Hazra S. Moeniralam

Evaluation of short-term consequences of hypoglycemia in an intensive care unit.

Background:Introduction of strict glycemic control has increased the risk for hypoglycemia in the intensive care unit. Little is known about the consequences of hypoglycemia in this setting. We examined short-term consequences (seizures, coma, and death) of hypoglycemia in the intensive care unit. Patients and Methods:All occurrences of hypoglycemia (glucose of <45 mg/dL) in our intensive care unit between September 1, 2002, and September 1, 2004, were identified. Patients with hypoglycemia (n = 156) were matched for time to hypoglycemia with control patients drawn from the at-risk population (nested case control method). Seizures observed within 8 hrs after hypoglycemia were scored. Discharge summaries for cases and controls were reviewed for occurrence of possible hypoglycemia-associated coma and death. A hazard ratio for in-hospital death was calculated with Cox regression analysis. Results:The hazard ratio for in-hospital death was 1.03 (95% confidence interval, 0.68–1.56; p = .88) in patients with a first occurrence of hypoglycemia relative to the controls without hypoglycemia, corrected for duration of intensive care unit admittance before hypoglycemia, age, sex, and Acute Physiology and Chronic Health Evaluation II score at admission. No cases of hypoglycemia-associated death were reported. Hypoglycemic coma was reported in two patients. Seizures after hypoglycemia were observed in one patient. Conclusions:In this study, no association between incidental hypoglycemia and mortality was found. However, this data set is too small to definitely exclude the possibility that hypoglycemia is associated with intensive care unit mortality. In three patients with possible hypoglycemia-associated coma or seizures, a causal role for hypoglycemia seemed likely but could not fully be established.

Tight glycaemic control: a survey of intensive care practice in the Netherlands

Sir: In this journal, Mackenzie et al. recently reported on a survey on the use of tight glycaemic control (TGC) in large English hospitals and their personal experience with this strategy [1]. They showed that, like other interventions in critically ill patients which have been shown to reduce morbidity and mortality [2–4], there is still little adoption of TGC by the critical care community in England. Indeed, only 25% of intensive care units (ICUs) reported blood glucose targets that were similar to those used in the landmark study by van den Berghe (i.e. a lower limit between 4.0 and 4.5 mmol/l and an upper limit of 6.0 or 6.1 mmol/l) [5]. Most ICUs that apply TGC report higher limits. Of note, it has been shown that more successful TGC (i.e., blood glucose concentration closer to 4.4 mmol/l) resulted in less morbidity, indicating the importance of adjusting insulin therapy to reach the lower limit [6]. The findings of Mackenzie et al. are, at least in part, in line with a recent survey in the Netherlands that was conducted during the annual meeting of the Dutch Society of Intensive Care Medicine in February 2005. At this meeting, attended by more than 200 Dutch intensivists, during a session on implementation strategies of new interventions the participants were surveyed on their feelings regarding and their current practice of TGC. Over 100 participants were present at this session, of which the majority (95%) were intensivists (90% of them working in a mixed medical–surgical ICU; 23% from universityaffiliated hospitals; 74% from ICUs with ≥5 beds). Of the participants, 69% stated that TGC was being applied in their ICU, while 7% said they would start with this intervention shortly. Only 62% used some sort of protocol, with blood glucose limits of 4.5–6.1 mmol/l in 26%, 4.5–8.0 mmol/l in 73%, and 4.5–10.0 mmol/l in 2% of cases. Glycaemic control was applied by nurses in only 18% of cases; it was applied by physicians alone or by nurses and physicians together in 16% and 65% of cases, respectively. None of the applicants said they were using a special team consisting of one physician and a team of nurses entirely responsible for glycaemic control. Thus, like the situation in England, in the Netherlands TGC is far from standard practice. Interestingly, the majority of applicants (56%) in our survey mentioned that severe hypoglycaemia was an unacceptable side effect of TGC, hampering its implementation. This fear of severe hypoglycaemia is fed by the personal experience of Mackenzie et al. In their study glycaemic control managed by nurses resulted in a 42% incidence of severe hypoglycaemia (blood glucose concentration < 2.2 mmol/l at any time). We were highly surprised by this finding and do not know how to interpret it. First, this incidence is in sharp contrast to our experience with TGC in “real life”: using the same definition, the incidence of severe hypoglycaemia was only 4% in a 2-year period after implementation of tight glycaemic control [7]. This incidence, by the way, is very much the same as that reported by van den Berghe [5]. It must be mentioned, however, that we used blood glucose limits of 4.5–8.0 mmol/l (and not 4.0–6.0 mmol/l). Second, we are not sure whether severe hypoglycaemia, defined as blood glucose concentration < 2.2 mmol/l at any time, is really that important. Isn’t this shooting oneself in the foot? How injurious is severe hypoglycaemia when it exists only for a short time? Studies are needed to determine whether incidental severe hypoglycaemia under TGC affects the outcome of ICU patients in any way. Finally, it might be of interest for the readers to see the protocol used by Mackenzie. We recently changed our protocol significantly, making it more easy for nurses to change insulin dose in response to changes in therapy as well as previous blood glucose concentrations, resulting in a decline in the incidence of severe hypoglycaemia of ~30% (unpublished data).

Preventive nebulization of mucolytic agents and bronchodilating drugs in invasively ventilated intensive care unit patients (NEBULAE): study protocol for a randomized controlled trial

BackgroundPreventive nebulization of mucolytic agents and bronchodilating drugs is a strategy aimed at the prevention of sputum plugging, and therefore atelectasis and pneumonia, in intubated and ventilated intensive care unit (ICU) patients. The present trial aims to compare a strategy using the preventive nebulization of acetylcysteine and salbutamol with nebulization on indication in intubated and ventilated ICU patients.Methods/DesignThe preventive nebulization of mucolytic agents and bronchodilating drugs in invasively ventilated intensive care unit patients (NEBULAE) trial is a national multicenter open-label, two-armed, randomized controlled non-inferiority trial in the Netherlands. Nine hundred and fifty intubated and ventilated ICU patients with an anticipated duration of invasive ventilation of more than 24 hours will be randomly assigned to receive either a strategy consisting of preventive nebulization of acetylcysteine and salbutamol or a strategy consisting of nebulization of acetylcysteine and/or salbutamol on indication. The primary endpoint is the number of ventilator-free days and surviving on day 28. Secondary endpoints include ICU and hospital length of stay, ICU and hospital mortality, the occurrence of predefined pulmonary complications (acute respiratory distress syndrome, pneumonia, large atelectasis and pneumothorax), and the occurrence of predefined side effects of the intervention. Related healthcare costs will be estimated in a cost-benefit and budget-impact analysis.DiscussionThe NEBULAE trial is the first randomized controlled trial powered to investigate whether preventive nebulization of acetylcysteine and salbutamol shortens the duration of ventilation in critically ill patients.Trial registrationNCT02159196, registered on 6 June 2014.

Effect of On-Demand vs Routine Nebulization of Acetylcysteine With Salbutamol on Ventilator-Free Days in Intensive Care Unit Patients Receiving Invasive Ventilation: A Randomized Clinical Trial

Importance It remains uncertain whether nebulization of mucolytics with bronchodilators should be applied for clinical indication or preventively in intensive care unit (ICU) patients receiving invasive ventilation. Objective To determine if a strategy that uses nebulization for clinical indication (on-demand) is noninferior to one that uses preventive (routine) nebulization. Design, Setting, and Participants Randomized clinical trial enrolling adult patients expected to need invasive ventilation for more than 24 hours at 7 ICUs in the Netherlands. Interventions On-demand nebulization of acetylcysteine or salbutamol (based on strict clinical indications, n = 471) or routine nebulization of acetylcysteine with salbutamol (every 6 hours until end of invasive ventilation, n = 473). Main Outcomes and Measures The primary outcome was the number of ventilator-free days at day 28, with a noninferiority margin for a difference between groups of −0.5 days. Secondary outcomes included length of stay, mortality rates, occurrence of pulmonary complications, and adverse events. Results Nine hundred twenty-two patients (34% women; median age, 66 (interquartile range [IQR], 54-75 years) were enrolled and completed follow-up. At 28 days, patients in the on-demand group had a median 21 (IQR, 0-26) ventilator-free days, and patients in the routine group had a median 20 (IQR, 0-26) ventilator-free days (1-sided 95% CI, −0.00003 to ∞). There was no significant difference in length of stay or mortality, or in the proportion of patients developing pulmonary complications, between the 2 groups. Adverse events (13.8% vs 29.3%; difference, −15.5% [95% CI, −20.7% to −10.3%]; P < .001) were more frequent with routine nebulization and mainly related to tachyarrhythmia (12.5% vs 25.9%; difference, −13.4% [95% CI, −18.4% to −8.4%]; P < .001) and agitation (0.2% vs 4.3%; difference, −4.1% [95% CI, −5.9% to −2.2%]; P < .001). Conclusions and Relevance Among ICU patients receiving invasive ventilation who were expected to not be extubated within 24 hours, on-demand compared with routine nebulization of acetylcysteine with salbutamol did not result in an inferior number of ventilator-free days. On-demand nebulization may be a reasonable alternative to routine nebulization. Trial Registration clinicaltrials.gov Identifier: NCT02159196

Massive haemolysis and erythrophagocytosis in Gram-negative sepsis

A 71-year-old woman with a history of hypertension, diabetes mellitus and chronic kidney failure was admitted to our emergency department with progressive abdominal pain for 1 d. She had no fever and was haemodynamically stable, but developed severe jaundice overnight and started to produce clear red urine. Laboratory results showed severe haemolysis with an indirect bilirubin of 214 lmol/l and a lactate dehydrogenase of 6274 iu/l. A blood film was performed, which showed massive erythrophagocytosis by neutrophils (top), abundant spherocytosis and incidental ghost cells (bottom). The neutrophils were vacuolated and showe toxic granulation with D€ ohle bodies. No fragments were visible and a direct antiglobulin test was negative using anti-IgG and anti-C3b/d antibodies, as well as anti-IgA and anti-IgM. Intravascular haemolysis due to severe sepsis was suspected, so broad-spectrum antibiotics were started. A computerized tomography scan showed no intra-abdominal pathology apart from a slight distension of the common bile duct. The patient was admitted to the intensive care unit for inotropes and respiratory support but died of overwhelming septic shock within 12 h. Post-mortem blood cultures revealed a Plesiomonas shigelloides and Escherichia coli bacteraemia. Autopsy showed haemorrhagic changes in the stomach, spleen and lungs. Several small abscesses in the liver were identified as the most likely source of the sepsis and cultures of these lesions showed the same pathogens that caused the bacteraemia. Erythrophagocytosis by circulating neutrophils is a rare phenomenon. It can be triggered by several mechanisms, including autoimmune haemolysis, spider venoms, quinine administration, certain types of leukaemia and bacteraemia. Clostridium perfringens toxins are notorious for causing massive haemolysis with very high mortality rates. Plesiomonas shigelloides and E. coli are Gram-negative bacilli that are known causes of sepsis. Both species are able to demonstrate haemolytic activity in vitro. Gram-negative sepsis can induce massive intravascular haemolysis with erythrophagocytosis. A peripheral blood film can help to identify this rare complication.