to 1.65). Colloids in hypertonic crystalloid compared to isotonic crystalloid Nine trials compared dextran in hypertonic crystalloid with isotonic crystalloid, including 1985 randomised participants. Pooled RR for mortality was 0.91 (95% CI 0.71 to 1.06). Authors’ conclusions There is no evidence fromrandomised controlled trials that resuscitationwith colloids reduces the risk of death, compared to resuscitation with crystalloids, in patients with trauma, burns or following surgery. Furthermore, the use of hydroxyethyl starch might increase mortality. As colloids are not associated with an improvement in survival and are considerably more expensive than crystalloids, it is hard to see how their continued use in clinical practice can be justified. The choice of fluid has considerable cost implications. Volume replacement with colloids is considerably more expensive than with crystalloids. Clinical studies have shown that colloids and crystalloids have different effects on a range of important physiological parameters. Because of these differences, all-cause mortality is arguably the most clinically relevant outcome measure in randomised trials comparing the two fluid types. The results of this updated meta-analysis have important policy implications. There is still no evidence that colloids are superior to crystalloids as a treatment for intravascular volume resuscitation in critically ill patients, and some of them may even increase mortality. In addition, colloids are considerably more expensive than crystalloids. The economic opportunity cost of ongoing colloid use is likely to be considerable, and for this reason the ongoing use of colloids is unjustified
- Perioperative fluid therapy influences clinical outcomes following major surgery. Fluid preparations may be based on a simple nonbuffered salt solution, such as normal saline, or may be modified with bicarbonate or bicarbonate precursor buffers, such as maleate, gluconate, lactate or acetate, to better reflect the human physiological state. These latter fluids have theoretical advantages over normal saline in preventing hyperchloraemic acidosis. A number of clinical studies have now compared fluid preparations with and without a buffer to achieve a balanced electrolyte solution for perioperative fluid resuscitation. Selection criteria We only included randomized trials of buffered versus non-buffered intravenous fluids for perioperative fluid resuscitation. The trials with other forms of comparisons such as crystalloids versus colloids and colloids versus different colloids were excluded. We also excluded trials using hypertonic fluids and dextrose-based fluids. Main results We identified 14 publications reporting 13 trials or comparisons with a total of 706 participants. For many of the outcomes reported, there was significant clinical and statistical heterogeneity. The primary outcome of mortality at any time was reported in only three studies with a total of 267 patients. The mortality rate was 2.9% for the buffered fluids group and 1.5% for the non-buffered fluids group but this difference was not statistically significant. The Peto OR was 1.85 (95% CI 0.37 to 9.33, P = 0.45, I2= 0%). Organ dysfunction was only presented for renal impairment. There was no difference in renal insufficiency leading to renal replacement therapy between the buffered and non-buffered groups (OR 0.61, 95% CI 0.23 to 1.63, P = 0.32, I2 = 0%). Markers of organ system failure as assessed by urine output, creatinine and its variables (for renal function), PaC02 (respiratory function) and postoperative nausea and vomiting (gastro-intestinal function) showed a statistically significant difference only in PaC02 levels. The mean difference was 1.18 with lower PaC02 levels in the non-buffered fluid group (95% CI 0.09 to 2.28, P = 0.03, I2 = 0%) compared to the buffered fluid group. There was no difference in intraoperative blood loss nor the volumes of intraoperative red cell or fresh frozen plasma transfused between groups. There was an increase in platelet transfusion in the non-buffered group which was statistically significant after analysing the transformed data (log transformation because the data were highly skewed). A number of metabolic differences were noted. There was a difference in postoperative pH of 0.06 units, lower in the non-buffered fluid group (95% CI 0.04 to 0.08, P < 0.00001, I2 = 74%). However, this difference was not maintained on postoperative day one. The non-buffered fluid group also had significantly greater base deficit, serum sodium and chloride levels. There was no difference demonstrated in length of hospital stay and no data were reported on cost or quality of life. Authors’ conclusions The administration of buffered fluids to adult patients during surgery is equally safe and effective as the administration of non-buffered saline-based fluids. The use of buffered fluids is associated with lessmetabolic derangement, in particular hyperchloraemia andmetabolic acidosis. Larger studies are needed to assess robust outcomes such as mortality. We included 14 publications in thisCochrane review, reporting data from13 trials with a total of 706 participants of whom368 received buffered fluids and 338 received non-buffered fluids. The patients who received buffered fluids had an acid-base balance that was more normal than for those who received non-buffered fluids; and the need for the transfusion of some blood products was reduced. Overall, buffered fluids are a safe and effective alternative to non-buffered fluids when given into the veins of patients undergoing surgery. The ideal intravenous fluid would be able to splint the circulation for an adequate period of time to replace missing plasma volume whilst being free of adverse affects. Intravenous fluids are manufactured by the addition of a mixture of electrolytes to water (making a crystalloid solution), and also sometimes a suspension of particles (making a colloid solution). A wide variety of fluid formulations exist, which differ in two basic ways. Firstly, the different component electrolytes that are in solution with water, which can interact with the body’s internal equilibrium once infused. Secondly, the addition of a suspended nonsoluble colloid material to exert oncotic pressure. The colloid versus crystalloid debate is one which has been extensively explored, the electrolyte formulation itself less so. We included studies on adults (aged 16 years and over) receiving intravenous fluids whilst undergoing any form of surgery. We included the administration of intravenous fluids with and without a buffer (bicarbonate or bicarbonate precursor buffer, such as maleate, gluconate, lactate or acetate) for the purpose of plasma volume expansion or maintenance during the perioperative period. In order to minimise confounding factors, we only considered trials where the sole difference between the experimental and control arms was the presence, or not, of a buffer in the fluid. We excluded studies that only compared crystalloids with colloids, or only compared fluids with different colloid components. However, trials with three or more arms were included if the other criteria were satisfied. Types of outcome measures Primary outcomes 1. Mortality (all time frames reported) Secondary outcomes 2. Clinically significant organ system dysfunction as defined in individual papers, including renal, pulmonary, hepatic, gastro-intestinal, coagulation, and central nervous system 3. Surrogatemeasures of organ systemdysfunction including urine output, serum creatinine, PaCO2, nausea and vomiting 4. Blood loss or transfusion requirement 5. Serum measures of coagulation such as prothrombin time, activated partial thromboplastin time, von Willebrand factor, antithrombin 3 activity, fibrinogen and thromboelastogram 6. Biochemical or electrolyte disturbances including pH, base excess, serumbicarbonate, serumsodium, potassium, calcium, chloride 7. Postoperative hospital length of stay 8. Functional health status and quality of lifemeasures as described by the identified papers 9. Cost The interventions varied between studies.Of the 14 included publications, eight used only crystalloids in their experimental and control arms (Chin 2006; Hadimioglu 2008; McFarlane 1994; O’Malley 2005; Scheingraber 1999; Takil 2002; Walsh 1983; Waters 2001). Of these, six compared lactated Ringer’s solution to normal saline (Chin 2006; O’Malley 2005; Scheingraber 1999; Takil 2002;Walsh 1983;Waters 2001) and two compared Plasmalyte 148 to normal saline (Hadimioglu 2008; McFarlane 1994). One trial (Hadimioglu 2008) had two buffered crystalloid arms, each of 30 patients (Plasmalyte 148 and lactated Ringer’s solution), and one normal saline arm of 30 patients. Platelet transfusion There were four studies with a total of 293 patients that detailed the volume of platelets transfused in each arm (Gan 1999;Martin 2002;Waters 2001;Wilkes 2001) where the data were suitable for analysis.Therewas a statistically significant difference in volume of platelets transfused between the two treatment groups.The pooled estimate showed a 242%(log ratio 1.23) higher platelet transfused (mL) in the non-buffered group compared to the buffered group (95%CI 24.61%to 848.77%, P = 0.02, I² = 0%) The base excess was -1.07 mmol/L in the buffered fluid group and -3.55 mmol/L in the non-buffered fluid group. There was a statistically significant difference between the groups with a mean difference of 2.48 mmol/L, lower in the non-buffered fluid group (95% CI 1.61 to 3.36, P < 0.00001, I² = 0%) The chloride level in the buffered fluid group at this time point was 107.0 mmol/L and the chloride level in the non-buffered fluid group was 116.8 mmol/L. There was a statistically significant difference between the groups with a mean difference of 9.8 mmol/L, higher in the non-buffered fluid group (95% CI -18.15 to -1.58, P = 0.02). The pooled data from three studies suggest that the overall mortality was low and there was no evidence that the choice of fluids, either buffered or non-buffered, influenced mortality. For the secondary outcomes, there were no differences in renal dysfunction and surrogate markers of renal dysfunction (urine output and serum creatinine) between groups. Some of the other secondary outcomes did reveal statistically significant differences, including a reduced postoperative pH (pH 7.33 versus 7.39, P < 0.00001), an increased postoperative base deficit (base deficit of 5.0 versus 1.5, P < 0.00001), a reduced postoperative serum bicarbonate (serum bicarbonate of 19 mmol/L versus 22 mmol/L, P < 0.00001) and reduced PaC02 (PaC02 of 36.17 mmHg versus 37.35 mmHg, P < 00001) in the non-buffered group compared to the buffered group. This suggests that buffered fluids are associated with a lesser degree of metabolic acidosis when given perioperatively. Postoperative chloride and sodium levels also showed statistically significant differences between groups. Higher postoperative serum chloride levels (chloride of 114 mmol/L versus 106 mmol/L, P = 0.0001) and serum sodium levels (sodium of 142 mmol/L versus 140 mmol/L, P < 0.00001) were seen in the non-buffered group compared to the buffered group. This might be anticipated from the higher sodium and chloride concentrations in these fluids. Higher serumchloride is a cause ofmetabolic acidosis (Stewart 1978) and may explain our findings of both lower pH and lower PaCO2 (secondary to respiratory compensation of the metabolic acidosis) when using non-buffered fluids. There were no statistically significant differences between groups in the volume of intraoperative blood loss, nor the volume of either red cells or fresh-frozen plasma transfused intraoperatively. Therewas a statistically significant difference in volume of platelets transfused between the two treatment groups.The pooled estimate showed a 242%increase in the volume of platelets transfused in the non-buffered group compared to the buffered group (P = 0.02).
- Intravenous fluid formulations whichmore closelymatch the constituents of human plasma have existed for some years (Hartmann 1934). In particular, these fluids contain a physiological buffer which helps to maintain the body’s acid-base balance. There are other notable differences in the composition of these buffered fluids. They have a variable amount of other electrolytes in them such as potassium, magnesium and calcium, which more closely reflect the composition of plasma. There are now several types of crystalloid and colloid solutions available which contain this physiological buffer (Table 1). Over the past few years, the effects of buffered and non-buffered fluids have been investigated and compared in a number of in vitro (Roche 2006), animal (Wilcox 1983) and healthy volunteer studies (Reid 2003;Williams 1999).
- The risk–benefit balance of GDT in high-risk surgical patients has been debated.9 There may be risk associated with the use of fluid boluses and inotropes in patients with a known limited cardiopulmonary reserve who have arterial pressure and heart rate within the ‘normal physiological range’. Treatment-related cardiopulmonary complications (total CVS complications, arrhythmias, acute pulmonary oedema, and acute myocardial ischaemia) have not been assessed previously. We hypothesized that goal-directed use of fluid and inotrope guided by haemodynamic monitoring in GDT is not associated with an increase in cardiopulmonary complications among high-risk surgical patients undergoing non-cardiac surgery. We only included randomized controlled trials (RCTs) reporting any of the following CVS outcomes: total CVS complications, arrhythmias, acute pulmonary oedema, and acute myocardial ischaemia. The analysis was limited to studies containing an adult general surgical population. GDT was defined as the use ofhaemodynamicmonitoringandtherapies aimedatmanipulating haemodynamics during the perioperative period to achieve a predetermined flow-related endpoint(s). GDT must have been started pre-emptively in the perioperative period (24 h before, intraoperative, or immediately after surgery) and applied after a clear protocol. The protocol must contain predetermined step-by-step instructions for the clinicians based on data obtained froma haemodynamic monitor or surrogates (e.g. lactate, oxygen extraction ratio), and direct therapy to achieve predefined goals. A total of 30 studies were identified as being suitable for the meta-analysis.69–98 However, eight of these studies did not providespecificdetailsonthenumberof patients with CVS complications.76 77 81 83 87 91 92 94 A total of 22 studies including 2129 patients were included in the meta-analysis. These 22 studies included a total of 2129 patients; 1104 in the GDTarmand 1025 in the control treatment arm. Fifteen studies reported rates of arrhythmias, 16 studies reported rates of acute myocardial ischaemia, and 15 studies reported rates of acute pulmonary oedema. The studies reporting arrhythmias, acute myocardial ischaemia, and acute pulmonary oedema included 1393, 1508, and 1468 patients, respectively. There were similar numbers of patients in the GDT and control arms. Eleven studies initiated GDT at the start of surgery, while the other studies initiated GDT before or immediately after surgery. The quality of the trials was analysed using the Jadad score. One of the studies did not report any CVS complications in either the control or the intervention group.74 Among the 2129 patients, 275 (12.9%) patients suffered CVS complications (Table 2). Among patients with complications, 23% had arrhythmias, 11% had acute myocardial ischaemia, and 19% had acute pulmonary oedema. Patients who were treated with GDT had a significant reduction in the total number of perioperative CVS events compared with those in the controlarm[OR 0.54, (0.38–0.76), P¼0.0005]. Subgroup analyses revealed that fluid and inotrope therapy [OR 0.55, (0.34–0.89), P¼0.01]wasassociated withareduction in CVS events: the OR for fluids alone was 0.57, (0.31–1.04), P¼0.07. Only a supranormal oxygen delivery goal was associated with a reduction in CVS complications [OR 0.50, (0.31–0.79), P¼0.002]. GDT using the minimally invasive cardiac output monitors, targeting either normal or supranormal physiological goals,was associated withasignificant reduction in the CVS events [OR 0.47, (0.31–0.73), P¼0.0008], whereas GDT using the PAC was not associated with any benefit or harm [OR 0.70, (0.38–1.29), P¼0.25]. Minimally invasive cardiac output monitors include the oesophageal Doppler monitor, and arterial pressure waveform analysis monitors. Fifteen studies including 1393 patients reported the rates of arrhythmias. A total of 7.2% patients were reported to have had perioperative arrhythmias. GDT was associated with a significant reduction in arrhythmias compared with patients treated in the control arm [OR 0.54, (0.35–0.85), P¼0.007]. The reduction in perioperative arrhythmias was associated with the use of fluids and inotropes [OR 0.58, (0.35–0.96), P¼0.03], a supranormal oxygen delivery goal [OR 0.55, (0.32–0.94), P¼0.03], and the use of minimally invasive cardiac output monitoring devices [OR 45, (0.24–0.83), P¼0.01] in the GDT-treated group. Fifteen studies including 1468 patients reported the rates of acute pulmonary oedema. A total of 5.6% of patients were reported to have had perioperative acute pulmonary oedema. The use of minimally invasive cardiac output monitors in GDT-treated patients was associated with a trend in the reduction in the rate of acute pulmonary oedema [OR 0.45, (0.18–1.11), P¼0.08]. There was no increased risk of acute pulmonary oedema among any subgroup of patients in the GDT group. Sixteen studies including1508patients reported the rates of acute myocardial ischaemia. A total of 3.2% of patients were reported to have had perioperative acute myocardial ischaemia. There was no increase in the incidence of acute myocardial ischaemia among patients in the GDT group. We found an absolute difference of 4.4% in CVS complications between the GDT-treated patients and the control group patients. Patients who received inotropes in addition to fluids would have been more likely to achieve supranormal oxygen delivery targets. We found a significantly lower incidence of arrhythmias associated with these factors. Reduced systemic inflammation due to improved microvascular perfusion82 or an improved cardiac performance with inotropes may be beneficial. Despite the use of fluidsandinotropes in this groupof highrisk surgical patients with limited cardiopulmonary reserve, the incidence of acute pulmonary oedema and acute myocardial ischaemia is not increased. Less invasive cardiac output monitors are associated with significantly less arrhythmias and overall CVS complications. This may relate to the complexity and invasive nature of the PAC in comparison with less invasive cardiac output monitors, 100–102 supporting the use of less invasive cardiac output monitors for perioperativeGDT.
- TERAPIA DIRIGIDA POR METAS Elegir monitoria según contexto VPP < 12 NO = Cristaloide balanceado (si IC disminuye considerar inotrópico) Determinar IC > 2.5 l/m/m2 no = inotrópico TAM en metas vasoactivo Control medida bienestar tisular periódica Revalorar cada 15 minutos
- Perioperative GDT is beneficial in high-risk surgical patients despite the various targets and monitors used. Markers of organ perfusion and circulation that can be directly measured are used as surrogates of tissue perfusion. GDT uses this practical approach of optimizing circulatory volume, flow, and perfusion (with fluids and inotropes) to prevent tissue hypoperfusion in the high-risk surgical patient. The reductions in immediate postoperative complications translate to overall benefits in healthcare costs, despite a requirement for an increase in healthcare resources to offer early GDT. Any perceived increase in resource allocation results in a lower patient mortality, morbidity, and therefore a financial benefit.106 Furthermore, a reduction in immediate postoperative complications has far-reaching effects, with a potential beneficial effect on long-term survival.107 Early GDT using administration of fluid challenges and inotropes guided by haemodynamic monitoring does not result in an increased rate of cardiac events in this cohort of patients with limited cardiopulmonary reserve. GDT in highrisk surgery is beneficial in reducing CVS events. This holds true irrespective of the choice of the monitored physiological parameter or haemodynamic monitor in use. It is unclear if the use of a haemodynamic monitor alone or the combination of an algorithm and a haemodynamic monitor confers the benefit. The benefit is most pronounced in patients receiving fluid and inotrope therapy to achieve a supranormal oxygen delivery target, with the use of minimally invasive cardiac out monitors. Once again, no monitoring device can replace the close observation of clinical variables and “no monitoring device can improve outcome unless coupled to a treatment which itself improves outcome.”49
- Joosten A. Defining Goals of Resuscitation in the critically I ll Patient. Crit Care Clin. 2015 TERAPIA DIRIGIDA POR METAS Elegir monitoria según contexto VPP < 12 NO = Cristaloide balanceado (si IC disminuye considerar inotrópico) Determinar IC > 2.5 l/m/m2 no = inotrópico TAM en metas vasoactivo Control medida bienestar tisular periódica Revalorar cada 15 minutos