bims-heshmo 2021-07-18 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021–07–18
eleven papers selected by
Andreia Luís, Ludwig Boltzmann Institute

Prehospital whole blood reduces early mortality in patients with hemorrhagic shock.
Hemorrhagic Shock and Resuscitation Causes Glycocalyx Shedding and Endothelial Oxidative Stress Preferentially in the Lung and Intestinal Vasculature.
Identification of Unique microRNA Expression Patterns in Bone Marrow Hematopoietic Stem and Progenitor Cells after Hemorrhagic Shock and Polytrauma in Young and Old Adult Mice.
Massive transfusions and severe hypocalcemia: An opportunity for monitoring and supplementation guidelines.
Whole blood at the tip of the spear: A retrospective cohort analysis of warm fresh whole blood resuscitation versus component therapy in severely injured combat casualties.
Choice of Whole Blood versus Lactated Ringers Resuscitation Modifies the Relationship Between Blood Pressure Target and Functional Outcome after Traumatic Brain Injury Plus Hemorrhagic Shock in Mice.
Involvement of Toll-Like Receptor 4 in Decreased Vasopressor Response Following Trauma/Hemorrhagic Shock.
Viral Micro-RNAs Are Detected in the Early Systemic Response to Injury and Are Associated With Outcomes in Polytrauma Patients.
Sample-to-Answer Diagnostic System for the Detection of Circulating Histones in Whole Blood.
The role of PD-L1 in the immune dysfunction that mediates hypoxia-induced multiple organ injury.
Successful Outcomes of Critically Ill Patients with Extreme Metabolic Acidosis Treated with Structured Approach: Case Series.

Transfusion. 2021 Jul;61 Suppl 1 S15-S21

Prehospital whole blood reduces early mortality in patients with hemorrhagic shock.

Maxwell A Braverman, Alison Smith, Douglas Pokorny, Benjamin Axtman, Charles Patrick Shahan, Lauran Barry, Hannah Corral, Rachelle Babbitt Jonas, Michael Shiels, Randall Schaefer, Eric Epley, Christopher Winckler, Elizabeth Waltman, Brian J Eastridge, Susannah E Nicholson, Ronald M Stewart, Donald H Jenkins.

   BACKGROUND: Low titer O+ whole blood (LTOWB) is being increasingly used for resuscitation of hemorrhagic shock in military and civilian settings. The objective of this study was to identify the impact of prehospital LTOWB on survival for patients in shock receiving prehospital LTOWB transfusion.
STUDY DESIGN AND METHODS: A single institutional trauma registry was queried for patients undergoing prehospital transfusion between 2015 and 2019. Patients were stratified based on prehospital LTOWB transfusion (PHT) or no prehospital transfusion (NT). Outcomes measured included emergency department (ED), 6-h and hospital mortality, change in shock index (SI), and incidence of massive transfusion. Statistical analyses were performed.
RESULTS: A total of 538 patients met inclusion criteria. Patients undergoing PHT had worse shock physiology (median SI 1.25 vs. 0.95, p < .001) with greater reversal of shock upon arrival (-0.28 vs. -0.002, p < .001). In a propensity-matched group of 214 patients with prehospital shock, 58 patients underwent PHT and 156 did not. Demographics were similar between the groups. Mean improvement in SI between scene and ED was greatest for patients in the PHT group with a lower trauma bay mortality (0% vs. 7%, p = .04). No survival benefit for patients in prehospital cardiac arrest receiving LTOWB was found (p > .05).
DISCUSSION: This study demonstrated that trauma patients who received prehospital LTOWB transfusion had a greater improvement in SI and a reduction in early mortality. Patient with prehospital cardiac arrest did not have an improvement in survival. These findings support LTOWB use in the prehospital setting. Further multi-institutional prospective studies are needed.

Keywords:  mortality; pre-hospital transfusion; propensity match; whole blood

DOI:  https://doi.org/10.1111/trf.16528
Shock. 2021 Feb 19.

Hemorrhagic Shock and Resuscitation Causes Glycocalyx Shedding and Endothelial Oxidative Stress Preferentially in the Lung and Intestinal Vasculature.

Sarah Abdullah, Mardeen Karim, Mark Legendre, Laura Rodriguez, Jessica Friedman, Aaron Cotton-Betteridge, Robert Drury, Jacob Packer, Chrissy Guidry, Juan Duchesne, Sharven Taghavi, Olan Jackson-Weaver.

INTRODUCTION: Hemorrhagic shock has recently been shown to cause shedding of a carbohydrate surface layer of endothelial cells known as the glycocalyx. This shedding of the glycocalyx is thought to be a mediator of the coagulopathy seen in trauma patients. Clinical studies have demonstrated increases in shed glycocalyx in the blood after trauma, and animal studies have measured glycocalyx disruption in blood vessels in the lung, skeletal muscle, and mesentery. However, no study has measured glycocalyx disruption across a wide range of vascular beds to quantify the primary locations of this shedding.
METHODS: In the present study, we used a rat model of hemorrhagic shock and resuscitation to more comprehensively assess glycocalyx disruption across a range of organs. Glycocalyx disruption was assessed by fluorescent-labelled wheat germ agglutinin or syndecan-1 antibody staining in flash frozen tissue.
RESULTS: We found that our model did elicit glycocalyx shedding, as assessed by an increase in plasma syndecan-1 levels. In tissue sections, we found that the greatest glycocalyx disruption occurred in vessels in the lung and intestine. Shedding to a lesser extent was observed in vessels of the brain, heart, and skeletal muscle. Liver vessel glycocalyx was unaffected, and kidney vessels, including the glomerular capillaries, displayed an increase in glycocalyx. We also measured reactive oxygen species (ROS) in the endothelial cells from these organs, and found that the greatest increase in ROS occurred in the two beds with the greatest glycocalyx shedding, the lungs and intestine. We also detected fibrin deposition in lung vessels following hemorrhage-resuscitation.
CONCLUSIONS: We conclude that the endothelium in the lungs and intestine are particularly susceptible to the oxidative stress of hemorrhage-resuscitation, as well as the resulting glycocalyx disruption. Thus these two vessel beds may be important drivers of coagulopathy in trauma patients.

DOI: https://doi.org/10.1097/SHK.0000000000001764
J Trauma Acute Care Surg. 2021 Jul 09.

Identification of Unique microRNA Expression Patterns in Bone Marrow Hematopoietic Stem and Progenitor Cells after Hemorrhagic Shock and Polytrauma in Young and Old Adult Mice.

Dijoia B Darden, Juan C Mira, Maria-Cecilia Lopez, Julie A Stortz, Brittany P Fenner, Lauren S Kelly, Dina C Nacionales, Ashrita Budharaju, Tyler J Loftus, Henry V Baker, Frederick A Moore, Scott C Brakenridge, Lyle L Moldawer, Alicia M Mohr, Philip A Efron.

BACKGROUND: After severe trauma, the older host experiences more dysfunctional hematopoiesis of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs), and dysfunctional differentiation of circulating myeloid cells into effective innate immune cells. Our main objective was to compare BM HSPC miR responses of old and young mice in a clinically relevant model of severe trauma and shock.
METHODS: C57BL/6 adult male mice aged 8-12 weeks (young) and 18-24 months (old) underwent polytrauma and hemorrhagic shock (PT) that engenders the equivalent of major trauma (injury severity score > 15). Pseudomonas pneumonia (PNA) was induced in some young and old adult mice 24 hours after PT. miR expression patterns were determined from lineage-negative enriched BM HSPCs isolated from PT and PT + PNA mice at 24- and 48-hours post-injury, respectively. Genome-wide expression and pathway analyses were also performed on bronchoalveolar lavage (BAL) leukocytes from both mouse cohorts.
RESULTS: miR expression significantly differed among all experimental conditions (p < 0.05), except for old-naïve vs old-injured (PT or PT + PNA) mice, suggesting an inability of old mice to mount a robust early miR response to severe shock and injury. In addition, young adult mice had significantly more leukocytes obtained from their BAL, and there were greater numbers of polymorphonuclear cells compared with old mice (59.8% vs 2.2%, p = 0.0069). Despite increased gene expression changes, BAL leukocytes from old mice demonstrated a more dysfunctional transcriptomic response to PT + PNA than young adult murine BAL leukocytes, as reflected in predicted upstream functional pathway analysis.
CONCLUSION: The miR expression pattern in BM HSPCs after PT(+/-PNA) is dissimilar in old versus young adult mice. In the acute post-injury phase, old adult mice are unable to mount a robust miR HSPC response. HSPC miR expression in old PT mice reflects a diminished functional status as well as a blunted capacity for terminal differentiation of myeloid cells.
LEVEL OF EVIDENCE: Basic Science.
STUDY TYPE: Experimental murine model.

DOI: https://doi.org/10.1097/TA.0000000000003350
Transfusion. 2021 Jul;61 Suppl 1 S188-S194

Massive transfusions and severe hypocalcemia: An opportunity for monitoring and supplementation guidelines.

Chad Hall, Andrea K Nagengast, Chris Knapp, Brandon Behrens, Elizabeth N Dewey, Andrew Goodman, Aravind Bommiasamy, Martin Schreiber.

   BACKGROUND: Massive transfusion protocols (MTPs) are associated with severe hypocalcemia, contributing to coagulopathy and mortality in severely injured patients. Severity of hypocalcemia following massive transfusion activation and appropriate treatment strategies remain undefined.
STUDY DESIGN AND METHODS: This was a retrospective study of all MTP activations in adult trauma patients at a Level 1 trauma center between August 2016 and September 2017. Units of blood products transfused, ionized calcium levels, and amount of calcium supplementation administered were recorded. Primary outcomes were ionized calcium levels and the incidence of severe ionized hypocalcemia (iCa ≤1.0 mmol/L) in relation to the volume of blood products transfused.
RESULTS: Seventy-one patients had an MTP activated during the study period. The median amount of packed red blood cells (PRBCs) transfused was 10 units (range 1-52). A total of 42 (59.1%) patients had periods of severe hypocalcemia. Patients receiving 13 or more units of PRBC had a greater prevalence of hypocalcemia with 83.3% having at least one measured ionized calcium ≤1.0 mmoL/L (p = .001). The number of ionized calcium levels checked and the amount of supplemental calcium given in patients who experienced hypocalcemia varied considerably.
DISCUSSION: Severe hypocalcemia commonly occurs during MTP activations and correlates with the number of packed red blood cells transfused. Monitoring of ionized calcium and amount of calcium supplementation administered is widely variable. Standardized protocols for recognition and management of severe hypocalcemia during massive transfusions may improve outcomes.

Keywords:  RBC transfusion; non-infectious; practices (surgical); transfusion; transfusion complications

DOI:  https://doi.org/10.1111/trf.16496
Surgery. 2021 Jul 09. pii: S0039-6060(21)00538-9. [Epub ahead of print]

Whole blood at the tip of the spear: A retrospective cohort analysis of warm fresh whole blood resuscitation versus component therapy in severely injured combat casualties.

Jennifer M Gurney, Amanda M Staudt, Deborah J Del Junco, Stacy A Shackelford, Elizabeth A Mann-Salinas, Andrew P Cap, Philip C Spinella, Matthew J Martin.

BACKGROUND: Death from uncontrolled hemorrhage occurs rapidly, particularly among combat casualties. The US military has used warm fresh whole blood during combat operations owing to clinical and operational exigencies, but published outcomes data are limited. We compared early mortality between casualties who received warm fresh whole blood versus no warm fresh whole blood.
METHODS: Casualties injured in Afghanistan from 2008 to 2014 who received ≥2 red blood cell containing units were reviewed using records from the Joint Trauma System Role 2 Database. The primary outcome was 6-hour mortality. Patients who received red blood cells solely from component therapy were categorized as the non-warm fresh whole blood group. Non- warm fresh whole blood patients were frequency-matched to warm fresh whole blood patients on identical strata by injury type, patient affiliation, tourniquet use, prehospital transfusion, and average hourly unit red blood cell transfusion rates, creating clinically unique strata. Multilevel mixed effects logistic regression adjusted for the matching, immortal time bias, and other covariates.
RESULTS: The 1,105 study patients (221 warm fresh whole blood, 884 non-warm fresh whole blood) were classified into 29 unique clinical strata. The adjusted odds ratio of 6-hour mortality was 0.27 (95% confidence interval 0.13-0.58) for the warm fresh whole blood versus non-warm fresh whole blood group. The reduction in mortality increased in magnitude (odds ratio = 0.15, P = .024) among the subgroup of 422 patients with complete data allowing adjustment for seven additional covariates. There was a dose-dependent effect of warm fresh whole blood, with patients receiving higher warm fresh whole blood dose (>33% of red blood cell-containing units) having significantly lower mortality versus the non-warm fresh whole blood group.
CONCLUSION: Warm fresh whole blood resuscitation was associated with a significant reduction in 6-hour mortality versus non-warm fresh whole blood in combat casualties, with a dose-dependent effect. These findings support warm fresh whole blood use for hemorrhage control as well as expanded study in military and civilian trauma settings.

DOI: https://doi.org/10.1016/j.surg.2021.05.051
J Neurotrauma. 2021 Jul 16.

Choice of Whole Blood versus Lactated Ringers Resuscitation Modifies the Relationship Between Blood Pressure Target and Functional Outcome after Traumatic Brain Injury Plus Hemorrhagic Shock in Mice.

Benjamin E Zusman, C Edward Dixon, Ruchira M Jha, Vincent Vagni, Jeremy Henchir, Shaun W Carlson, Keri Janesko-Feldman, Zachary Bailey, Deborah A Shear, Janice Gilsdorf, Patrick M Kochanek.

  Civilian traumatic brain injury (TBI) guidelines recommend resuscitation of hypotensive TBI patients with crystalloids. However, increasing evidence suggests that whole blood (WB) resuscitation may improve physiological and survival outcomes at lower resuscitation volumes, and potentially at a lower mean arterial blood pressure (MAP), than crystalloid after TBI and hemorrhagic shock (HS). The objective of this study was to assess whether WB resuscitation with two different MAP targets improved behavioral and histological outcomes compared with Lactated Ringers (LR)in a mouse model of TBI+HS. Anesthetized mice (n=40) underwent controlled cortical impact followed by HS (MAP=25-27mmHg; 25min), and were randomized to five groups for a 90min resuscitation: LR with MAP target of 70mmHg (LR70), LR60, WB70, WB60, and monitored sham. Mice received a 20mL/kg bolus of LR or autologous WB followed by LR boluses (10ml/kg) every 5min for MAP below target. Shed blood was reinfused after 90min. Morris Water Maze testing was performed on days 14-20 post-injury. Mice were euthanized (21d) to assess contusion and total brain volumes. Latency to find the hidden platform was greater vs. sham for LR60 (p<0.002) and WB70 (p<0.007) but not LR70 or WB60. WB resuscitation did not reduce contusion volume or brain tissue loss. WB targeting a MAP of 60mmHg did not compromise function vs a 70mmHg target after CCI+HS, but further reduced fluid requirements (p<0.03). Using LR, higher achieved MAP was associated with better behavioral performance (rho= -0.67, p=0.028). Use of WB may allow lower MAP targets without compromising functional outcome, which could facilitate pre-hospital TBI resuscitation.

Keywords:  ANIMAL STUDIES; Behavior; THERAPEUTIC APPROACHES FOR THE TREATMENT OF CNS INJURY; controlled cortical impact

DOI:  https://doi.org/10.1089/neu.2021.0157
Crit Care Explor. 2021 Jul;3(7): e0469

Involvement of Toll-Like Receptor 4 in Decreased Vasopressor Response Following Trauma/Hemorrhagic Shock.

Rafi Mazor, Fernando Dos Santos, Joyce B Li, Federico Aletti, Geert Schmid-Schonbein, Erik B Kistler.

  Refractory vascular failure due to the inability of vascular smooth muscle to respond to vasoconstrictors such as phenylephrine is a final common pathway for severe circulatory shock of any cause, including trauma/hemorrhagic shock. Increased inflammation, Toll-like receptor 4 activation, and decreased response of the alpha-1 adrenergic receptors which control vascular tone have been reported in trauma/hemorrhagic shock.
HYPOTHESIS: In trauma/hemorrhagic shock, Toll-like receptor 4 activation contributes to vascular failure via decreased bioavailability of adrenergic receptors.
DESIGN AND MEASUREMENTS: Trauma/hemorrhagic shock was induced in Wistar rats (laparotomy combined with mean arterial pressure at 40 mm Hg for 90 min followed by 2 hr resuscitation with Lactated Ringers solution). To inhibit Toll-like receptor 4, resatorvid (TAK-242) and resveratrol were used, and plasma was collected. Smooth muscle cells were incubated with lipopolysaccharide (10 ng/mL) or plasma. Inflammatory cytokines were screened using dot-blot. Toll-like receptor 4 and nuclear factor κB activation and cellular localization of the alpha-1 adrenergic receptor were measured by immunofluorescence imaging and Western blot analysis. Clustered regularly interspaced short palindromic repeats/Cas9 was used to knock out Toll-like receptor 4, and calcium influx following stimulation with phenylephrine was recorded.
MAIN RESULTS: Trauma/hemorrhagic shock caused a decreased response to phenylephrine, whereas Toll-like receptor 4 inhibition improved blood pressure. Trauma/hemorrhagic shock plasma activated the Toll-like receptor 4/nuclear factor κB pathway in smooth muscle cells. Double labeling of Toll-like receptor 4 and the alpha-1 adrenergic receptor showed that these receptors are colocalized on the cell membrane. Activation of Toll-like receptor 4 caused cointernalization of both receptors. Calcium influx was impaired in cells incubated with trauma/hemorrhagic shock plasma but restored when Toll-like receptor 4 was knocked out or inhibited.
CONCLUSIONS: Activation of the Toll-like receptor 4 desensitizes vascular smooth muscle cells to vasopressors in experimental trauma/hemorrhagic shock by reducing the levels of membrane alpha-1 adrenergic receptor.

Keywords:  Toll-like receptor 4; adrenergic receptor; biological availability; shock hemorrhagic; vascular smooth muscle; vasoconstrictor

DOI:  https://doi.org/10.1097/CCE.0000000000000469
Crit Care Med. 2021 Jul 02.

Viral Micro-RNAs Are Detected in the Early Systemic Response to Injury and Are Associated With Outcomes in Polytrauma Patients.

Diego Vicente, Seth A Schobel, Simone Anfossi, Hannah Hensman, Felipe Lisboa, Henry Robertson, Vivek Khatri, Matthew J Bradley, Masayoshi Shimizu, Timothy G Buchman, Thomas A Davis, Christopher J Dente, Allan D Kirk, George A Calin, Eric A Elster.

OBJECTIVES: To evaluate early activation of latent viruses in polytrauma patients and consider prognostic value of viral micro-RNAs in these patients.
DESIGN: This was a subset analysis from a prospectively collected multicenter trauma database. Blood samples were obtained upon admission to the trauma bay (T0), and trauma metrics and recovery data were collected.
SETTING: Two civilian Level 1 Trauma Centers and one Military Treatment Facility.
PATIENTS: Adult polytrauma patients with Injury Severity Scores greater than or equal to 16 and available T0 plasma samples were included in this study. Patients with ICU admission greater than 14 days, mechanical ventilation greater than 7 days, or mortality within 28 days were considered to have a complicated recovery.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: Polytrauma patients (n = 180) were identified, and complicated recovery was noted in 33%. Plasma samples from T0 underwent reverse transcriptase-quantitative polymerase chain reaction analysis for Kaposi's sarcoma-associated herpesvirus micro-RNAs (miR-K12_10b and miRK-12-12) and Epstein-Barr virus-associated micro-RNA (miR-BHRF-1), as well as Luminex multiplex array analysis for established mediators of inflammation. Ninety-eight percent of polytrauma patients were found to have detectable Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus micro-RNAs at T0, whereas healthy controls demonstrated 0% and 100% detection rate for Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus, respectively. Univariate analysis revealed associations between viral micro-RNAs and polytrauma patients' age, race, and postinjury complications. Multivariate least absolute shrinkage and selection operator analysis of clinical variables and systemic biomarkers at T0 revealed that interleukin-10 was the strongest predictor of all viral micro-RNAs. Multivariate least absolute shrinkage and selection operator analysis of systemic biomarkers as predictors of complicated recovery at T0 demonstrated that miR-BHRF-1, miR-K12-12, monocyte chemoattractant protein-1, and hepatocyte growth factor were independent predictors of complicated recovery with a model complicated recovery prediction area under the curve of 0.81.
CONCLUSIONS: Viral micro-RNAs were detected within hours of injury and correlated with poor outcomes in polytrauma patients. Our findings suggest that transcription of viral micro-RNAs occurs early in the response to trauma and may be associated with the biological processes involved in polytrauma-induced complicated recovery.

DOI: https://doi.org/10.1097/CCM.0000000000005181
ACS Sens. 2021 Jul 16.

Sample-to-Answer Diagnostic System for the Detection of Circulating Histones in Whole Blood.

Micaela L Everitt, David J Boegner, Konstantin G Birukov, Ian M White.

  Severe internal trauma results in millions of hospitalizations each year, including thousands of deaths caused by subsequent multiple organ failure. The majority of these deaths occur within the first 24 h, and thus, rapid diagnosis of internal trauma severity is necessary for immediate treatment. For early organ damage identification, diagnosis in point-of-care settings is crucial for rapid triage and treatment. Recent reports suggest that circulating histones may serve as a biomarker for severe organ damage and the risk of multiple organ failure. Here, we report a point-of-care diagnostic system that utilizes the inherent interactions between histones and DNA for the fluorescence-based detection of histones in whole blood. In the assay, histones within the sample are wrapped by DNA, thus preventing an intercalating dye from binding the DNA and fluorescing. To allow for quantitative fluorescent measurements to be made in a point-of-care setting, we integrate a rapid, automated blood separation step into our assay. Furthermore, we eliminate manual reagent additions using a thermally responsive alkane partition (TRAP), thus making the system sample-to-answer. Finally, we demonstrate the assay in a portable fluorescence reader compatible with a point-of-care environment. We report a limit of detection 112 ng/mL in whole blood, suggesting that our device can be used to rapidly diagnose internal trauma severity and the likelihood of multiple organ failure in near-patient settings.

Keywords:  histones; multiple organ failure; point-of-care; portable; sample-to-answer; severe trauma; whole blood

DOI:  https://doi.org/10.1021/acssensors.1c00886
Cell Commun Signal. 2021 Jul 13. 19(1): 76

The role of PD-L1 in the immune dysfunction that mediates hypoxia-induced multiple organ injury.

Yang Sun, Jin Tan, Yuyang Miao, Qiang Zhang.

  Hypoxia is a pathological condition common to many diseases, although multiple organ injuries induced by hypoxia are often overlooked. There is increasing evidence to suggest that the hypoxic environment may activate innate immune cells and suppress adaptive immunity, further stimulating inflammation and inhibiting immunosurveillance. We found that dysfunctional immune regulation may aggravate hypoxia-induced tissue damage and contribute to secondary injury. Among the diverse mechanisms of hypoxia-induced immune dysfunction identified to date, the role of programmed death-ligand 1 (PD-L1) has recently attracted much attention. Besides leading to tumour immune evasion, PD-L1 has also been found to participate in the progression of the immune dysfunction which mediates hypoxia-induced multiple organ injury. In this review, we aimed to summarise the role of immune dysfunction in hypoxia-induced multiple organ injury, the effects of hypoxia on the cellular expression of PD-L1, and the effects of upregulated PD-L1 expression on immune regulation. Furthermore, we summarise the latest information pertaining to the involvement, diagnostic value, and therapeutic potential of immunosuppression induced by PD-L1 in various types of hypoxia-related diseases, including cancers, ischemic stroke, acute kidney injury, and obstructive sleep apnoea. Video Abstract.

Keywords:  Hypoxia; Immune dysfunction; Multiple organ injuries; PD-1; PD-L1

DOI:  https://doi.org/10.1186/s12964-021-00742-x
Clin Med Insights Case Rep. 2021 ;14 11795476211025138

Successful Outcomes of Critically Ill Patients with Extreme Metabolic Acidosis Treated with Structured Approach: Case Series.

Sasa Dragic, Danica Momcicevic, Biljana Zlojutro, Milka Jandric, Tijana Kovacevic, Vlado Djajic, Ognjen Gajic, Pedja Kovacevic.

   Introduction: Hydrogen ion concentration which is expressed as pH value is in human blood maintained in narrow physiological range (7.36-7.44 in arterial blood). This range is crucial for normal functioning of most biochemical reactions. Extreme acidosis with pH < 6.8 is incompatible with life, unless pathophysiologic process is rapidly reversed. Timely, standardized, and structured approach to assessment and management of extreme critical illness is essential to maximize the chances of patient's survival.
Cases: We present a series of 3 critically ill patients admitted to Medical intensive care unit (MICU) diagnosed with extreme metabolic acidosis (pH ⩽ 6.8). Each patient was treated using Checklist for Early Recognition and Treatment of Acute Illness and INjury (CERTAIN) which is a standard decision support tool in our MICU. Causes of extreme metabolic acidosis included hemorrhagic shock, sepsis, and acute renal failure and diabetic ketoacidosis. Rapid assessment, prompt resuscitation (IV fluids, vasopressors, mechanical ventilation, and renal replacement), and application of specific causal treatment led to positive outcomes in all 3 patients.
Discussion: Medical physiology textbooks set the lower limit of pH value at which life is possible to 6.8. However, examples from clinical practice show that if adequate resuscitation measures are taken early in the acute phase of the disease, the biochemical cascade of reactions that are considered irreversible (at pH ⩽ 6.8) may be reversed after all.
Conclusion: Critical care approach to extreme metabolic acidosis is a prime example of applied clinical physiology where basic science and clinical practice connect. With these case series we show that timely and structured approach to critical illness shifts the boundaries of reversibility for some of the most severe physiologic derangements.

Keywords:  Acid-base status; acidosis; buffer; lactate

DOI:  https://doi.org/10.1177/11795476211025138