Resuscitation highlights in 2021.

BACKGROUND: This review is the latest in a series of regular annual reviews undertaken by the editors and aims to highlight some of the key papers published in Resuscitation during 2021. METHODS: Hand-searching by the editors of all papers published in Resuscitation during 2021. Papers were selected based on then general interest and novelty and were categorised into themes. RESULTS: 98 papers were selected for brief mention. CONCLUSIONS: Resuscitation science continues to evolve and incorporates all links in the chain of survival.

Tumor-selective transgene expression in vivo mediated by an E2F-responsive adenoviral vector.

Recent data suggest that many tumors, such as malignant gliomas, have disrupted pRB function, either because of RB-1 gene mutations or as a result of mutations affecting upstream regulators of pRB such as cyclin D1 or p16/INK4a/MTS1 (ref. 1-5). Tumor suppression by pRB has been linked to its ability to repress E2F-responsive promoters such as the E2F-1 promoter. Thus, a prediction, which has not yet been demonstrated experimentally in vivo, is that E2F-responsive promoters should be more active in tumor cells relative to normal cells because of an excess of "free" E2F and loss of pRB/E2F repressor complexes. We demonstrate that adenoviral vectors that contain transgenes driven by the E2F-1 promoter can mediate tumor-selective gene expression in vivo, allowing for eradication of established gliomas with significantly less normal tissue toxicity than seen with standard adenoviral vectors. Our data indicate that de-repression of the E2F-1 promoter occurs in cancer cells in vivo, a finding that can be exploited to design viral vectors that mediate tumor-selective gene expression.

Resuscitation highlights in 2020.

BACKGROUND: This review is the latest in a series of regular annual reviews undertaken by the editors and aims to highlight some of the key papers published in Resuscitation during 2020. The number of papers submitted to the Journal in 2020 increased by 25% on the previous year.MethodsHand-searching by the editors of all papers published in Resuscitation during 2020. Papers were selected based on then general interest and novelty and were categorised into general themes.ResultsA total of 103 papers were selected for brief mention in this review.ConclusionsResuscitation science continues to evolve rapidly and incorporate all links in the chain of survival.

Airway management during in-hospital cardiac arrest: An international, multicentre, retrospective, observational cohort study.

AIM: To determine the type of airway devices used during in-hospital cardiac arrest (IHCA) resuscitation attempts. METHODS: International multicentre retrospective observational study of in-patients aged over 18 years who received chest compressions for cardiac arrest from April 2016 to September 2018. Patients were identified from resuscitation registries and rapid response system databases. Data were collected through review of resuscitation records and hospital notes. Airway devices used during cardiac arrest were recorded as basic (adjuncts or bag-mask), or advanced, including supraglottic airway devices, tracheal tubes or tracheostomies. Descriptive statistics and multivariable regression modelling were used for data analysis. RESULTS: The final analysis included 598 patients. No airway management occurred in 36 (6%), basic airway device use occurred at any time in 562 (94%), basic airway device use without an advanced airway device in 182 (30%), tracheal intubation in 301 (50%), supraglottic airway in 102 (17%), and tracheostomy in 1 (0.2%). There was significant variation in airway device use between centres. The intubation rate ranged between 21% and 90% while supraglottic airway use varied between 1% and 45%. The choice of tracheal intubation vs. supraglottic airway as the second advanced airway device was not associated with immediate survival from the resuscitation attempt (odds ratio 0.81; 95% confidence interval 0.35-1.8). CONCLUSION: There is wide variation in airway device use during resuscitation after IHCA. Only half of patients are intubated before return of spontaneous circulation and many are managed without an advanced airway. Further investigation is needed to determine optimal airway device management strategies during resuscitation following IHCA.

Potential cervical spine injury and difficult airway management for emergency intubation of trauma adults in the emergency department--a systematic review.

BACKGROUND: Emergency airway management for trauma adults is practised by physicians from a range of training backgrounds and with differing levels of experience. The indications for intubation and technique employed are factors that vary within EDs and between hospitals. OBJECTIVES: To provide practical evidence based guidance for airway management in trauma resuscitation: first for the trauma adult with potential cervical spine injury and second the management when a difficult airway is encountered at intubation. SEARCH STRATEGY AND METHODOLOGY: Full literature search for relevant articles in Medline (1966-2003), EMBASE (1980-2003), and the Cochrane Central Register of Controlled Trials. Relevant articles relating to adults and written in English language were appraised. English language abstracts of foreign articles were included. Studies were critically appraised on a standardised data collection sheet to assess validity and quality of evidence. The level of evidence was allocated using the methods of the Australian National Health and Medical Research Council.

Factors influencing the retention and chemical stability of poly(ethylene glycol)-lipid conjugates incorporated into large unilamellar vesicles.

Poly(ethylene glycol)(PEG)-lipid anchor conjugates can prolong the circulation lifetimes of liposomes following intravenous injection. In this work we investigate the influence of the lipid anchor and the nature of the chemical link between the PEG and lipid moieties on circulation lifetime. It is shown that incorporation of N-(monomethoxypoly(ethylene glycol)2000-succinyl)-1-palmitoyl-2-oleoylphosphatidylethanolamide (MePEG2000-S-POPE) into large unilamellar vesicles (LUVs) composed of distearoylphosphatidylcholine (DSPC) and cholesterol (DSPC/cholesterol/MePEG2000-S-POPE, 50:45:5, mol/mol) results in only small increases in the circulation lifetimes as observed in mice. This is shown to be due to rapid removal of the hydrophilic coating in vivo, which likely arises from exchange of the entire PEG-lipid conjugate from the liposomal membrane, although chemical breakdown of the PEG-lipid conjugate is also possible. The chemical stability of four different linkages was tested, including succinate, carbamate and amide linkages between MePEG derivatives and the amino head group of PE, as well as a direct link to the phosphate head group of phosphatidic acid (PA). The succinate linkage was found to be the most labile. The anchoring capability of DSPE as compared to POPE in PEG-PE conjugates was also examined. It is shown that incorporation of MePEG2000-S-DSPE conjugates into DSPC/cholesterol LUVs results in little loss of the PEG coating in vivo, long circulation lifetimes and reduced chemical breakdown of the PEG-lipid conjugate. This work establishes that DSPE is a considerably more effective anchor for PEG2000 than POPE and that the chemical stability of PEG-PE conjugates is sensitive to the nature of the linkage and exchangeability of the PEG-PE complex. We suggest that retention of the PEG coating is of paramount importance for prolonged circulation lifetimes.

The presence of GM1 in liposomes with entrapped doxorubicin does not prevent RES blockade.

The incorporation of ganglioside GM1 or phosphatidylethanolamine-polyethyleneglycol conjugates into liposomes can result in extended circulation lifetimes in vivo. This has been attributed to an ability to avoid uptake by the reticuloendothelial system (RES), specifically the phagocytic cells of the liver and spleen. Here we examine whether a representative large unilamellar vesicle (LUV) formulation which contains GM1 (distearoylphosphatidylcholine/cholesterol/GM1, 45:45:10 mol/mol), actually does avoid the RES. It is shown that a pre-dose of LUVs which contain GM1 and entrapped doxorubicin blocks the accumulation of subsequently injected empty distearoylphosphatidylcholine/cholesterol liposomes in liver. It is therefore concluded that liposomes exhibiting extended circulation lifetimes can induce RES blockade and do not avoid uptake by liver phagocytes.

Kupffer cells do not play a role in governing the efficacy of liposomal mitoxantrone used to treat a tumor model designed to assess drug delivery to liver.

A tumor model designed to assess liposome-mediated drug delivery to liver has been used in an attempt to better understand the mechanism of activity of liposomal mitoxantrone, a liposomal anticancer drug formulation that appears to be uniquely effective in treating this tumor model. Reductions in liposomal mitoxantrone accumulation in the liver were achieved either by use of poly(ethylene)glycol (PEG)-modified lipids or by methods designed to deplete liver phagocytes, a method referred to as hepatic mononuclear phagocytic system (MPS) blockade. A 2-fold reduction in mitoxantrone delivery to the liver was obtained using a mitoxantrone formulation with PEG-modified lipids, and a 3-fold reduction was obtained when liposomal mitoxantrone was given to animals pretreated to induce hepatic MPS blockade. Results demonstrate that the liposomal mitoxantrone formulation prepared with PEG-modified lipids was significantly less active than the formulations that did not contain PEG lipids, with median survival times of 17 days and 100% 60-day survival, respectively. In contrast, hepatic MPS blockade had no effect on the therapeutic activity of 1,2-dimyristoyl phosphatidylcholine/cholesterol (DMPC/Chol) mitoxantrone (100% 60-day survival). These data suggest that the hepatic MPS does not play a role in mediating the therapeutic activity of DMPC/Chol mitoxantrone in the treatment of liver localized disease. Results with formulations prepared with a PEG-stabilized surface, however, suggest that nonspecific methods to decrease liposome cell interactions inhibit the therapeutic activity of DMPC/Chol mitoxantrone.

Theophylline poisoning--a review of 64 cases.

Sixty-four cases of theophylline poisoning were reviewed. All but two cases represented international self poisoning. The majority of patients were young females who presented acutely after ingestion of sustained release preparations prescribed for asthma. Serum theophylline levels (mean 365 mumol/l, SD 177) indicated a high risk of toxicity. Electrolyte and metabolic abnormalities (hypokalaemia, hypomagnesaemia, hypophosphataemia, hyperglycaemia, acid-base disturbances and leucocytosis) were common. Serum potassium, serum glucose, leucocyte count and length of stay in the intensive care unit all correlated strongly with maximum serum theophylline level (p less than 0.001). The low incidence of life-threatening manifestations of severe toxicity (hypotension, serious arrhythmias or seizures) and excellent outcome, contrasts with many previous reports. The results support the use of a management regimen which emphasizes intensive supportive therapy and restricts the use of charcoal haemoperfusion.

Hyponatraemic states following 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') ingestion.

BACKGROUND: Life-threatening and fatal hyponatraemic complications following ecstasy use have previously been documented. AIM: To define clinical features of hyponatraemia following the ingestion of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy'). DESIGN: Retrospective case series. METHODS: All enquiries to the London centre of the National Poisons Information Service (NPIS) between December 1993 and March 1996 were screened for cases of MDMA use associated with hyponatraemia (serum sodium <130 mmol/l). History of fluid consumption, presenting features and subsequent clinical course were recorded. RESULTS: Seventeen patients, aged 15-26 years, were identified. Serum sodium levels ranged between 107 mmol/l and 128 mmol/l. In six patients, biochemical results were consistent with inappropriate secretion of antidiuretic hormone (SIADH). Analytical confirmation of MDMA ingestion was obtained in 10 patients. Ten patients were known to have ingested a large amount of non-alcoholic or alcoholic fluid. The clinical pattern was remarkably uniform, with initial vomiting and disturbed behaviour, followed in 11 patients by seizures. Drowsiness, a mute state and disorientation were observed for up to 3 days. Two patients died; 14 made a complete recovery. DISCUSSION: MDMA can cause life-threatening hyponatraemic encephalopathy when accompanied by excessive fluid ingestion. The mechanism involves inappropriate secretion of antidiuretic hormone.

Amniotic fluid embolism: a case report and review.

A 41-year old primigravida underwent caesarean section because of foetal distress following prostin induction of labour. Intraoperative coagulopathy, haemorrhage and hypotension necessitated a hysterectomy. Subsequently, she developed respiratory and renal failure, requiring mechanical ventilation and haemodialysis. She made a full recovery. The likely diagnosis was amniotic fluid embolism (AFE), a rare complication of pregnancy with a variable presentation, ranging from cardiac arrest and death through to mild degrees of organ system dysfunction with or without coagulopathy. The differential diagnosis includes pre-eclamptic toxaemia/pregnancy-induced hypertension, anaphylaxis and pulmonary embolism. There is no diagnostic test for AFE; the finding of foetal elements in the maternal circulation is non-specific. Historically, AFE was thought to induce cardiovascular collapse by mechanical obstruction of the pulmonary circulation. It is now thought that a combination of left ventricular dysfunction and acute lung injury occur, with activation of several of the clotting factors. An immunological basis for these effects is postulated. There is no specific therapy and treatment is supportive. The mortality of the condition remains high.

Prognostic outcome indicators following hanging injuries.

Hanging as a method of attempting suicide is increasing in incidence. A retrospective review of victims of hanging injuries presenting to our institution over a 5-year period was performed. Forty-two cases were reviewed. Drug and/or alcohol ingestion was identified in 70% of cases. There were no cervical spine injuries identified, although two unexpected thoracic spine fractures were found. There was an 88% survival rate, with a low incidence (5%) of poor neurological outcome. The Glasgow Coma Score at scene or on arrival at hospital was found to be a prognostic indicator. Victims without spontaneous cardiac output at scene did not survive, even if cardiopulmonary resuscitation was successful initially.

Late deaths in multiple trauma patients receiving intensive care.

We reviewed the cause and timing of death of all the patients who died within hospital following multiple trauma and admission to a multidisciplinary intensive care unit (ICU) that also acts as a tertiary referral centre for neurosurgery. The ICU database identified 101 such patients in a 3-year period and their records were reviewed retrospectively. There were 40 (39%) deaths within 24 h of admission to the ICU, 38 of which resulted from severe brain injury and two from haemorrhagic shock (HS). A further 61 (60%) deaths occurred more than 24 h after the time of admission to ICU (mean 7 days; range 2-49 days), of which 46 (75%) were due to severe brain injury. While these findings do not question the promulgated tri-modal distribution of death following trauma, they are at variance with the view that the third peak of deaths is due mainly to multiple organ failure. When severe head injury accompanies multiple trauma, it is likely to be the major determinant of late mortality. If outcome from major trauma is to be improved, then a greater emphasis needs to be placed on the prevention and optimal management of severe brain injury.

Intra-aortic balloon counterpulsation for cardiogenic shock due to cardiac contusion in an elderly trauma patient.

Blunt thoracic trauma may cause cardiac contusion and cardiogenic shock resistant to inotropic support. The use of intra-aortic balloon counterpulsation (IABCP) as a mechanical means of augmenting cardiac function following cardiac contusion is rare with case reports largely limited to its use in young trauma patients. We describe the case of a frail, 80-year-old woman who suffered cardiac contusion in a motor vehicle crash. She developed cardiogenic shock with electrocardiograph changes, elevated troponin T and severe global dysfunction on echocardiography. She was successfully managed with invasive monitoring, inotropic support and IABCP. This case provides support for aggressive resuscitation even in the very elderly as recovery from severe cardiac contusion may be possible.

The Medical Emergency Team: 12 month analysis of reasons for activation, immediate outcome and not-for-resuscitation orders.

OBJECTIVE: To describe the reasons for, and immediate outcome following Medical Emergency Team (MET) activation. METHODS: Retrospective analysis of MET calls in 1998. RESULTS: There were 713 MET calls to 559 in-patients. Of the 559 patients 252 (45%) were admitted to ICU and 49 (6.9%) died during the MET response. The three commonest criteria for calling the MET were a fall in GCS>2 (n=155); a systolic blood pressure<90 mmHg (n=142) and a respiratory rate>35 (n=109). Cardiac arrests accounted for 61 calls and had an immediate mortality of 59%. The most common MET criterion associated with admission to ICU was a respiratory rate >35. Of patients who received MET calls based only on the 'worried' criterion 16% were admitted to ICU. The MET felt that a not-for-resuscitation order would have been appropriate in 130 cases (23%). NFR orders were documented during 27 of the MET calls. CONCLUSIONS: The MET system provides objective and subjective criteria by which medical and nursing staff can identify patients who become acutely unwell. A high proportion of these patients will require admission to Intensive Care. The MET system also provides the opportunity to identify patients for whom an NFR order should be considered.

The respiratory system during resuscitation: a review of the history, risk of infection during assisted ventilation, respiratory mechanics, and ventilation strategies for patients with an unprotected airway.

The fear of acquiring infectious diseases has resulted in reluctance among healthcare professionals and the lay public to perform mouth-to-mouth ventilation. However, the benefit of basic life support for a patient in cardiopulmonary or respiratory arrest greatly outweighs the risk for secondary infection in the rescuer or the patient. The distribution of ventilation volume between lungs and stomach in the unprotected airway depends on patient variables such as lower oesophageal sphincter pressure, airway resistance and respiratory system compliance, and the technique applied while performing basic or advanced airway support, such as head position, inflation flow rate and time, which determine upper airway pressure. The combination of these variables determines gas distribution between the lungs and the oesophagus and subsequently, the stomach. During bag-valve-mask ventilation of patients in respiratory or cardiac arrest with oxygen supplementation (> or = 40% oxygen), a tidal volume of 6-7 ml kg(-1) ( approximately 500 ml) given over 1-2 s until the chest rises is recommended. For bag-valve-mask ventilation with room-air, a tidal volume of 10 ml kg(-1) (700-1000 ml) in an adult given over 2 s until the chest rises clearly is recommended. During mouth-to-mouth ventilation, a breath over 2 s sufficient to make the chest rise clearly (a tidal volume of approximately 10 ml kg(-1) approximately 700-1000 ml in an adult) is recommended.