Heleen M. Oudemans-van Straaten

Effect of preoperative oral immune-enhancing nutritional supplement on patients at high risk of infection after cardiac surgery: a randomised placebo-controlled trial

BACKGROUND Elderly patients and those with poor ventricular function have increased morbidity and mortality rates when undergoing surgery. We aimed to ascertain whether an oral immune-enhancing nutritional supplement could improve preoperative host defence, and subsequently lower postoperative infections and organ dysfunction in patients undergoing elective cardiac surgery who are at high risk of infection. METHODS In this prospective, randomised, double-blind, placebo-controlled study, we randomly assigned 50 patients who were scheduled to undergo coronary artery bypass to receive either an oral immune-enhancing nutritional supplement containing L-arginine, omega3 polyunsaturated fatty acids, and yeast RNA (n=25), or a control (n=25) for a minimum of 5 days. Patients were included if they were aged 70 years or older, or had an ejection fraction of less than 0.4, or were scheduled to undergo mitral valve replacement. The main outcome was preoperative host defence (delayed-type hypersensitivity response to recall antigens, expression of HLA-DR epitopes on monocytes, and concentration of interleukin 6 in plasma). Analysis was per protocol. FINDINGS Five patients (two in the treatment group) were excluded because they did not take the minimum dose. Preoperative expression of HLA-DR epitopes on monocytes was significantly higher in patients given the study treatment (109% [95% CI 92-128]) than those given the control (69% [58-82]) compared with baseline (100%) (p=0.02, repeated measures ANOVA). However, concentration of interleukin 6 was significantly lower in the treatment group (0.90 pg/L [0.69-1.18]) than in the control group (1.94 pg/L [1.45-2.59]) (p=0.032, repeated measures ANOVA). Additionally, delayed-type hypersensitivity response to recall antigens improved preoperatively and remained better until hospital discharge. INTERPRETATION Intake of an oral immune-enhancing nutritional supplement for a minimum of 5 days before surgery can improve outlook in high-risk patients who are undergoing elective cardiac surgery.

Myocardial performance in elderly patients after cardiopulmonary bypass is suppressed by tumor necrosis factor

The aim of this study was to determine whether elderly patients (aged > or = 65 years, n = 20) in comparison with younger patients (aged < or = 55 years, n = 23) demonstrate a different biochemical and hemodynamic response to coronary artery bypass operations. In the elderly group, we calculated a smaller body surface area (p < 0.01) than that in the younger group, and more female patients were included in this group (p < 0.05). During cardiopulmonary bypass, the elderly had higher endotoxin plasma concentrations (p < 0.01) than the younger patients, and significantly more circulating tumor necrosis factor-alpha was found after operation (p < 0.04). In the intensive care unit, the elderly patients had a significantly higher pulmonary capillary wedge pressure (p < 0.001), a higher mean pulmonary artery pressure (p < 0.01), and a lower calculated left ventricular stroke work index (p < 0.05). Multivariate analysis for the postoperative outcome showed that the intergroup differences in tumor necrosis factor-alpha, mean pulmonary artery pressure, and pulmonary capillary wedge pressure could be explained mainly by the difference in age between the groups and that the calculated left ventricular stroke work index difference could be explained by the difference in circulating tumor necrosis factor-alpha levels. Thus in elderly patients higher circulating endotoxin and tumor necrosis factor-alpha concentrations were detected than in younger patients, which clinically resulted in a suppressed myocardial performance.

Vitamin C revisited

This narrative review summarizes the role of vitamin C in mitigating oxidative injury-induced microcirculatory impairment and associated organ failure in ischemia/reperfusion or sepsis. Preclinical studies show that high-dose vitamin C can prevent or restore microcirculatory flow impairment by inhibiting activation of nicotinamide adenine dinucleotide phosphate-oxidase and inducible nitric oxide synthase, augmenting tetrahydrobiopterin, preventing uncoupling of oxidative phosphorylation, and decreasing the formation of superoxide and peroxynitrite, and by directly scavenging superoxide. Vitamin C can additionally restore vascular responsiveness to vasoconstrictors, preserve endothelial barrier by maintaining cyclic guanylate phosphatase and occludin phosphorylation and preventing apoptosis. Finally, high-dose vitamin C can augment antibacterial defense. These protective effects against overwhelming oxidative stress due to ischemia/reperfusion, sepsis or burn seems to mitigate organ injury and dysfunction, and promote recovery after cardiac revascularization and in critically ill patients, in the latter partially in combination with other antioxidants. Of note, several questions remain to be solved, including optimal dose, timing and combination of vitamin C with other antioxidants. The combination obviously offers a synergistic effect and seems reasonable during sustained critical illness. High-dose vitamin C, however, provides a cheap, strong and multifaceted antioxidant, especially robust for resuscitation of the circulation. Vitamin C given as early as possible after the injurious event, or before if feasible, seems most effective. The latter could be considered at the start of cardiac surgery, organ transplant or major gastrointestinal surgery. Preoperative supplementation should consider the inhibiting effect of vitamin C on ischemic preconditioning. In critically ill patients, future research should focus on the use of short-term high-dose intravenous vitamin C as a resuscitation drug, to intervene as early as possible in the oxidant cascade in order to optimize macrocirculation and microcirculation and limit cellular injury.

Circulating endothelin in cardiac operations: influence of blood pressure and endotoxin

BACKGROUND Endothelin is involved in the control of cardiovascular and renal functions and acts as a neuromodulator. METHODS In a prospective study among 15 male patients who underwent coronary artery bypass grafting, we investigated the release pattern and possible stimuli of circulating endothelin. RESULTS We detected a steep increase in endothelin concentrations after the onset of cardiopulmonary bypass (CPB), and a second minor increase during CPB. The steep increase in endothelin concentrations correlated with the change in arterial pressures at the onset of CPB (r = -0.57; p < 0.03). The slow increase in endothelin concentrations during CPB, however, correlated with mean endotoxin levels during and after CPB (r = 0.60; p < 0.02). CONCLUSIONS The change in arterial pressure at the onset of CPB seems to induce a steep and fast increase in circulating endothelin level, which is probably mediated through the baroreceptors. The slow increase in endothelin level during CPB is associated with increased circulating endotoxin concentration. It may be that either endothelin-mediated vasoconstriction induces endotoxin transmigration from the intestine or endotoxin stimulates secretion from endothelial cells.

Fluid overload and acute kidney injury: cause or consequence?

There is increasing evidence that fluid overload and acute kidney injury (AKI) are associated but the exact cause-effect relationship remains unclear. Wang and colleagues analysed patients admitted to 30 intensive care units in China and found that fluid accumulation was independently associated with an increased risk of AKI and mortality. This commentary focuses on the close pathophysiological link between AKI and fluid overload and discusses the implications for clinical practice. It outlines some of the challenges, including the difficulty in diagnosing fluid overload reliably with current methods, and stresses the importance of personalised fluid therapy with physiological end-points to avoid the deleterious effects of fluid overload.

Glycemic control: please agree to disagree.

Two dissenting views on glycemic control during critical illness were recently published in Intensive Care Medicine. The first interpretation by Marik [1] recommends a “no-touch” approach based on the adaptive and physiological properties of stress hyperglycemia, which provides a benefit that largely outweighs the risks of absolute or relative hypoglycemia associated with intensive insulin therapy. The second interpretation by Gunst and Van den Berghe [2] strongly advocates tight glycemic control by intensive insulin therapy (IIT) on the basis of the prevention of the toxicity of prolonged hyperglycemia, and on the favorable risk-to-benefit ratio reported in the pioneering clinical studies performed in Leuven [3–5]. These apparently irreconcilable viewpoints on the same set of data highlight the current status of our knowledge. Is the debate closed? Will the opponents leave the scientific community with the bitter feeling of a hopeless issue? Probably not, as the debate surrounding glycemic control in the ICU unraveled important findings briefly summarized in the next paragraphs. The majority of the medical community agrees with the risks associated with hypoglycemia, severe hyperglycemia, and high glycemic variability. Thus, glucose control is not debated, but tight glucose control is. The uncertainty regards optimal glucose targets. U‐shaped curve Observational studies reflecting daily life, applying more or less tight glucose control, found a U-shaped association between mean blood glucose levels and mortality with the lowest mortality observed for the 7–9 mM range. Not only hypoglycemia but also severe hyperglycemia and high glycemic variability were associated with a poor outcome, and the strength of the associations of each domain is additive with each other [6–9]. Notably, the most favorable range was higher than the tight glucose range (4.4–6.1 mM), questioning the safety of ‘low normal’ glucose concentrations, which may be hypoglycemic during critical illness. However, association is no proof of causation. We therefore do not know whether the prevention or correction of hyperglycemia, hypoglycemia, and high variability will improve the outcome, or alternatively whether these domains of dysglycemia are only markers of the severity of disease.

Coronary angiography after cardiac arrest: Rationale and design of the COACT trial

BACKGROUND Ischemic heart disease is a major cause of out-of-hospital cardiac arrest. The role of immediate coronary angiography (CAG) and percutaneous coronary intervention (PCI) after restoration of spontaneous circulation following cardiac arrest in the absence of ST-segment elevation myocardial infarction (STEMI) remains debated. HYPOTHESIS We hypothesize that immediate CAG and PCI, if indicated, will improve 90-day survival in post-cardiac arrest patients without signs of STEMI. DESIGN In a prospective, multicenter, randomized controlled clinical trial, 552 post-cardiac arrest patients with restoration of spontaneous circulation and without signs of STEMI will be randomized in a 1:1 fashion to immediate CAG and PCI (within 2 hours) versus initial deferral with CAG and PCI after neurological recovery. The primary end point of the study is 90-day survival. The secondary end points will include 90-day survival with good cerebral performance or minor/moderate disability, myocardial injury, duration of inotropic support, occurrence of acute kidney injury, need for renal replacement therapy, time to targeted temperature control, neurological status at intensive care unit discharge, markers of shock, recurrence of ventricular tachycardia, duration of mechanical ventilation, and reasons for discontinuation of treatment. SUMMARY The COACT trial is a multicenter, randomized, controlled clinical study that will evaluate the effect of an immediate invasive coronary strategy in post-cardiac arrest patients without STEMI on 90-day survival.

How to Give Vitamin C a Cautious but Fair Chance in Severe Sepsis

Overwhelming inflammation and oxidative stress contribute to the high morbidity and mortality of sepsis by causing vasoplegia, capillary leakage, and organ failure. This provided the strong rationale for Paul Marik’s group to target both uncontrolled inflammation and oxidative stress in an attempt to improve patient outcome. In their provocative before and after study, they administered a combination of IV vitamin C, hydrocortisone, and thiamine in the early phase of severe sepsis and found a considerable decrease in organ failure and mortality. Results are reported in this issue of CHEST.

Oxygen Supplementation Among Patients in the Intensive Care Unit

In Reply Our Viewpoint examined the concept of birth centers and suggested a path to broader adoption in the United States through a network of hospital-affiliated birth centers, a model used in the United Kingdom. The Birthplace in England national prospective cohort study accounted for 95% of freestanding midwifery units in the United Kingdom, collecting comprehensive data across different delivery settings with high response rates.1 We thought the generalizability of these data were stronger than available US studies. The outcomes were excellent for low-risk women and their infants and provide a strong case for hospital-affiliated outpatient birth centers. By contrast, the most comprehensive study evaluating outcomes among US birth centers comes from a voluntary registry run by the American Association of Birth Centers2 into which birth centers voluntarily opt in or out. The study2 included 79 birth centers, which represent approximately 25% of the freestanding birth centers in the United States. Although these data demonstrate good maternal and infant outcomes, the potential for selection bias reduces generalizability. We agree that accreditation of birth centers is essential for enhancing safe care. However, approximately two-thirds of US birth centers are not accredited, which undermines confidence in the accreditation process. Additionally, we advocate for a more robust collaboration protocol than is outlined by the Commission for the Accreditation of Birth Centers.3 Although standards by the American Association of Birth Centers require a “transfer arrangement with a hospital,” the description of such an agreement is minimal. A prearranged plan for access to acute services must exist, but no written agreement is required between the birth center and the receiving facility. The birth center does not have to provide practice protocols to collaborating physicians or hospitals unless specifically asked. The only handoff required before transfer is a call to the hospital. We envision a more collaborative process in which hospital-based physicians and birth center midwives agree and mutually create practice protocols, including conditions necessitating patient transfer and logistical arrangements for safe transfer. Such processes could lead to significantly better care for patients and enhanced hospital-based clinician support of a birth center model. Although adverse neonatal outcomes to low-risk mothers are rare, they occur. One study found that over a 2-year period in Oregon, planned out-of-hospital births were associated with higher rates of perinatal death than planned in-hospital births.4 Although these data are not directly applicable to outpatient birth centers because they included all planned out-of hospital births including home births, they raise concerns regarding the risks of out-of-hospital births. Certified nurse midwives are trained in neonatal resuscitation, but in their role as primary caregivers, their focus should be on the delivering mother. Furthermore, although many perinatal clinicians, including nurse midwives and obstetricians, are trained in newborn care and maintain Neonatal Resuscitation Program certification, resuscitation skills significantly deteriorate 2 to 3 months after certification.5 To mitigate skill loss, we advocate that an advanced-practice clinician dedicated to newborn care, such as a pediatrician or nurse practitioner, work in both hospital and birth center settings to maintain their resuscitation skills. These clinicians should be immediately available for birth center deliveries needing emergent neonatal resuscitation.

Vitamin therapy in critically ill patients: focus on thiamine, vitamin C, and vitamin D

Introduction Recent hypothesis-generating studies have sparked new interest in an old concept: adjuvant vitamin therapy in critical illness or “metabolic resuscitation”. In this minireview, we report on the most promising players in this setting: thiamine (vitamin B1), vitamin C, and vitamin D. Their main characteristics are summarized in Table 1 (see also electronic supplementary material, ESM).