Breast Cancer in Young Women

There are a number of issues specific to breast cancer diagnosis in young women:

1 Breast cancer is uncommon in young women. It is associated with more-aggressive behavior and a worse prognosis. These clinical observations have recently been verified by histologic and biochemical analyses of these cancers.

2 Young women undergoing breast-conservation therapy can have a higher rate of local recurrence than older women, and this issue should be specifically addressed in preoperative counseling of these women.

3 Long life expectancy, issues of fertility, and risk of premature menopause resulting from cytotoxic chemotherapy are concerns unique to the young breast cancer patient.

4 Issues related to a new diagnosis of breast cancer associated with pregnancy bring up a multitude of issues in this vulnerable population.

5 Psychosocial issues of sexuality and self-image can warrant interventions in this population.

Recovery and neurological evaluation

Recovery after a craniotomy procedure is an important step for the success of a neurosurgical procedure. During this process, it is necessary to pursue all of the objectives of current neurosurgical anaesthesia: maintain brain homeostasis, avoid oedema formation (hyponatremia, seizures, steroids withdrawal), control intracranial pressure (normocapnia, normothermia, prevent shivering and nausea or vomiting), prevent and treat pain.Immediate post-procedural neurological evaluation is mandatory to detect any postoperative cerebral complication as soon as possible. If the patient does not obey command, extubation has to be delayed. After posterior fossa procedures, intact cranial nerve functions must be confirmed before extubation.If extubation is not possible and a delayed recovery is indicated, intracranial pressure monitoring may become useful. “Sedation windows” are needed in order to perform neurological evaluations at regular, predefined time points for detection of complications and for minimizing the duration of mechanical ventilation.A brain CT should be performed rapidly when a unexpected neurological deficit or change in consciousness have evolved. In many neurosurgical centers, a systematic CT-scan is performed in the first 24-hours after surgery in order to detect a clinically silent neurosurgical complication.Even if an intensive care unit is not available after a craniotomy procedure, central neurosurgical patients require an intensive neurological and haemodynamic monitoring at least for the time period of one night after surgery. Neurosurgery and anaesthesia experts should be immediately available over 24-hours every day in case of severe complications.

• Provide "stress-free recovery” for central neurosurgical patients

• Avoid hypertension, hypercapnia, shivering, pain and coughing

• Perform neurological examination as soon as possible after surgery

• A neurological score is recommended in order to improve follow-up.

• Maintain normothermia, normotension, euvolemia and normoosmolality

• Closely and continuously monitor over at least 24 hours after surgery

• Perform CT or MR immediately if neurological deterioration or seizures occur

• Control the ICP if postoperative sedation becomes necessary

• Work on anaesthetic techniques and monitoring that allows for intra- and post-operative homeostasis is needed, and research to minimize anaesthesia- and procedure-related sequelae is warranted

• Finding a good neurological score to be applied on postoperative craniotomy patients and for improving the detection of cerebral complications would be helpful

• Identifying markers of postcraniotomy brain damage to guide therapy would be useful

Physiology and pathophysiology of the vasopressinergic system

The field of neurohormonal physiology is highly complex. Since vasopressin was isolated in the early 1950s, much has been learnt about its function in health and disease, but we are far from a complete understanding of its different and diverse functions, and have much to discover in terms of the complex interactions between vasopressin and other neurohormones and mediators. The development of specific agonists and antagonists for the different vasopressin receptors in recent years has enabled research to examine their individual and combined roles in physiological homeostasis more precisely, and to propose therapeutic uses for these agents in various common disease processes. Vasopressin and its analogues have also been used in the treatment of diabetes insipidus, bleeding oesophageal varices, shock, particularly septic shock, and cardiopulmonary resuscitation. Further research into the physiological roles of vasopressin, the complex signalling pathways associated with receptor stimulation, and the multiple feedback loops which regulate vasopressin secretion and release will offer improved insight into this fascinating peptide, and provide future targets for therapeutic investigation.

• many aspects of vasopressin's functions remain poorly understood

• further research is needed to improve understanding of the molecular basis of receptor function using newly developed specific vasopressin receptor antagonists

• ongoing studies will help to elucidate the complex mechanisms regulating vasopressin synthesis and release, and the interactions of vasopressin with other neurohormonal and vasoregulatory pathways

• clinical studies are warranted to evaluate further the role of vasopressin receptor antagonists in various disease processes, including congestive heart failure and hyponatraemia

Thermoregulatory management for mild therapeutic hypothermia

Mild therapeutic hypothermia is an important neuroprotective concept after out-of-hospital cardiac arrest^{[*37] and [*97]} and improves outcome after pediatric ischemic hypoxic encephalopathy.⁴⁸ Many studies are currently ongoing to determine additional evidence-based indications for mild therapeutic hypothermia.This article presented numerous possibilities and methods for the induction and maintenance of therapeutic hypothermia. There are several feasible, efficient and affordable options to implement mild therapeutic hypothermia in any intensive care setting – neither financial restraints nor infrastructural issues should therefore be reasons not to provide patients adequate neuroprotective treatment.In summary, a recommendation for any specific cooling method or any particular sedation regimen is not possible yet – more evidence and further clinical studies are needed to establish optimized hypothermia treatment procedures.

Conflict of interest

Dr. Oliver Kimberger: No conflict of interest.Dr. Andrea Kurz: No conflict of interest.

• For a fast induction and efficient maintenance of mild therapeutic hypothermia shivering and vasoconstriction thresholds have to be lowered.

• Apart from general anaesthetics meperidine, dexmedetomidine, nefopam, buspirone and skin warming lower thermoregulatory thresholds.

• With a well balanced combination of different anti-shivering drugs mild therapeutic hypothermia can be induced and maintained in awake patients, e.g. to allow neurological monitoring.

• Accurate measurement of core temperature during mild therapeutic hypothermia is very important. Pulmonary artery, oesophagus, nasopharynx, bladder or tympanic temperature should be used for core temperature measurement.

• During hypothermia the half-life of all drugs is notably prolonged, and dosing has to be adjusted accordingly.

• There are many efficient cooling methods commercially available, an evidence-based recommendation for any specific method has yet to be established.

• Research is warranted on new drugs lowering the shivering threshold without concomitant sedation and respiratory toxicity.

• Further large clinical trials are necessary to explore additional indications for mild therapeutic hypothermia.

Influence of fluid therapy on the haemostatic system of intensive care patients

Haemostatic side-effects may be either beneficial or unwanted depending on the status of a given patient. Attenuation of hypercoagulability may be beneficial in patients at risk for thrombotic episodes. In patients at risk for bleeding, however, the anticoagulant effects may translate into blood loss and transfusion requirements. Judging by currently available evidence, adverse haemostasis effects appear to be inherent to colloidal molecules, although dextran, hetastarch and pentastarch definitely have a more pronounced impact than tetrastarch, gelatin and albumin (evidence level Ib). Especially in the era of colloids with minimal, predictable and well-described influences on the haemostatic system, other adverse side-effects become of utmost importance in decision making in fluid management. Tetrastarch appears to be a suitable volume expander in the routine intensive care setting due to its high volume efficacy and safety index. Contra-indications and maximum daily doses need to be acknowledged. Gelatins have even lower inhibitory effects on clot strength compared with tetrastarch, but volume efficacy is also lower and anaphylactoid reactions are more frequent. Dextrans are potent anticoagulants with a high risk for adverse reactions. Albumin has negligible effects on haemostasis, but low volume efficacy and costs limit the use of a blood product as a routine volume replacement fluid.

• colloidal molecules inhibit platelet function (in carrier solutions without calcium): dextran ≥ hetastarch > pentastarch > gelatin ≥ tetrastarch, albumin

• colloidal molecules decrease vWF and factor VIII: dextran ≥ hetastarch > pentastarch > gelatin ≥ tetrastarch, albumin

• colloidal molecules induce hypocoagulability and decrease fibrin polymerization: dextran > hetastarch > pentastarch > tetrastarch > gelatin > albumin

• to avoid potential acidosis-induced changes in haemostasis, plasma-adapted carrier solutions may be used instead of saline-based solutions

• effect of colloidal molecules on blood loss: dextran > hetastarch > pentastarch > gelatin, tetrastarch, albumin

• postoperative fluid therapy (in the absence of bleeding complications) should improve rheology and should not aggravate postoperative activation of coagulation. A moderate inhibitory effect on thrombin generation and platelet hyper-reactivity may be favourable

• crystalloids, HES and gelatins are most frequently used in postoperative hypercoagulability

• fluids with anticoagulant and antiplatelet side-effects (such as dextrans) attenuate hypercoagulability^{[50] and [94]}, but cannot be used as a substitute for thrombosis prophylaxis if indicated

• there is no clear recommendation for any particular fluid therapy and for different types of colloids in sepsis

• tetrastarch, gelatins and crystalloids are most frequently used in sepsis-associated coagulopathy; tetrastarch may exert anti-inflammatory effects while preserving haemostasis. Gelatins have lower inhibitory effects on clot strength compared with tetrastarch, but their volume efficacy is also lower. Albumin has negligible effects on haemostasis, but low volume efficacy and costs limit the use of a blood product as a routine volume replacement fluid in sepsis. Dextrans are not recommended in sepsis due to potent anticoagulant effects with a high risk for adverse reactions

• in patients with severe liver failure, fluids with negligible effects on haemostasis and organ function are required. Potato-derived tetrastarch was associated with mild-to-moderate hyperbilirubinaemia⁶¹ and is contraindicated in patients with severe hepatic impairment

• long-term use of hyperoncotic solutions is not indicated in intensive care patients at risk for renal failure

• there are differences between older generations of HES and tetrastarch. Hetastarches and pentastarches should not be used in renal failure

• contra-indications (e.g. anuria) and maximum daily doses for tetrastarch need to be acknowledged

• binding of organic compounds such as prostaglandins to amylopectin and linear chains of amylose in potato-derived HES preparations may impair the antiplatelet effect⁹⁷

• the content of calcium in the crystalloid carrier solutions is unlikely to affect calcium re-infusion after the haemofilter in citrate anticoagulation

• in the absence of firm evidence⁹⁸, tetrastarch appears to be superior to other fluids in massive bleeding due to its volume efficacy and safety

• small-volume resuscitation is reported to result in smaller haemostatic derangements compared with conventional colloidal resuscitation.⁸¹

• it remains to be determined whether extracellular coating impairs platelet procoagulant activity by modifying the binding of constituents of the prothrombinase and tenase complex to the negatively charged phospholipids exposed on activated platelets

• the exact mechanisms for the decrease in factor VIII and vWF by colloids has not been elucidated fully

• studies are warranted to elucidate the effect of potato-derived tetrastarch on haemostasis, especially after high-dose, long-term application

• future papers on HES need to clearly indicate molar substitution, C2/C6 ratio, molecular weight, suspension medium and oncotic characteristics in order to permit precise interpretation of the results

• large-scale clinical studies on the clinical relevance of acid-base disturbance after colloid infusions are warranted

• a head-to-head comparison of balanced tetrastarch and balanced gelatins on blood loss and transfusion requirements in patients at risk for bleeding is needed

• the relationship between bleeding and laboratory coagulation parameters (e.g. clot polymerization) in the presence of synthetic colloids remains open to question in humans

• a head-to-head comparison of balanced tetrastarch, balanced gelatins and albumin on side-effects on haemostasis in septic patients is needed

• adequately powered in-vivo studies employing a clinically relevant methodology are needed. Infusion of 20 mL/kg colloid within 10 min does not necessarily represent common clinical situations

• the effect of fluid therapy on micro-embolization, organ and cognitive functions warrants evaluation in well-designed experimental settings

• although often used as a parameter of effectiveness⁹⁹, mortality may not be a suitable outcome parameter due to the many confounding factors, even in well-standardized animal experiments.¹⁰⁰ Survival rate was comparable in rabbits resuscitated with gelatin, HES or crystalloid, but survival time was longest in HES-treated animals³⁹

Pharmacokinetic aspects of fluid therapy

Volume kinetics could be a useful tool to better understand fluid distribution and its implications for fluid therapy. By using non-linear regression, it is possible to fit dilution data to an equation that describes fluid distribution in one- and two-volume models reasonably well. These models could be adapted to fit different clinical situations. In the future, it would be useful to design models similar to target control infusion models in pharmacokinetics. Such models should probably use dilution of Hb or other endogenous tracers in combination with blood pressure as endpoints.

• peri-operative fluid therapy continues to be an exercise in empiricism, with nagging questions about efficacy and complications

• in 1997, several authors introduced kinetic modeling (volume kinetics) describing the peak effects and clearance of intravenously infused fluids in terms similar to those used in pharmacokinetics

• this chapter briefly summarizes currently accepted principles of fluid therapy, discusses the general approach to kinetic analysis of fluid therapy, reviews currently available data defining kinetic responses to fluid therapy, and speculates about future applications of this approach

• further research is warranted where anaesthetic drugs in combination with haemorrhage are studied kinetically in humans

• it is important to implement a non-invasive analysis of an endogenous tracer such as Hb to facilitate future use of kinetic models for fluids

• an outcome study comparing fluid administration according to kinetic principles vs standard of care is warranted

Nerve grafts are rarely necessary and are unlikely to improve sexual function in men undergoing anatomic radical prostatectomy

I remain skeptical about the value of nerve grafts in restoring sexual function in men who undergo wide excision of the neurovascular bundle and am concerned that it may encourage urologists to pursue wide excision where it is neither necessary nor useful.

Patients who have invasion of the neurovascular bundles on both sides to the point where it is necessary to excise both neurovascular bundles are not curable with surgery.

Today, most men with localized prostate cancer who undergo surgery can have preservation of both neurovascular bundles.

Patients who have extensive disease outside the prostate are less likely to recover sexual function regardless of the status of their nerves and are unlikely to benefit from placement of a nerve graft.

A randomized properly performed study of nerve grafts should be carried out before nerve grafts are widely accepted in the management of localized prostate cancer.

The most valuable thing one can do to ensure the recovery of sexual function in a patient where it was necessary to widely excise one neurovascular bundle is not a nerve graft. Rather, it is precise preservation of the contralateral neurovascular bundle.

Hypothermia during cardiac surgery

During cardiac surgery procedures, the first item to consider is whether the surgery will be performed with or without CPB, because its use implies the utilization of heat exchange and the possibility of controlling the core body temperature.Although irrefutable advantages of the use of hypothermia instead of normothermia during CPB have not been reported, it seems wise to maintain a mild core body temperature (34–35 °C) in order to preserve brain function during potential ischaemic periods due to intra-operative incidences. Beyond the objective of maintaining a specific core temperature, it is much more important, from the point of view of overall postoperative brain outcome, to avoid brain hyperthermia during the rewarming period at the end of CPB. This hyperthermia is secondary to fast rewarming, with uncontrolled arterial temperature infusion ≥39 °C trying to reduce the development of post-CPB hypothermia as a consequence of afterdrop. Brain hyperthermia is highly prevalent in cardiac surgery, but is often poorly understood and not taken into account. The main reason for this is the absence of specific monitoring to detect brain desaturation and ischaemia.The authors propose the use of a mild temperature during CPB, combined with active heat transfer by application of a peripheral on the body surface. This reduces the need for intensive rewarming with closer values for the core and peripheral temperatures.

Epilogue

As reported by Flynn et al⁶³, available reports are flawed by inconsistencies in cardioplegic technique and inadequate definitions of normothermic systemic perfusion. These flaws make definition of the independent effects of warm blood cardioplegia and normothermic CPB uncertain. The American College of Cardiology/American Heart Association (ACC/AHA) guidelines for CABG (1999) reported that ‘no strong argument can currently be made for warm versus cold and crystalloid versus blood cardioplegia’ in patients with normal left ventricular function. The guidelines go on to report ‘certain techniques may offer a wider margin of safety for special patient subsets’. However, the evidence for such a wide safety margin is documented only as: ‘Several studies have suggested that blood cardioplegia (compared to crystalloid) may offer a greater margin of safety during CABG performed on patients with acute coronary occlusion, failed angioplasty, urgent re-vascularisation for unstable angina, and/or chronically impaired left ventricular function’. According to the 2005 update, ‘additional manoeuvres to reduce type 2 neurological injury include maintenance of steady cerebral blood flow during CPB, avoidance of cerebral hyperthermia during and after CPB, meticulous control of perioperative hyperglycemia, and avoidance and limitation of post-operative cerebral oedema’.⁷³Finally, it should be remembered that the cost of preventing intra-operative hypothermia is much less than the cost of treating its adverse consequences.⁷⁴ Moreover, in cases where some type of CPB is performed, warming of the peripheral compartment reduces the afterdrop and the need for intensive rewarming, thus reducing the probability of inducing brain hyperthermia, the cause of many deleterious effects.³³

• Nowadays there is no consistent clear advantage of cold over warm of normothermic CPB.

• Mild brain cooling (2–5 °C) confers protection from ischaemic brain injury, and reduces infarct size in transient middle artery occlusion. So it seems wise to maintain a mild core body temperature (34–35 °C) during CPB.

• Maintenance of normothermia throughout the non-CPB phases of CABG is associated with reduced myocardial ischaemic injury, lower SVR and higher cardiac index.

• If core temperature is preserved but skin temperature is lowered, local bleeding time increases.

• The strict avoidance of hyperthermia during rewarming period is mandatory, because it could exacerbate brain injury.

• Mild temperature during CPB, combined with warming of the peripheral compartment reduces the afterdrop and the need for intensive rewarming, thus reducing the probability of inducing brain hyperthermia in addition to postoperative hypothermia.

• Till now, we do not know which is the most appropriate temperature for CPB during cardiac surgery, in terms of improving brain and no brain overall perioperative outcome.

• Further studies are needed to find a more accurate way of monitoring brain temperature and the possible relationship between brain hyperthermia and postoperative neurocognitive deficits.

• More efforts are required to determine the effects of hypothermia on drug disposition and response, and thus delineate better dosing guidelines.

• Further studies are needed to clarify which is the more efficient warm system to maintain the patients actively warmed during OPCAB.

Sternal wound infections

The incidence of DSWI after cardiac surgery is approximately 1.1% with an associated mortality of 13%. These numbers have changed little in the last 20 years despite numerous advances in the care of patients undergoing cardiac surgery. This is likely a reflection of an older patient population with more co-morbidities in the modern era. Many of the risk factors for DSWI are not modifiable. However, treating these diseases when possible, particularly glucose intolerance with insulin infusions seems beneficial in reducing the incidence of DSWI. There is active investigation into the utility of eradicating S. aureus from the naso-pharyngeal and skin flora. To this end, mupirocin and chlorhexidine gluconate may prove beneficial. While there has been some interest in using glycopeptides (vancomycin) for surgical prophylaxis in areas where MRSA infections are highly prevalent, this practice is not supported by any evidence based literature.

• The use of insulin infusions to maintain glucose levels < 200 mg/dl perioperatively appears to be beneficial in preventing DSWIs. However, very tight intraoperative glucose control (80–100 mg/dl) may increase the risk of stroke and death.

• Eradication of Staphylococcus aureus from the naso-pharygeal flora with topical mupirocin and/ or chlorhexidine oral rinse is a low risk intervention that may decrease the incidence of DSWI as well as antibiotic usage

• It appears that even in hospitals with a high incidence of methicillin resistant S. aureus surgical site infections first generation cephalosporins (cefazolin) are superior to glycopeptides (vancomycin) for surgical prophylaxis.

• The low incidence of DSWIs makes the performance of appropriately powered, randomized trials difficult.

• Large, multi-center trials are needed to evaluate the efficacy of interventions such as the eradication of S. aureus from the nasopharynx in preventing DSWIs.

• Like many complications from cardiac surgery including neurocognitive dysfunction and renal impairment, there is likely no “silver bullet” that will prevent DSWIs. As such, the focus should be on system-based approaches that incorporate multiple modalities of prevention.

Réparation à l'Etage Ventriculaire (REV Procedure): Not a Rastelli Procedure Without Conduit

Since the introduction of the REV procedure in 1980, this operation has become our procedure of choice for patients with transposition of the great arteries, VSD, and POT obstruction. The classical Rastelli procedure is indicated only in patients in whom the presence of a well-functioning pulmonary valve is deemed necessary (i.e., hypoplastic right ventricle, inadequate pulmonary arterial bed). Compared with the Rastelli operation, the REV procedure may have definite advantages:

1. The REV operation creates a straight, short left ventricular-aortic tunnel, provides proper alignment of the aorta with the left ventricular chamber, and practically eliminates the risk of late subaortic stenosis.

2. Complete repair is feasible in patients in whom a Rastelli procedure would be contraindicated because of unfavorable intracardiac anatomy (i.e., restrictive VSD, abnormal attachment of tricuspid chordae on the conal septum).

3. The absence of an extracardiac conduit to restore the right ventricular-pulmonary artery continuity reduces the need for reoperation due to recurrent POT obstruction. In most patients, the long-term outcome of the reconstructed right ventricular outflow tract may be similar to that of a repaired tetralogy of Fallot. However, the need to relieve right ventricular outflow tract obstruction, although reduced in comparison with the Rastelli procedure, is not eliminated completely.

4. Because of its feasibility in most intracardiac situations and because it obviates the need for an extracardiac conduit, the REV procedure can be performed in infants and small children, thus avoiding, in most patients, an initial palliative step.