Peter E. Spronk

Nitroglycerin in septic shock after intravascular volume resuscitation

In patients with septic shock, oxygen consumption is increased, but oxygen delivery and extraction is impaired, partly because of microcirculatory shutdown and shunting. Orthogonal polarisation spectral (OPS) imaging allows visualisation of the microcirculation. We used this technique to assess microcirculatory flow in septic-shock patients who had a mean arterial blood pressure of more than 60 mm Hg and central venous pressure greater than 12 mm Hg. The infusion of 0.5 mg of nitroglycerin intravenously then resulted in a marked increase in microvascular flow on OPS imaging. Improved recruitment of the microcirculation could be a new resuscitation endpoint in septic shock.

A Randomized, Blinded, Multicenter Trial of Lipid-Associated Amphotericin B Alone versus in Combination with an Antibody-Based Inhibitor of Heat Shock Protein 90 in Patients with Invasive Candidiasis

BACKGROUND Mycograb (NeuTec Pharma) is a human recombinant monoclonal antibody against heat shock protein 90 that, in laboratory studies, was revealed to have synergy with amphotericin B against a broad spectrum of Candida species. METHODS A double-blind, randomized study was conducted to determine whether lipid-associated amphotericin B plus Mycograb was superior to amphotericin B plus placebo in patients with culture-confirmed invasive candidiasis. Patients received a lipid-associated formulation of amphotericin B plus a 5-day course of Mycograb or placebo, having been stratified on the basis of Candida species (Candida albicans vs. non-albicans species of Candida). Inclusion criteria included clinical evidence of active infection at trial entry plus growth of Candida species on culture of a specimen from a clinically significant site within 3 days after initiation of study treatment. The primary efficacy variable was overall response to treatment (clinical and mycological resolution) by day 10. RESULTS Of the 139 patients enrolled from Europe and the United States, 117 were included in the modified intention-to-treat population. A complete overall response by day 10 was obtained for 29 (48%) of 61 patients in the amphotericin B group, compared with 47 (84%) of 56 patients in the Mycograb combination therapy group (odds ratio [OR], 5.8; 95% confidence interval [CI], 2.41-13.79; P<.001). The following efficacy criteria were also met: clinical response (52% vs. 86%; OR, 5.4; 95% CI, 2.21-13.39; P<.001), mycological response (54% vs. 89%; OR, 7.1; 95% CI, 2.64-18.94; P<.001), Candida-attributable mortality (18% vs. 4%; OR, 0.2; 95% CI, 0.04-0.80; P = .025), and rate of culture-confirmed clearance of the infection (hazard ratio, 2.3; 95% CI, 1.4-3.8; P = .001). Mycograb was well tolerated. CONCLUSIONS Mycograb plus lipid-associated amphotericin B produced significant clinical and culture-confirmed improvement in outcome for patients with invasive candidiasis.

Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients : a multicentre, double-blind, placebo-controlled randomised trial

BACKGROUND Delirium is frequently diagnosed in critically ill patients and is associated with adverse outcome. Impaired cholinergic neurotransmission seems to have an important role in the development of delirium. We aimed to establish the effect of the cholinesterase inhibitor rivastigmine on the duration of delirium in critically ill patients. METHODS Patients (aged ≥18 years) who were diagnosed with delirium were enrolled from six intensive care units in the Netherlands, and treated between November, 2008, and January, 2010. Patients were randomised (1:1 ratio) to receive an increasing dose of rivastigmine or placebo, starting at 0·75 mL (1·5 mg rivastigmine) twice daily and increasing in increments to 3 mL (6 mg rivastigmine) twice daily from day 10 onwards, as an adjunct to usual care based on haloperidol. The trial pharmacist generated the randomisation sequence by computer, and consecutively numbered bottles of the study drug according to this sequence to conceal allocation. The primary outcome was the duration of delirium during hospital admission. Analysis was by intention to treat. Duration of delirium was censored for patients who died or were discharged from hospital while delirious. Patients, medical staff, and investigators were masked to treatment allocation. Members of the data safety and monitoring board (DSMB) were unmasked and did interim analyses every 3 months. This trial is registered with ClinicalTrials.gov, number NCT00704301. FINDINGS Although a sample size of 440 patients was planned, after inclusion of 104 patients with delirium who were eligible for the intention-to-treat analysis (n=54 on rivastigmine, n=50 on placebo), the DSMB recommended that the trial be halted because mortality in the rivastigmine group (n=12, 22%) was higher than in the placebo group (n=4, 8%; p=0·07). Median duration of delirium was longer in the rivastigmine group (5·0 days, IQR 2·7-14·2) than in the placebo group (3·0 days, IQR 1·0-9·3; p=0·06). INTERPRETATION Rivastigmine did not decrease duration of delirium and might have increased mortality so we do not recommend use of rivastigmine to treat delirium in critically ill patients. FUNDING ZonMw, the Netherlands Brain Foundation, and Novartis.

Bench-to-bedside review: Sepsis is a disease of the microcirculation

Microcirculatory perfusion is disturbed in sepsis. Recent research has shown that maintaining systemic blood pressure is associated with inadequate perfusion of the microcirculation in sepsis. Microcirculatory perfusion is regulated by an intricate interplay of many neuroendocrine and paracrine pathways, which makes blood flow though this microvascular network a heterogeneous process. Owing to an increased microcirculatory resistance, a maldistribution of blood flow occurs with a decreased systemic vascular resistance due to shunting phenomena. Therapy in shock is aimed at the optimization of cardiac function, arterial hemoglobin saturation and tissue perfusion. This will mean the correction of hypovolemia and the restoration of an evenly distributed microcirculatory flow and adequate oxygen transport. A practical clinical score for the definition of shock is proposed and a novel technique for bedside visualization of the capillary network is discussed, including its possible implications for the treatment of septic shock patients with vasodilators to open the microcirculation.

Relationship between sublingual and intestinal microcirculatory perfusion in patients with abdominal sepsis

Objective:To evaluate the relation between sublingual and intestinal microcirculatory alterations in patients with abdominal sepsis. Design:Prospective observational study. Setting:A 23-bed mixed intensive care unit of a tertiary teaching hospital. Patients:Twenty-three patients with abdominal sepsis and a newly constructed intestinal stoma were included in the study group. Nineteen outpatient healthy individuals with an intestinal stoma and ten nonsepsis patients with a <24-hr-old intestinal stoma were included as controls. Interventions:None. Measurements and Main Results:Orthogonal polarization spectral imaging of the sublingual and intestinal microcirculation was performed on days 1 and 3. In addition, variables of systemic hemodynamics, such as cardiac index, heart rate, blood pressure, central venous pressure, and dosages of vasopressor and inotropic agents, were obtained. On day 1 there was no correlation of the microvascular flow index between the sublingual and intestinal microcirculatory beds (Spearmans rho [rs] = .12; 95% confidence interval, −.51 to .31; p = .59). Furthermore, there was no significant correlation between microcirculatory alterations and variables of systemic circulation (rs ≤ .25). On day 3, however, a correlation between sublingual and intestinal microcirculatory flow appeared to be restored (rs = .74; 95% confidence interval, .28–.92; p = .006), mainly due to a normalization of flow in both regions. Conclusions:On day 1 of abdominal sepsis there is a complete dispersion of flow, not only between hemodynamic compartments of a different order but also between the sublingual and intestinal microcirculation. Over time, both sublingual and intestinal microvascular flow indexes trended to normal values.

Development and validation of PRE-DELIRIC (PREdiction of DELIRium in ICu patients) delirium prediction model for intensive care patients: observational multicentre study

Objectives To develop and validate a delirium prediction model for adult intensive care patients and determine its additional value compared with prediction by caregivers. Design Observational multicentre study. Setting Five intensive care units in the Netherlands (two university hospitals and three university affiliated teaching hospitals). Participants 3056 intensive care patients aged 18 years or over. Main outcome measure Development of delirium (defined as at least one positive delirium screening) during patients’ stay in intensive care. Results The model was developed using 1613 consecutive intensive care patients in one hospital and temporally validated using 549 patients from the same hospital. For external validation, data were collected from 894 patients in four other hospitals. The prediction (PRE-DELIRIC) model contains 10 risk factors—age, APACHE-II score, admission group, coma, infection, metabolic acidosis, use of sedatives and morphine, urea concentration, and urgent admission. The model had an area under the receiver operating characteristics curve of 0.87 (95% confidence interval 0.85 to 0.89) and 0.86 after bootstrapping. Temporal validation and external validation resulted in areas under the curve of 0.89 (0.86 to 0.92) and 0.84 (0.82 to 0.87). The pooled area under the receiver operating characteristics curve (n=3056) was 0.85 (0.84 to 0.87). The area under the curve for nurses’ and physicians’ predictions (n=124) was significantly lower at 0.59 (0.49 to 0.70) for both. Conclusion The PRE-DELIRIC model for intensive care patients consists of 10 risk factors that are readily available within 24 hours after intensive care admission and has a high predictive value. Clinical prediction by nurses and physicians performed significantly worse. The model allows for early prediction of delirium and initiation of preventive measures. Trial registration Clinical trials NCT00604773 (development study) and NCT00961389 (validation study).

Routine use of the confusion assessment method for the intensive care unit : a multicenter study

RATIONALE Delirium is often unrecognized in ICU patients and associated with poor outcome. Screening for ICU delirium is recommended by several medical organizations to improve early diagnosis and treatment. The Confusion Assessment Method for the ICU (CAM-ICU) has high sensitivity and specificity for delirium when administered by research nurses. However, test characteristics of the CAM-ICU as performed in routine practice are unclear. OBJECTIVES To investigate the diagnostic value of the CAM-ICU in daily practice. METHODS Teams of three delirium experts including psychiatrists, geriatricians, and neurologists visited 10 ICUs twice. Based on cognitive examination, inspection of medical files, and Diagnostic and Statistic Manual of Mental Disorders, 4th edition, Text Revision criteria for delirium, the expert teams classified patients as awake and not delirious, delirious, or comatose. This served as a gold standard to which the CAM-ICU as performed by the bedside ICU-nurses was compared. Assessors were unaware of each others conclusions. MEASUREMENTS AND MAIN RESULTS Fifteen delirium experts assessed 282 patients of whom 101 (36%) were comatose and excluded. In the remaining 181 (64%) patients, the CAM-ICU had a sensitivity of 47% (95% confidence interval [CI], 35%-58%); specificity of 98% (95% CI, 93%-100%); positive predictive value of 95% (95% CI, 80%-99%); and negative predictive value of 72% (95% CI, 64%-79%). The positive likelihood ratio was 24.7 (95% CI, 6.1-100) and the negative likelihood ratio was 0.5 (95% CI, 0.4-0.8). CONCLUSIONS Specificity of the CAM-ICU as performed in routine practice seems to be high but sensitivity is low. This hampers early detection of delirium by the CAM-ICU.

Treatment of hypophosphatemia in the intensive care unit: a review

IntroductionCurrently no evidence-based guideline exists for the approach to hypophosphatemia in critically ill patients.MethodsWe performed a narrative review of the medical literature to identify the incidence, symptoms, and treatment of hypophosphatemia in critically ill patients. Specifically, we searched for answers to the questions whether correction of hypophosphatemia is associated with improved outcome, and whether a certain treatment strategy is superior.ResultsIncidence: hypophosphatemia is frequently encountered in the intensive care unit; and critically ill patients are at increased risk for developing hypophosphatemia due to the presence of multiple causal factors. Symptoms: hypophosphatemia may lead to a multitude of symptoms, including cardiac and respiratory failure. Treatment: hypophosphatemia is generally corrected when it is symptomatic or severe. However, although multiple studies confirm the efficacy and safety of intravenous phosphate administration, it remains uncertain when and how to correct hypophosphatemia. Outcome: in some studies, hypophosphatemia was associated with higher mortality; a paucity of randomized controlled evidence exists for whether correction of hypophosphatemia improves the outcome in critically ill patients.ConclusionsAdditional studies addressing the current approach to hypophosphatemia in critically ill patients are required. Studies should focus on the association between hypophosphatemia and morbidity and/or mortality, as well as the effect of correction of this electrolyte disorder.

Mild hypoglycemia is independently associated with increased mortality in the critically ill

IntroductionSevere hypoglycemia (blood glucose concentration (BG) < 40 mg/dL) is independently associated with an increased risk of mortality in critically ill patients. The association of milder hypoglycemia (BG < 70 mg/dL) with mortality is less clear.MethodsProspectively collected data from two observational cohorts in the USA and in The Netherlands, and from the prospective GLUCONTROL trial were analyzed. Hospital mortality was the primary endpoint.ResultsWe analyzed data from 6,240 patients: 3,263 admitted to Stamford Hospital (ST), 2,063 admitted to three institutions in The Netherlands (NL) and 914 who participated in the GLUCONTROL trial (GL). The percentage of patients with hypoglycemia varied from 18% to 65% among the different cohorts. Patients with hypoglycemia experienced higher mortality than did those without hypoglycemia even after stratification by severity of illness, diagnostic category, diabetic status, mean BG during intensive care unit (ICU) admission and coefficient of variation (CV) as a reflection of glycemic variability. The relative risk (RR, 95% confidence interval) of mortality associated with minimum BG < 40, 40 to 54 and 55 to 69 mg/dL compared to patients with minimum BG 80 to 109 mg/dL was 3.55 (3.02 to 4.17), 2.70 (2.31 to 3.14) and 2.18 (1.87 to 2.53), respectively (all P < 0.0001). The RR of mortality associated with any hypoglycemia < 70 mg/dL was 3.28 (2.78 to 3.87) (P < 0.0001), 1.30 (1.12 to 1.50) (P = 0.0005) and 2.11 (1.62 to 2.74) (P < 0.0001) for the ST, NL and GL cohorts, respectively. Multivariate regression analysis demonstrated that minimum BG < 70 mg/dL, 40 to 69 mg/dL and < 40 mg/dL were independently associated with increased risk of mortality for the entire cohort of 6,240 patients (odds ratio (OR) (95% confidence interval (CI)) 1.78 (1.39 to 2.27) P < 0.0001), 1.29 (1.11 to 1.51) P = 0.0011 and 1.87 (1.46 to 2.40) P < 0.0001) respectively.ConclusionsMild hypoglycemia was associated with a significantly increased risk of mortality in an international cohort of critically ill patients. Efforts to reduce the occurrence of hypoglycemia in critically ill patients may reduce mortality

Impaired microcirculation predicts poor outcome of patients with acute myocardial infarction complicated by cardiogenic shock

AIMS we investigated the relationship between sublingual perfused capillary density (PCD) as a measure of tissue perfusion and outcome (i.e. occurrence of organ failure and mortality) in patients with cardiogenic shock from acute myocardial infarction. METHODS AND RESULTS we performed a prospective study in 68 patients. Using Sidestream Dark Field imaging, PCD was measured after hospital admission (T0, baseline) and 24 h later (T1). We compared patients with baseline PCD ≤ median to patients with baseline PCD > median. Sequential organ failure assessment (SOFA) scores were calculated at both time points. The Kaplan-Meier 30-day survival analyses were performed and predictors of 30-day mortality were identified. The baseline PCD was a predictor of the change in the SOFA score between T0 and T1 (ΔSOFA; ρ = -0.25, P = 0.04). Organ failure recovered more frequently in patients with PCD > median (>10.3 mm mm(-2); n = 33) than in patients with PCD ≤ median (n = 35; 52 vs. 29%, P < 0.05). Twenty-two patients (32%) died: 17 patients (49%) with PCD ≤ median vs. 5 patients (15%) with PCD > median (P = 0.004). After adjustment, the cardiac power index [odds ratio (OR): 0.48, 95% CI: 0.24-0.94) and PCD (OR: 0.65, 95% CI: 0.45-0.92) remained significant predictors of 30-day outcome. Patients with baseline sublingual PCD ≤ median that improved at T1 had a considerable better prognosis relative to patients who had a persistently low PCD. CONCLUSION diminished sublingual PCD, at baseline or following treatment, is associated with development of multi-organ failure and is a predictor of poor outcome in patients with acute myocardial infarction complicated by cardiogenic shock.