Olivier Lesieur

High versus Low Blood-Pressure Target in Patients with Septic Shock

BACKGROUND The Surviving Sepsis Campaign recommends targeting a mean arterial pressure of at least 65 mm Hg during initial resuscitation of patients with septic shock. However, whether this blood-pressure target is more or less effective than a higher target is unknown. METHODS In a multicenter, open-label trial, we randomly assigned 776 patients with septic shock to undergo resuscitation with a mean arterial pressure target of either 80 to 85 mm Hg (high-target group) or 65 to 70 mm Hg (low-target group). The primary end point was mortality at day 28. RESULTS At 28 days, there was no significant between-group difference in mortality, with deaths reported in 142 of 388 patients in the high-target group (36.6%) and 132 of 388 patients in the low-target group (34.0%) (hazard ratio in the high-target group, 1.07; 95% confidence interval [CI], 0.84 to 1.38; P=0.57). There was also no significant difference in mortality at 90 days, with 170 deaths (43.8%) and 164 deaths (42.3%), respectively (hazard ratio, 1.04; 95% CI, 0.83 to 1.30; P=0.74). The occurrence of serious adverse events did not differ significantly between the two groups (74 events [19.1%] and 69 events [17.8%], respectively; P=0.64). However, the incidence of newly diagnosed atrial fibrillation was higher in the high-target group than in the low-target group. Among patients with chronic hypertension, those in the high-target group required less renal-replacement therapy than did those in the low-target group, but such therapy was not associated with a difference in mortality. CONCLUSIONS Targeting a mean arterial pressure of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg, in patients with septic shock undergoing resuscitation did not result in significant differences in mortality at either 28 or 90 days. (Funded by the French Ministry of Health; SEPSISPAM ClinicalTrials.gov number, NCT01149278.).

Determinants of recovery from severe posterior reversible encephalopathy syndrome.

Objective Few outcome data are available about posterior reversible encephalopathy syndrome (PRES). We studied 90-day functional outcomes and their determinants in patients with severe PRES. Design 70 patients with severe PRES admitted to 24 ICUs in 2001–2010 were included in a retrospective cohort study. The main outcome measure was a Glasgow Outcome Scale (GOS) of 5 (good recovery) on day 90. Main Results Consciousness impairment was the most common clinical sign, occurring in 66 (94%) patients. Clinical seizures occurred in 57 (81%) patients. Median mean arterial pressure was 122 (105–143) mmHg on scene. Cerebral imaging abnormalities were bilateral (93%) and predominated in the parietal (93%) and occipital (86%) white matter. Median number of brain areas involved was 4 (3–5). Imaging abnormalities resolved in 43 (88%) patients. Ischaemic and/or haemorrhagic complications occurred in 7 (14%) patients. The most common causes were drug toxicity (44%) and hypertensive encephalopathy (41%). On day 90, 11 (16%) patients had died, 26 (37%) had marked functional impairments (GOS, 2 to 4), and 33 (56%) had a good recovery (GOS, 5). Factors independently associated with GOS<5 were highest glycaemia on day 1 (OR, 1.22; 95%CI, 1.02–1.45, p = 0.03) and time to causative-factor control (OR, 3.3; 95%CI, 1.04–10.46, p = 0.04), whereas GOS = 5 was associated with toxaemia of pregnancy (preeclampsia/eclampsia) (OR, 0.06; 95%CI, 0.01–0.38, p = 0.003). Conclusions By day 90 after admission for severe PRES, 44% of survivors had severe functional impairments. Highest glycaemia on day 1 and time to causative-factor control were strong early predictors of outcomes, suggesting areas for improvement.

Refusal of Intensive Care Unit Admission Due to a Full Unit

RATIONALE Intensive care unit (ICU) beds are a scarce resource, and patients denied intensive care only because the unit is full may be at increased risk of death. OBJECTIVE To compare mortality after first ICU referral in admitted patients and in patients denied admission because the unit was full. METHODS Prospective observational multicenter cohort study of consecutive patients referred for ICU admission during two 45-day periods, conducted in 10 ICUs. MEASUREMENTS AND MAIN RESULTS Of 1,762 patients, 430 were excluded from the study, 116 with previously denied admission to another ICU and 270 because they were deemed too sick or too well to benefit from ICU admission. Of the remaining 1,332 patients, 1,139 were admitted, and 193 were denied admission because the unit was full (65 were never admitted, 39 were admitted after bumping of another patient, and 89 were admitted on subsequent referral). Crude Day 28 and Day 60 mortality rates in the nonadmitted and admitted groups were 30.1 versus 24.3% (P = 0.07) and 33.3 versus 27.2% (P = 0.06), respectively. Day 28 mortality adjusted on age, previous disease, Glasgow scale score less than or equal to 8, shock, creatinine level greater than or equal to 250 μmol/L, and prothrombin time greater than or equal to 30 seconds was nonsignificantly higher in patients refused ICU admission only because of a full unit compared with patients admitted immediately. Patients admitted after subsequent referral had higher mortality rates on Day 28 (P = 0.05) and Day 60 (P = 0.04) compared with directly admitted patients. CONCLUSIONS Delayed ICU admission due to a full unit at first referral is associated with increased mortality.

Withholding or withdrawal of treatment under French rules: a study performed in 43 intensive care units

BackgroundIn France, decisions to limit treatment fall under the Leonetti law adopted in 2005. Leading figures from the French world of politics, science, and justice recently claimed for amendments to the law, considering it incomplete. This study, conducted before any legislative change, aimed to investigate the procedural aspects of withholding/withdrawing treatment in French ICUs and their adequacy with the existing law.MethodsThe characteristics of patients qualified for a withholding/withdrawal procedure were prospectively collected in 43 French ICUs. The study period (60 or 90 days under normal operating conditions) took place in the first half of 2013.ResultsDuring the study period, 777 (14 %) of 5589 admitted patients and 584 (52 %) of 1132 patients dying in the ICU had their treatment withheld or withdrawn. Whereas 344 patients had treatment(s) withheld (i.e., not started or not increased if already engaged), 433 had one or more treatment(s) withdrawn. Withdrawal of treatment was applied in 156 of 223 (70 %) brain-injured patients, compared to 277 of 554 (50 %) patients with other reasons for admission (p < 0.01). At the time of the decision-making, the patient’s wishes were known in 181 (23 %) of the 777 cases in one or more different way(s): 73 (9.4 %) from the patient, 10 (1.3 %) by advance directives, 10 (1.3 %) through a designated trusted person, and 108 (13.9 %) reported by the family or close relatives. An external consultant was involved in less than half of all decisions (356 of 777, 46 %). Of the 777 patients qualified for a withholding/withdrawal procedure, 133 (17 %) were discharged alive from the hospital (126 after withholding, 7 after withdrawal).ConclusionsMore than half of deaths in the study population occurred after a decision to withhold or withdraw treatment. Among patients under withholding/withdrawal procedures, brain-injured subjects were more likely to undergo a withdrawal procedure. The prevalence of advance directives and designated trusted persons was low. Because patients’ preferences were unknown in more than three quarters of cases, decisions remained primarily based on medical judgment. Limitations, especially withholding of treatment, did not preclude survival and hospital discharge.

Blackwater fever: a fatal case

Sir: Up to the 1940 s, blackwater fever (BWF) was an important cause of mortality in Africa, associated with Plasmodium falciparum (Pf) malaria and quinine in Caucasian people [1, 2]. BWF has almost disappeared since the use of synthetic antimalarials. Unfortunately the spread of chloroquine resistance has led to the reintroduction of quinine. We report acute haemolysis similar to the old description of BWF. A French man aged 44, who had been living in Central Africa for 9 years, had febrile episodes irregularly treated with quinine. On May 27, 1996, he returned to France with weakness, abdominal pain and headache. On June 7, he took quinine 400 mg every 6 h because his temperature was 39°C. Within 12 h of treatment, the fever worsened to 40 °C. On admission, he was conscious. The haemodynamic and respiratory variables were good. Examination revealed jaundice and hepatosplenomegaly. Haemoglobin was 115 g/1. Four blood films were negative. The quinine was discontinued. On June 8 (day 2), the patient became oliguric with haemoglobinuria. He developed Coombs-positive haemolysis and acute renal failure. Haemoglobin was 39 g/ 1. Haptoglobin was unmeasurable. Bilirubin was 684 ~mol/1 while other liver function tests were normal. Admitted to the ICU (day 3), the patient underwent exchange transfusion. Because artemesinin was not available, a loading dose of 600 mg chloroquine was administered. Renal failure was treated with haemodialysis. Alteration of consciousness occurred after the onset of haemodialysis. The lumbar puncture was normal. The day after, gastric bleeding was associated with consumptive coagulopathy (prothrombin time 20 %, fibrinogen 1.3 g/l, factor II 35 %, V 10 %, VII-X 36 %, D-dimers undetectable, platelets 40000/91). Despite the basic supportive care, circulatory shock with pulmonary oedema occurred on day 7, and the patient died on day 8. The patient was free from G6PD deficiency and haemoglobinopathies. Other causes of haemolysis (infectious diseases, toxic agents, transfusion incompatibility) were excluded. He had high levels of antiPf antibodies suggestive of a recent malaria attack. Nevertheless no malaria parasites or pigment were observed on postmortem liver and spleen-biopsy specimens. BWF may involve immune lysis of quinine-sensitized erythrocytes, Most of the cases had a history of irregular prophylaxis with quinine. Haemolysis occurs after the treatment of suspected malaria by a large or even a small dose of quinine [2]. BWF associated with mefloquine and halofantrine has also been reported [3, 4]. Once immune haemolysis was confirmed, we were reluctant to use any of these drugs for this reason. On the other hand, some authors regard BWF as a complication of malaria only coincidentally related to the use of quinine [5]. Haemolysis could result from a hyperparasitemic state that remains undetected because of a massive lysis of infected erythrocytes. Chemotherapy should therefore be started at the earliest possible opportunity. The connection between BWF and malaria remains unclear. The mechanism of the haemolysis and its link with quinine gave rise to a bitter controversy in which many authors took part. Despite our struggle to review these reports we did not find guidelines to optimize care for such a rare but life-threatening syndrome. However quinine, as a triggering factor of haemolysis, should be discontinued.

Eligibility of patients withheld or withdrawn from life-sustaining treatment to organ donation after circulatory arrest death: epidemiological feasibility study in a French Intensive Care Unit

BackgroundTransplantation brings sustainably improved quality of life to patients with end-stage organ failure. Persisting shortfall in available organs prompted French authorities and practitioners to focus on organ retrieval in patients withdrawn from life-sustaining treatment and awaiting cardiac arrest (Maastricht classification category III). The purpose of this study was to assess the theoretical eligibility of non-heart-beating donors dying in the intensive care unit (ICU) after a decision to withhold or withdraw life-sustaining treatment (WoWt).MethodsWe collected the clinical and biological characteristics of all consecutive patients admitted to our ICU and qualified for a WoWt procedure under the terms of the French Leonetti law governing end-of-life care during a 12-month period. The theoretical organ donor eligibility (for kidney, liver, or lung retrieval) of deceased patients was determined a posteriori 1) according to routine medical criteria for graft selection and 2) according to the WoWt measures implemented and their impact on organ viability.ResultsA total of 596 patients (mean age: 67 ± 16 yr; gender ratio M/F: 1.6; mean SAPS (Simplified Acute Physiology Score) II: 54 ± 24) was admitted to the ICU, of which 84 patients (mean age: 71 ± 14 yr, 14% of admissions, gender ratio M/F: 3.2) underwent WoWt measures. Eight patients left the unit alive. Forty-four patients presented a contraindication ruling out organ retrieval either preexisting admission (n = 20) or emerged during hospitalization (n = 24). Thirty-two patients would have been eligible as kidney (n = 23), liver (n = 22), or lung donors (n = 2). Cardiopulmonary support was withdrawn in only five of these patients, and three died within 120 minutes after withdrawal (the maximum delay compatible with organ viability for donor grafts).ConclusionsIn this pilot study, a significant number of patients deceased under WoWt conditions theoretically would have been eligible for organ retrieval. However, the WoWt measures implemented in our unit seems incompatible with donor organ viability. A French multicenter survey of end-of-life practices in ICU may help to identify potential appropriate organ donors and to interpret nation-specific considerations of the related professional, legal, and ethical frameworks.

Grief Symptoms in Relatives who Experienced Organ Donation Request in the ICU

Rationale: Studies show that the quality of end‐of‐life communication and care have a significant impact on the living long after the death of a relative and have been implicated in the burden of psychological symptoms after the ICU experience. In the case of organ donation, the patients relatives are centrally involved in the decision‐making process; yet, few studies have examined the impact of the quality of communication on the burden of psychological symptoms after death. Objectives: To assess the experience of the organ donation process and grief symptoms in relatives of brain‐dead patients who discussed organ donation in the ICU. Methods: We conducted a multicenter longitudinal study in 28 ICUs in France. Participants were the relatives of brain‐dead patients who were approached to discuss organ donation. Relatives were followed‐up by phone at three time points: at 1 month, to complete a questionnaire describing their experience of the organ donation process; at 3 months, to complete the Hospital Anxiety and Depression Scale and the Impact of Event Scale‐Revised; and at 9 months, to complete the Impact of Event Scale‐Revised and the Inventory of Complicated Grief. Measurements and Main Results: In total, 202 relatives of 202 patients were included, of whom 158 consented to and 44 refused organ donation. Interviews were conducted at 1, 3, and 9 months with 78%, 68%, and 58% of relatives, respectively. The overall experience of the organ donation process was significantly more burdensome for relatives of nondonors. They were more dissatisfied with communication (27% vs. 10%; P = 0.021), more often shocked by the request (65% vs. 19%; P < 0.0001), and more often found the decision difficult (53% vs. 27%; P = 0.017). However, there were no significant differences in grief symptoms measured at 3 and 9 months between the two groups. Understanding of brain death was associated with grief symptoms; our results show a higher prevalence of complicated grief symptoms among relatives who did not understand the brain death process than among those who did (75% vs. 46.1%; P = 0.026). Conclusions: Experience of the organ donation process varied between relatives of donor versus nondonor patients, with relatives of nondonors experiencing lower‐quality communication, but the decision was not associated with subsequent grief symptoms. Importantly, understanding of brain death is a key element of the organ donation process for relatives.

“It Was the Only Thing I Could Hold Onto, But…”: Receiving a Letter of Condolence After Loss of a Loved One in the ICU

Objectives: Family members of patients who die in the ICU often remain with unanswered questions and suffer from lack of closure. A letter of condolence may help bereaved relatives, but little is known about their experience of receiving such a letter. The objective of the study was to understand bereaved family members’ experience of receiving a letter of condolence. Design: Qualitative study using interviews with bereaved family members who received a letter of condolence and letters written by these family members to the ICU team. This study was designed to provide insight into the results of a larger randomized, controlled, multicenter study. Setting: Twenty-two ICUs in France. Subjects: Family members who lost a loved one in the ICU and who received a letter of condolence. Measurements and Main Results: Thematic analysis was used and was based on 52 interviews and 26 letters. Six themes emerged: 1) a feeling of support, 2) humanization of the medical system, 3) an opportunity for reflection, 4) an opportunity to describe their loved one, 5) continuity and closure, and 6) doubts and ambivalence. Possible difficulties emerged, notably the re-experience of the trauma, highlighting the absence of further support. Conclusions: This study describes the benefits of receiving a letter of condolence; mainly, it humanizes the medical institution (feeling of support, confirmation of the role played by the relative, supplemental information). However, this study also shows a common ambivalence about the letter of condolence’s benefit. Healthcare workers must strive to adapt bereavement follow-up to each individual situation.

Changes in limitations of life-sustaining treatments over time in a French intensive care unit: A prospective observational study

Background: Variability exists between ICUs in the limitations of therapy. Moreover practices may evolve over time. This single‐center observational study aimed to compare withholding or withdrawing practices between 2012 and 2016. Methods: For each period and patient concerned by limitations, withholding “do‐not start”, withholding “do‐not‐increase” and withdrawal measures were recorded. Results: At a four‐year interval, the rate of patients undergoing withholding or withdrawal rose from 10 to 23% and 4 to 7%, respectively. The proportion of patients dying in the ICU with previous limitations increased (53 to 89%), as did patients discharged alive despite withholding instructions (12 to 36%). The overall mortality (28%) was stable over time as the rate of failed resuscitation attempt declined (47 to 11%). In 2016 vs 2012, limitations started earlier following admission: 1 vs 7 days for withholding” do‐not‐start”, 4 vs 8 for withholding “do‐not‐increase”, 4 vs 7 for withdrawal. Notwithstanding the outcome and limitations applied, the median length of ICU stay of patients involved dropped from 13 days in 2012 to 8 days in 2016. Conclusion: A timely inclination to forego hopeless treatments resulted in a lower rate of failed resuscitations before death without change in global mortality. HighlightsTreatment limitations are increasingly common and occurred earlier during ICU stay.Patients wishes regarding end‐of‐life care should be better addressed by caregivers.Advance care planning reduces both ICU stay and the rate of failed resuscitations.